Efficacy of Adjunctive Chlorhexidine in non-surgical treatment of Peri-Implantitis/Peri-Implant Mucositis: An updated systematic review and meta-analysis

Objective: The current review aimed to assess the efficacy of adjunctive chlorhexidine (CHX) in the non-surgical treatment of peri-implantitis/peri-implant mucositis. Methods: PubMed, Embase, Science Direct, CENTRAL, and Google Scholar databases were searched up to 10th March 2022 for relevant randomized controlled trials or controlled clinical trials. Results: Fourteen studies were included. Meta-analysis revealed significantly lower probing depths in peri-implant mucositis patients using CHX adjuncts as compared to controls (SMD: -1.49 95% CI: -2.56, -0.42 I2=95% p=0.006). However, the same effect was not noted in peri-implantitis (SMD: -1.18 95% CI: -0.04, 2.40 I2=96% p=0.06). CHX was not found to improve bleeding of probing in peri-implant mucositis while sufficient data was unavailable for peri-implantitis. Results on other outcome variables were conflicting. Conclusion: Evidence on the efficacy of adjunctive CHX for peri-implant mucositis is conflicting. Similarly, strong conclusions on the effect of CHX for peri-implantitis cannot be drawn due to limited number of studies. Overall, there seems to be a trend of non-significant impact of CHX on outcomes of peri-implant mucositis as well as peri-implantitis.


INTRODUCTION
Dental implants have become the primary mode of prosthetic rehabilitation of partially or completely edentulous patients. Indeed, trends from the USA suggest that there has been a 1000% increase in the use of dental implants from 1999 to 2016 and these numbers are bound to increase even further. 1 The clinical course of dental implants is not without complications. Estimates suggest that around 19-65% and 1-47% of implants are affected by peri-implant mucositis and peri-implantitis, respectively. 2 Peri-implant mucositis is a reversible inflammatory lesion affecting the mucosa surrounding an endosseous implant without loss of supporting peri-implant bone. 3 Untreated peri-implant mucositis may lead to peri-implantitis which is clinically diagnosed by evidence of progressive marginal bone loss, probing depths of ≥6mm, and presence of bleeding on probing (BOP). 4 Plaque is the most important initiator of peri-implant mucositis. 5 Research also suggests that the anaerobic gram-negative bacterial flora seen in peri-implantitis is analogous to periodontitis. 6 However, the clinical course of the disease may be modified based on several risk factors like prior history or concurrent

Systematic Review
Efficacy of Adjunctive Chlorhexidine in non-surgical treatment of Peri-Implantitis/Peri-Implant Mucositis: An updated systematic review and meta-analysis presence of periodontitis, smoking, diabetes, prosthetic flaws, keratinized mucosa width, and lack of regular follow-up. 7 Also, soft tissues surrounding an implant demonstrate significantly severