Controlled release devices as adjuvants in nonsurgical periodontal therapy: A systematic review

Abstract

Controlled release devices (CRD) have been widely studied regarding their application in periodontal therapy. Therefore, the present study aims to evaluate the use and effectiveness of controlled-release devices in nonsurgical periodontal therapy through a systematic review. The research was carried out in six different databases, namely: Online Medical Literature Search and Analysis System (Medline-PubMed), Web of Science, Science Direct, Scopus, Scielo, and Google Scholar. The descriptors “Delayed-Action Preparation,” “Therapeutics,” and “Periodontitis,” were used with their EntryTerms and connected through the Boolean operators AND and OR. A total of 2847 studies were found, and after applying the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist flowchart, 34 were selected using the eligibility criteria. After that, the qualitative results were tabulated and the risk of bias in each of them was evaluated. It can be observed that the use of CRD presents itself as a successful alternative for adjuvant treatment to periodontal therapy, a fact due to its availability and local concentration in the crevicular fluid. However, further clinical research is still needed to develop devices that are effective, with an easy and quick application, as well as available at a good cost–benefit ratio.

INTRODUCTION

Periodontitis is an infectious disease of the oral cavity caused by biofilm, resulting in tissue destruction of the dental support tissues, which can often lead to total tooth loss.[1]

For this clinical condition, the most widespread management is scaling and root planing (SRP), which has the principle of removing the biofilm and calculus that are located at the supra and subgingival level.[2] This mechanical treatment depends a lot on the manual skill of the professional who does it, and thus, the success of the management depends on this factor, as well as on the difficulty of the site to be treated.[3]

Due to the factors that generate a limitation in SRP, there are alternative strategies in the process of treating periodontitis, such as the use of locally acting drugs, which can be used together with mechanical treatment.[4] Therefore, in this context, such drugs can be used locally, within the periodontal pocket, and try to have their controlled release, so that their substantivity increases in the location.[5]

These controlled release devices (CRD) can be presented in various forms, such as films, fibers, gels, implants, microparticles, and nanoparticles.[6] Therefore, the aim of this study was to evaluate the use and effectiveness of controlled-release devices as adjuvants in nonsurgical periodontal therapy, through a systematic review.

MATERIALS AND METHODS

This is a systematic literature review carried out from June to July 2020. This study was registered on the PROSPERO platform (https://www.crd. york.ac.uk/prospero) following the established methodological criteria, standardized data extraction, and review protocol by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist (Cochrane). By using searches of PubMed/Medline, Science Direct, Web of Science, Google Scholar, Scielo, and Scopus, full reports of randomized, controlled, double-blind trials published in peer-reviewed journals were identified.

Eligibility criteria

Descriptors registered in Mesh and Decs were used, along with their Entry Terms through various search strategies [Table 1], based on PICOT elements for a systematic review.

Table 1.

Electronic database and search strategy

PubMed
#1 (Delayed-Action Preparation) [Mesh] (Delayed Action Preparations) AND (Delayed-Action Preparation) AND (Controlled-Release Preparations) AND (Controlled Release Preparations) AND (Controlled-Release Preparation) AND (Controlled-Release Formulations) AND (Controlled Release Formulations) AND (Controlled-Release Formulation) AND (Sustained-Release Preparations) AND (Sustained-Release Preparation) AND (Extended Release Preparations) AND (Extended Release Preparation) AND (Slow Release Formulation) AND (Sustained Release Formulation) AND (Sustained Release Formulation) AND (Extended Release Formulations) AND (Extended Release Formulation) AND (Timed-Release Preparations) AND (Timed Release Preparations) AND (Timed-Release Preparation) AND (Depot Preparations) AND (Depot Preparation) AND (Prolonged-Action Preparations) AND (Prolonged-Action Preparation) BUSCA #1 AND #2 AND #3	#2 (Therapeutics) [Mesh] (Therapeutic) AND (Therapy) AND (Therapies) AND (Treatment) AND (Treatments)	#3 (Periodontitis) [Mesh] AND (Periodontitides) AND (Pericementitis) AND (Pericementitides
Science Direct
#1 (Delayed-Action Preparation) OR (Delayed Action Preparations) OR (Controlled-Release Preparations) BUSCA #1 AND #2 AND #3	#2 (Therapeutics) OR (Therapeutic)	#3 (Periodontitis) OR (Periodontitides) OR (Pericementitis) OR (Pericementitides)
Web of Science
#1 (Delayed-Action Preparation) OR (Delayed Action Preparations) BUSCA #1 AND #2 AND #3	#2 (Therapeutics) OR (Therapeutic)	#3 (Periodontitis) OR (Periodontitides) OR (Pericementitis)
Scorpus
#1 (Delayed-Action Preparation) OR (Delayed Action Preparations) BUSCA #1 AND #2 AND #3	#2 (Periodontitis) OR (Periodontitides)	#3 (Therapeutics) OR (Therapy)
Scielo
#1 (Delayed-Action Preparation) OR (Delayed Action Preparations) BUSCA #1 AND #2 AND #3	#2 (Therapeutics) OR (Therapeutic)	#3 (Periodontitis) OR (Periodontitides) OR (Pericementitis)
Scholar Google
#1 (Delayed-Action Preparation) OR (Delayed Action Preparations) BUSCA #1 AND #2 AND #3	#2 (Therapeutics) OR (Therapeutic)	(Periodontitis) OR (Periodontitides) OR (Pericementitis)

• Population (P): Patients with periodontal disease

• Intervention (I): Use of controlled-release devices in adjuvant treatment to mechanical therapy in patients with periodontal disease

• Comparison (C): Patients with only mechanical treatment as a control

• Most important outcome (O): Improvement in periodontal parameters of insertion level and bleeding on probing (BOP)

• Types of studies (T): Randomized clinical trials.

Search strategy

Searches were performed in the PubMed, Science Direct, Web of Science, Scopus, Scielo, and Academic Google databases, up to July 12, 2020, with no limitation for the dates of published articles [Table 1].

Randomized clinical trials in patients with periodontal disease were included, comparing the use of controlled-release devices in the adjuvant treatment to mechanical therapy with only mechanical treatment as a control group, with the main outcome being the improvement of periodontal parameters of the level of insertion and bleeding the survey [Figure 1].

Figure 1.

Eligibility criteria used for the study.

After performing the searches in the databases described above, 2847 studies were found, of which 204 were duplicates. From a critical reading of their titles and abstracts, 2784 articles were excluded. Sixty-three records were then read in full, of which 29 were excluded for not meeting the eligibility criteria [Figure 1], resulting in a total of 34 studies included in the qualitative synthesis [Figure 2].

Figure 2.

Article selection flowchart according to the PRISMA checklist. PRISMA – Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Bias risk assessment

The risk of bias assessment was performed to assess the reliability of the findings, using the parameters: randomization, population standardization, blinding of the evaluator and the study population, incomplete results, selectivity of reporting results, and other risks. When the authors reported these parameters, they were marked as a positive response, if not described in the study, the negative response was marked.

The risk of bias assessment was performed to measure the reliability of the findings, following the Cochrane standards and evaluated in the Review Manager program (RevMan 5.1), in seven domains related to the assessment of selection bias, performance, detection, attrition, and reporting, which can be judged into three categories: low risk, high risk, and uncertain risk.

Data extraction

The data obtained were tabulated into Microsoft Office Excel 2016 software (Microsoft Corporation, Redmond, WA, USA) being registered author and year of research development, groups tested, in addition to the main results obtained [Table 2].

Table 2.

Evaluation of the results of selected articles

Author/year	Sample size/age	Groups	Methods	Results
Moran et al., 1990[7]	69 patients, 47,6 years on average	Chlorhexidine strips MT strips TE strips SRP + MT strips SRP No treatment	Analysis of white blood cells in crevicular gingival exudate Clinical parameters: BOP, PD, CAL	Improvements were seen in all clinical parameters in the groups using the strips. However, patients who received SRP + MT strips had superior results. In addition, this group also showed greater reductions in the analysis of gingival exudate, compared to the other treatments
Hitzig et al., 1994[8]	28 patients, 34-73 years	SRP + MT 5% SRP	Clinical parameters: VPI, GI, BOP, PD e CAL	The analysis of data from 28 patients indicated that both SRP and the use of MT in the periodontal pocket decreased PD and BOP. However, during the treatment, these results were more effective in the group that received Metronidazol 5%
Jones et al., 1994[9]	51 patients, 28-68 years	SRP MC + SRP MC No treatment	Clinical parameters: VPI, PD, BOP, CAL and GI Microbiological parameters: anaerobic culture, DNA probes and monoclonal antibodies to Pg, Pi or Aa	The reduction in VPI with MC + SRP was significantly greater than all other groups at one month and greater than negative control and SRP at 3 months. MC + SRP was effective in reducing GI in the first month and with no statistically relevant difference with the control group after 3 months. MC showed efficacy in reducing Pg and Pi cultures after one month. Aa was with low frequency at baseline (0 to 7.7%) that no data is shown
Newman et al., 1994[10]	113 patients, 21 + years	SRP SRP + TE strips	Clinical parameters: PD, BOP and CAL	At 1, 3, and 6 months, TE fiber therapy was significantly better at reducing PD (P<0.05) and reducing BOP (P<0.05) than SRP alone. At 6 months, TE treatment was significantly better and in clinical attachment gain (P<0.05) than the SRP group
Drisko et al., 1995[11]	116 patients, 25-74 years	SRP SRP + TE strips for 10 days TE strips for 10 days Two serial fiber applications during 10 days	Clinical parameters: PD, CAL, PI and BOP	All treatments resulted in similar improvements in clinical parameters compared to baseline and were equally effective in treating periodontitis
Radvar et al., 1996[12]	67 patients, 25-75 years	SRP + 25% TE Fibers SRP + 2% MC gel SRP + 25% MT gel SRP	Clinical parameters: PD, CAL, BOP and MGI	The reduction in PD was significantly greater in the SRP + TE group than in the SRP alone group (P=0.002). The difference between groups in improvement of CAL or BOP was not significant. SRP + TE resulted in the greatest reduction in MGI scores, which was significantly greater than all other groups. Although the frequency of sites with suppuration was markedly reduced after all treatments, only in the SRP + TE group this index reached zero
Soskolne et al., 1997[13]	94 patients, 30-65 years	SRP + 2.5 mg Chlorhexidine chip SRP	Clinical parameters: PD, CAL, BOP, VPI and GI	Regions where SRP + 2.5 mg Chlorhexidine Chip was applied were superior to the control group in all parameters, however the significant differences in CAL only appeared after the 3rd month (0.31 mm±0.057 vs. 0.23 mm±0.055)
Jeffcoat et al., 1998[14]	447 patients, 30-79 years	SRP + 2.5 mg Chlorhexidine chip SRP + Placebo chip SRP	Clinical parameters: BOP, PD, VPI, GI and CAL	After 9 months, the group that showed the best results in all parameters was the SRP + 2.5 mg Chlorhexidine chip. The proportion of patients who evidenced a PD reduction from baseline of 2 mm or more at 9 months was significantly higher in the chlorhexidine chip group (19%) compared to the SRP controls (8%) (P<0.05)
Lie et al., 1998[15]	18 patients, 36-77 years	SRP SRP + 25% MT SRP + 3% TE	Clinical parameters: PD, CAL, BOP Microbiological parameters: commercial test kit	There were no significant differences between groups
Kinane and Radvar, 1999[16]	79 patients, 45 on average years	SRP SRP + 25% TE fibers (SRP + TE) SRP + 2% MC gel SRP + 25% MT gel	Clinical parameters: PD, BOP, CAL and MGI	Improvements in clinical parameters were greater in all three adjuvant treatment groups than the SRP alone. The reduction in PD at all time points was significantly greater in the SRP + TE group than in the isolated SRP group (P<0.01). The greatest reduction in BOP occurred in the SRP + TE group at the 6-week and 3-month periods, but these differences were
				not statistically significant when compared across all treatment groups (P=0.78 and P=0.90, respectively)
Wong et al., 1999[17]	30 patients, 33-69 years	SRP + tetracycline fibers SRP	Subgingival plaque samples were collected at baseline, 1, 3 and 6 months after fiber removal for microbiological analysis by immunofluorescence Clinical parameters: PI, PD and CAL	PI and PD significantly decreased in both groups. There was a reduction in bacterial cell count and pathogenic periodontium in both groups, but no statistical difference was observed between them
Jeffcoat et al., 2000[18]	45 patients, 30-80 years	SRP + 2.5 mg Chlorhexidine chip SRP + Placebo chip SRP	Clinical parameters: PD and CAL Radiographic parameters: Bone loss and bone gain	The data showed that patients who received the chlorhexidine chip as an adjuvant to SRP had better results in clinical and radiographic parameters, with a reduction in probing depth and no bone loss site, unlike the placebo group, which had bone loss in 11% of patients. Application sites
Wolinsky et al., 2001[19]	207 patients, 25-75 years	SRP + Doxycycline Hyclate in Gel SRP	The two groups received 3 subdivisions, in relation to patients who underwent SRP before starting treatment, in the following timeframe: 2-6; 6-12 and + 12 months. The clinical parameters being evaluated: CAL, PD and BOP	When comparing the two applied groups, the analysis of variance of the results did not show significant differences between them, since all subgroups showed improvements in the clinical parameters evaluated in relation to the initial picture
Purucker et al., 2001[20]	30 patients, 20-40 years	SRP + systemic amoxicillin/clavulanic acid (500 mg) (2 weeks) SRP + Tetracycline fibers (1 week)	Three months after SRP, the patients were divided into two groups and the baseline values and after 15, 30, 41 and 54 weeks of clinical parameters PD, CAL and BOP were evaluated	The two groups showed a significant decrease in PD and CAL gain, however, they did not differ statistically when compared. There was a reduction in BOP in both groups, with better clinical values for Group 1
Friesen et al., 2002[21]	24 patients, 26-69 years	SRP + 1 TE strip application SRP + multiple TE strip applications SRP No treatment	Clinical parameters: PD, BOP, PI, GI, GCF and CAL	SRP + multiple TE strip applications significantly reduced probing depth compared to SRP and untreated. SRP + multiple applications of TE strips reduced marginal bleeding compared to all groups. No group affected GCF, but there was a reduction in GCF over time
Grisi et al., 2002[22]	20 patients, 35-56 years	SRP SRP + CHX	Clinical parameters: PI, BOP, GR, PD and CAL Microbiological parameters: BANA test	The groups showed significant improvements in all parameters analyzed, but there were no statistically significant differences between the two groups for any parameter analyzed except BOP, which was significantly reduced in the SRP group
Salvi et al., 2002[23]	47 patients, 29-71 years	Atridox® Elyzol® Dental Gel PerioChip®	Clinical parameters: PI, BOP, PD, CAL Microbiological parameters: Bacterial count	Atridox demonstrated significant improvement in PD and CAL compared to others
Paquette et al., 2003[24]	271 patients, 21-70 years	SRP SRP + placebo adjuvant SRP + minocycline microspheres	Clinical parameters: PD, CAL and BOP	The sites treated with SRP + minocycline microspheres showed a significant PD decrease in the first month, differing from the other groups. At 3 months, the three groups showed similar results, while at 9 months, Group 3 presented statistically different results from the other groups, demonstrating a greater advance in the treatment
Paquette et al., 2004[25]	499 patients, 30+ years	SRP SRP + minocycline microspheres 1 mg	Clinical parameters: PD and BOP	Significantly more sites treated with adjuvant minocycline microspheres exhibited PS <5 mm at 1 (P=0.0009) and 3 (P=0.01) months compared to sites treated with SRP alone, both in the general population and in smokers. More sites decreased by 1, 2, or 3 mm in the adjuvant minocycline group than in the isolated SRP group at 1 and 3 months, both overall and in smokers (P<0.05)
Emingil et al., 2004[26]	30 patients, 37-61 years	SRP + 20 mg Doxycycline capsule SRP + Placebo capsule	Immunofluorescence for Collagenase-2 (MMP-8) analysis Clinical parameters: PD, CAL, GBI and VPI	Clinical parameters showed good results in both groups, however at the 9th month of treatment, the group treated with doxycycline capsule showed better results in clinical parameters, and still found lower levels of metalloproteinases than in the placebo group
Kaner et al., 2007[27]	41 patients, 18-40 years	SRP + CHX SRP + amox/metranidazol	Clinical parameters: CAL, PD, BOP and Pus	CAL, PD, BOP were significantly reduced in both groups after 3 months. In the SRP + CHX group, PD significantly increased again between 3 and 6 months. Patients treated with SRP + Amox/MT showed significantly greater CAL gain and BOP reduction after 6 months. Pus remained detectable only in patients with CHX chip
Kasaj et al., 2007[28]	20 patients, 20-60 years	SRP + 2.5 mg Chlorhexidine Chip SRP	Clinical parameters: VPI, GBI, GR, CAL and BOP	The group that used the controlled-release device as an adjuvant to SRP, after 6 months of treatment, reduced BOP by 42%, differing significantly from the control group, which only reduced by 9% without using the chip
Paolantonio et al., 2008[29]	116 patients, 33-65 years	SRP SRP + Chlorhexidine chip	Clinical parameters: VPI, PD, BOP, MGI and CAL Microbiological Parameters: Colony Forming Unit Count	PD and BOP were significantly lower at 3 and 6 months compared to baseline scores for both treatments. In addition, PD and BOP were reduced in the SRP + Chlorhexidine treatment group compared to SRP alone at 3 and 6 months. While MGI was similar in the two treatments at 3 months, it was reduced in the SRP + CHX treatment group at 6 months
Tomasi et al., 2008[30]	32 patients, 25-75 years	SRP SRP + 8.8% Doxycycline Gel	Clinical parameters: PD, BOP, PI assessed initially and 3 and 9 months after treatment	There were no statistical differences between the two groups regarding the improvement of clinical parameters. It was also shown that periodontal pocket reduction was not improved by doxycycline gel
Machtei et al., 2011[31]	60 patients, 18-59 years	SRP + PerioChip® SRP + Flurbiprofen Chip®	Clinical parameters: BOP, GR, PD and CAL	Both showed significant improvements in the clinical parameters evaluated, however, they did not differ statistically from each other
Agarwal et al., 2012[32]	61 patients, 30-50 years	SRP + 0.5% CLM SRP + placebo	Clinical parameters: PI, mSBI, GI, PD and CAL	Both groups performed well, but the adjuvant use of 0.5% CLM as a controlled drug delivery system improved the clinical outcome
Rao et al., 2013[33]	50 patients, 30-50 years	1 SRP + Metmorphine Gel 1% SRP + placebo	Clinical parameters: mSBI, PD and CAL Radiographic parameters: IBD	Group 1 showed a greater decrease in mSBI, PD and CAL gain at 3 and 6 months, as well as a higher level of PD at 6 months, compared to the results of Group 2
Kathariya et al., 2014[34]	98 patients, 25-50 years	SRP + CLM 0.5% SRP + placebo	Clinical parameters: GI, mSBI, BOP, PI, PD, CAL Microbiological parameters: Reverse phase high pressure liquid chromatography	Patients treated with SRP + CLM 0.5% showed improved reductions in GI, BOP and PD, and gains in CAL over time compared to the placebo group. However, no statistically significant differences were observed for PI. The mean concentration of CLM was detected in the gingival fluid for up to 7 weeks
Ahamed et al., 2013[35]	12 patients, 25-55 years	SRP + 10% Doxycycline Hyclate SRP	Clinical parameters: PD, CAL, GI, VPI and GBI Microbiological analysis: Cocos, Bacilli and Spirochetes	At 180 days of study, both groups showed a significant periodontal improvement. There was a significant gain in the level of clinical attachment in patients who received SRP + Doxycycline Hyclate. As for microbiological analysis, the reduction in spirochete count was more significant in the experimental group
Rao et al., 2013[33]	50 patients, 30-50 years	SRP + 1.2% Simvastatin Gel SRP + Placebo Gel	Clinical parameters: PD, CAL e mSBI Radiographic Parameters: IBD	The group treated with SRP followed by 1.2% simvastatin gel showed good results. Patients did not experience adverse reactions and there was a complete filling of bone defects in addition to improvement in all clinical parameters evaluated
Pattnaik et al., 2015[36]	20 patients, 29-54 years	SRP + 2.5 mg CHX SRP	Clinical parameters: PD, CAL and GI Microbiological parameters: Microbiological Detection by PCR	SRP + CHX showed more satisfactory results there was a statistically significant reduction in the proportion of occurrence of Porphyromonas gingivalis and Tannerella forsythia by the SRP + CHX group. Our data suggest that SRP + CHX has a significantly better and prolonged effect compared to SRP alone on CAL and microorganism clearance
Pradeep et al., 2015[37]	65 patients, 25-55 years	SRP + 1.2 mg RSV SRP + placebo	Clinical parameters: mSBI, PD and CAL Radiographic Parameters: IBD	SRP + 1.2 mg RSV generated greater reduction in PD and GI, along with an increase in CAL gain
Pradeep and Thorat, 2010[38]	60 patients, 25-45 years	SRP + 1.2% SMV SRP + placebo	Clinical parameters: mSBI, PD and CAL Radiographic Parameters: IBD	PS reduction and average CAL gain were more significant in SRP + 1.2% SMV. A significantly higher mean percentage of bone filling was found in the SRP + 1.2% SMV group
Yang, 2015[39]	138 patients, 18-65 years	Minocycline hydrochloride hydrochloride + SRP Metronidazole + Minocycline Hydrochloride strip	Clinical parameters: PD and BOP	Compared to Minocycline Hydrochloride Hydrochloride + SRP, the GI, VPI and the PD of patients in two groups were significantly reduced. In addition, the range of reduction in the experimental group was significantly greater than in the control group

SRP – Scaling and root planing; BOP – Bleeding on probing; PD – Probing depth; CAL – Clinical attachment level; VPI – Visible plaque index; PI – Plaque index; GI – Gingival index; GR – Gingival recession; GCF – Gingival crevicular fluid; CLM – Clarithromycin; MC – Minocycline; TE – Tetracycline; RSV – Rosuvastatin; SMV – Simvastatin; Pus – Suppuration; Pg – Porphyromonas gingivalis, Pi – Prevotella intermedia; Aa – Actinobacillus actinomycetemcomitans; MT – Metronidazole; mSBI – Modified sulcus bleeding index; GBI – Gingival bleeding index; MGI – Modified gingival index; IBD – Radiologic assessment of intrabony defect; BANA – N-benzoil-DL-arginine-2-naphthyamide; MMP – Matrix metalloproteinase 8; CHX – Chlorhexidine Digluconate; PCR – Polymerase chain reaction; DNA – Deoxyribonucleic acid; P – Level of significance

RESULTS

Descriptive analysis

It is observed that all articles found can be classified as randomized clinical trials, in which the main findings about controlled-release devices in periodontal treatment are found in Table 2. The sample sizes are completely different, ranging from 12 to 499 patients. The age of patients ranges from 18 to 80 years old. Among the ways in which experimental drugs are presented in the articles, we can mention chips, strips, microspheres, topical applicators, and diamond-like carbon strips. For evaluating the management of periodontitis of controlled-released devices, the evaluation method of choice was BOP, probing depth (PD), clinical attachment level, periodontal pocket debridement, visible plaque index, plaque index (PI), gingival index (GI), gingival recession, gingival crevicular fluid, modified sulcus bleeding index, gingival bleeding index, modified gingival index, inflammatory bowel disease (radiologic assessment of intrabony defect), papillary bleeding score, as well as microbiological analysis by immunofluorescence. The follow-up periods were similar, with evaluations immediately after the treatment, in the 1^st h and 1^st day. Later follow-up ranged from 1 month to a year.

All randomized clinical trials included in this review performed a comparison between SRP and controlled-release drugs, with the most present being chlorhexidine (CHX) (8 articles), tetracycline (8 articles), followed by metronidazole (6 articles), minocycline (5 articles), doxycycline (4 articles), amoxicillin (3 articles), clindamycin (2 articles), simvastatin (2 articles), and rosuvastatin, clavulin and metamorphine (1 article). Regarding the results of the studies, it was observed that practically all of them had better clinical parameters when the experimental groups of controlled-release drugs are associated with conventional nonsurgical periodontal therapy. Only four studies obtained results with no statistically significant difference between the interventions presented.

Bias risk

It is noted that 15 articles have a low risk of bias, while the others being classified between medium and high risk [Figure 3].

Figure 3.

Assessment of individual bias risks of articles

Regarding the specific items of each risk assessment, it is noted that in relation to random sequence generation, blinding of participants and personnel, and blinding of outcome assessment, more than 50% of the articles presented these descriptions in their study. About allocation concealment, less than half of the studies describe this item. Regarding the other topics such as incomplete outcome data, selective reporting, and other biases, more than 75% of the authors detail these aspects [Figure 4].

Figure 4.

Risk of bias for all studies

DISCUSSION

CRDs have been widely studied since the 1990s as adjuvant SRP therapy for the treatment of periodontitis since antimicrobial drugs act directly on the etiopathogenesis of periodontal diseases.[7] Therefore, CHX is a drug that causes minimal side effects to the patient, with low toxicity and potent antimicrobial activity. Thus, the use of CHX-based biodegradable chips as CRD in the adjuvant treatment of periodontal disease is already reported in the literature, using the association of the SRP procedure.[14,18] It was shown that the adjunct use of the CHX chip provided a significant reduction in PS and NIC compared to the group treated only with SRP, mainly in a 9-month period analysis, which may be due to the effective CRD method of the pharmacological principle throughout the treatment period, further suggesting that the CHX chip is a safe and effective adjuvant chemotherapy agent for the treatment of periodontitis.[14] Regarding the assessment of the risk of bias, this study presented a low risk, which demonstrates the reliability of such findings. Furthermore, its use in the form of fibers, also associated with SRP, has been shown to improve the periodontal condition.[30,35] Information supported by such studies present a low risk of bias.

In addition to improving the clinical parameters, the CHX chip enables a control of the subgingival microflora, due to its gradual release by diffusion, and its concentration is sustained at a level sufficient to create a bacteriostatic medium for a prolonged period. This indicates the short-term effect of SRP and the long-term effect of CRD.[13,18] Furthermore, its action together with flurbiprofen is also beneficial, due to the additional anti-inflammatory effect of flurbiprofen.[31] Furthermore, after analyzing the risk of bias, this study was classified as low risk, showing its reliability.

Also in this context, it was noted that the use of CHX chip together with the systemic use of amoxicillin/metronidazole is superior in the treatment of periodontitis than local therapy alone.[27] Such evidence can be reinforced because the study demonstrated a low risk of bias, which makes it possible to transpose these findings, given a clinical reality. In line with most of the findings, literary data revealed that the CHX chip was not able to promote any additional clinical and microbiological benefits beyond that achieved with SRP after the 9-month period, and this result may be associated with the action of serum proteins of the subgingival environment, which can reduce the antimicrobial activity of CHX.[22] Still, after assessing the risk of bias, this study showed a medium risk, not having enough support to validate this information. In addition, the literature demonstrates that, in addition to the efficacy of CHX-loaded diamond-like carbon strip, the clinical success of the treatment is directly related to the patients’ motivation to respond well to oral hygiene instructions and the SRP mode.[23,28]

The use of metronidazole as a controlled-release drug has been widely investigated in the literature, as its use promotes a selective effect on obligate anaerobic pathogens present in the subgingival plaque and generates few biological side effects when compared to other antimicrobials, such as tetracycline.[15] In line with this information, studies show that mechanical therapy alone has similar results to the application of either metronidazole 25% or tetracycline 3%. A limiting factor for these findings is their short duration since the clinical relevance of these subtle improvements caused by the long-term use of subgingival medications is not yet known. With regard to the risk of bias, this study presented a moderate overall risk, as it has a high risk of allocation concealment and blinding of the participants involved.[15]

Other findings show that tetracycline and minocycline gel associated with SRP improves PD, PB, and CAL parameters in periodontal disease, making tetracycline fiber more effective over time. This fact is due to the high levels of this drug, above 1.6 mg/mL in the crevicular fluid over 10 days, which was not achieved by any of the other drugs.[16] These findings corroborate those of Salvi et al.,[23] who observed that doxycycline generated benefits with respect to PD and CAL. Furthermore, it is important to emphasize that this clinical trial has a high level of bias, which indicates that its results cannot be consistent with clinical reality.

These results contrast with those obtained by Hitzig et al.,[8] who when analyzing patients distributed among the SRP groups, isolated, and associated with the single application of 5% metronidazole in a collagen transport device, identified that both groups were effective in decreasing PD, PB, and GI, the group treated with the associated drug showed to be significantly better. The good performance of metronidazole 5% can be explained by the choice of the delivery system, which, in this case, was collagen. As it is biocompatible, it is well tolerated and does not cause any damage as a local inflammatory reaction. Another advantage of using collagen is that, as it is a resorbable material, patients do not need to return to the office for removal. The study presented a low risk of bias, and it is possible to infer that it provides more reliable information.

Moran et al. in 1990, investigated the effectiveness of CHX acrylic strips, metronidazole, tetracycline, SRP, and the combination of SRP and metronidazole strips in the treatment of severe periodontitis and it was possible to observe that there was no statistical difference.[7] Although the author justifies the effective action of metronidazole against the gingival microflora and the ability of its antimicrobial activity not to be neutralized by protein components of the crevicular fluid, unlike the other substances evaluated. The study in question has a low risk of bias, which indicates the reliability of the findings.

Still in this context, Radvar et al. observed that tetracycline was the adjuvant treatment significantly superior to other drugs of the same class, with regard to PS and modified GI, in addition to being the only drug that prevented 100% of suppurations in the treated sites and this is possibly due to the sustained concentration of tetracycline at very high levels in the crevicular fluid for 10 days, which was not sustained by the other antibiotics.[12] The trial demonstrated a low overall risk of bias, however, with regard to blinding the participants, it presented a high risk.

In addition to being used alone in gel, fiber, strip, or chip form, metronidazole can also be combined with other antimicrobials, such as minocycline and amoxicillin.[27,39] Minocycline hydrochloride is a member of the tetracycline class, which presents itself as a new controlled-release periodontal formulation that has a broad antibacterial effect on Gram-negative bacteria such as Escherichia coli, Cray bacillus, enteric bacilli, and Gram-positive bacteria such as staphylococci and pneumobacilli.[24,39] Jones et al. observed that minocycline administered at the subgingival level in the form of a biodegradable powder can act as an adjunct treatment for SRP, which proves to be beneficial in reducing PDs in addition to the benefit seen only with SRP.[9] These findings diverge from those found by Paquette et al.[24] where they indicate that minocycline microspheres are complementary to straightening. Furthermore, Jones et al. elucidated that the mechanism of action of minocyclines is due to the inhibition of the progression of periodontitis by blocking the activity of metalloproteinases, regardless of their antimicrobial properties.[9] The work carried out by Jones et al.,[9] despite presenting an uncertain risk of bias for most of its parameters.

Kaner et al. in a study developed in 2007 found that CHX chip together with systemic amoxicillin and metronidazole showed a significant gain in CAL and reduction in PD, in addition to maintaining undetectable suppurations.[27] The combination of amoxicillin and metronidazole is a widely used first-choice protocol that is extremely effective in combating the periodontal pathogen Aggregatibacter actinomycetemcomitans. With regard to the risk of bias, this clinical trial presents a low risk, which indicates the great relevance of the results obtained.

In addition, minocycline associated with metronidazole is able to reduce the PI, among other clinical parameters indicative of periodontal tissue inflammation, generating fewer adverse effects, in addition to maintaining periodontal health. This association of drugs demonstrates an effect on Gram-negative bacteria such as Escherichia coli and on Gram-positive bacteria such as staphylococci and pneumobacillus, in addition to promoting the proliferation of fibroblasts and periodontal ligament cells.[39] The study in question has a low risk of bias, indicating that the findings obtained are more reliable.

Tetracyclines in fibers as a form of application also show a positive effect in periodontal therapy. Some authors applied it in single or multiple fibers, where all alternatives were positive. Tetracycline fibers can affect host response through anticollagenase activity. In addition, it was noted that the preconditioning of root surfaces with this substance can promote the migration of periodontal ligament cells, where reduction in collagenase activity in the crevicular fluid was also observed, as well as the atenuation of the severity of inflammation in the gingival sites. Also corroborating this thesis, Lie et al.[15] in 1998 found that the topical application of 25% metronidazole gel and 3% tetracycline gel provided reduced and similar augmentative clinical and microbiological effects when compared to subgingival SRP alone. None of these studies had acceptable reliability, ranging from uncertain to high.[10,11,15]

Wong et al.[17] observed that tissue invasion by A. actinomycetemcomitans can help propagate other groups of bacteria by protecting them from the action of controlled-release tetracycline fibers. In addition, this multicenter study also highlighted the possibility of reducing the effectiveness of tetracycline in periodontal pockets when the same location had already been treated with the same drug, thus promoting the spread of tetracycline-resistant bacteria. Corroborating Purucker et al.,[20] where they analyzed a reduction in clinical inflammatory parameters, however, there was a greater recurrence in patients who associated this local pharmacological therapy with systemic antibiotics. In addition, PS reducing activity has been reported when tetracycline is associated with RAR when applied in multiple locations by increasing the concentration of antibiotic in the oral region fully.[21] However, the article has significant limitations regarding the risk of bias analysis.

The benefit of using multiple applications of strips in periodontal pockets in relation to the single strip is already well explained by some authors, as antibiotic concentrations are much higher and for longer, thus allowing a broader therapeutic window. Furthermore, it is known that this formulation has a potential role in the activity of periodontal matrix metalloproteinases, thus promoting a reduction in inflammation and tissue destruction.[16,21]

Furthermore, doxycycline also has its beneficial effect, as the application of this agent with a semi-fluid composition has the potential to penetrate areas where mechanical instrumentation is difficult, such as furcation and vertical defects, in addition to demonstrating lower levels of matrix metalloproteinases.[19,26] This information is more relevant because these findings demonstrate a low risk of bias. Going against this, Ahamed et al.[35] points out that this drug has no additional benefit to mechanical therapy, however, the study demonstrated the risk of an uncertain bias, which may need a more controlled investigation to obtain a level of greater relevance.

In this same perspective, Machtei et al.,[31] in 2011, observed an improvement in all clinical periodontal parameters in patients treated with SRP associated with CHX Chips and SRP combined with flurbiprofen, and this is due to the anti-infective effect of the application of these chips it caused the microbial flora with chlorhexidine and the inflammatory response with flurbiprofen. However, the results had no statistically relevant differences between them, which suggests that mechanical therapy alone is not as effective, but also highlights that the use of the drug without the SRP will be ineffective, regardless of the drug used. This article presents a low risk of bias, with an uncertain risk only because it has inconclusive results.

Clarithromycin is an agent with a broad antimicrobial spectrum, high bioavailability, and studies indicate that its distribution in tissues is very significant, and may reach higher levels in inflamed gums than in healthy gums.[32,34] Both the studies that evaluated the clarithromycin gel presented an uncertain risk regarding selection, performance, and detection bias, which imposes limitations on the clinical relevance of this work.

Pradeep et al.[37] used rosuvastatin as an adjuvant treatment, resulting in gain in GI, insertion level, and reduction in PD, also demonstrating bone formation in defective intraosseous sites. And such results may, therefore, provide a new view on the use of this substance for a possible periodontal regeneration, due to its capacity to stimulate bone formation, inducing osteoblast differentiation and inhibiting osteoclast differentiation, thus reducing bone resorption. In another study, the application of 1.2% simvastatin gel as an adjuvant to mechanical therapy in periodontal pockets has also been suggested. The results found provided a new direction in the field of gingival healing in smokers, in addition to suggesting an anti-inflammatory effect.[33] Furthermore, Pradeep and Thorat[38] observed that 1.2% simvastatin gel as an adjunct to SRP resulted in excellent improvement in periodontal parameters. The efficacy of Simvastatin can be attributed to the fact that it is a lipophilic statin, which in its mechanism of action diffuses through the cell membrane and specific transporters, having favorable pharmacological properties[33] In this sense, it differs somewhat from rosuvastatin, which is a hydrophilic statin, and they are not permeable to the lipid bilayer and depend on specific transporters for entry into cells, but they also have great pharmacological properties, such as minimal metabolism and liver selectivity[37] Regarding the assessment of the risk of bias, the studies with Simvastatin and Rosuvastatin had low overall risk, which demonstrates reliability in the clinical findings, with only uncertain risk for patient selection and blinding.

In short, the vast majority of clinical trials performed showed that patients had good acceptability to treatment, tolerated the drug well and did not present adverse effects during the entire follow-up.[19,23,26,27,31,32]

Despite the many benefits found clinically, some authors emphasize that further studies are needed, such as controlled, randomized, multicenter, and long-term clinical trials to determine the clinical, histological, and radiographic effect of treatment in patients with periodontal disease.[33] This information goes against what has been highlighted by other authors about the importance of further studies to establish the effects of drugs in different cases of periodontitis and other types of periodontal disease.[19,35]

Given the above, we found that sustained-release devices proved to be an effective alternative for adjuvant treatment to nonsurgical periodontal therapy, with the most relevant not being the antimicrobial used, but rather its availability and concentration in the crevicular fluid. Furthermore, resorbable chips, gels, and ointments proved to be more clinically viable options, as they do not require consultations to remove the device, as is the case with acrylic fibers and strips, which, for this reason, have a lower cost–benefit ratio. We also emphasize the fundamental role that the association of controlled-release drugs with conventional SRP therapy for the nonsurgical management of periodontal conditions. In this context, further clinical research should be carried out in the future with the objective of developing devices that are easy and quick to apply, and cost-effective.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.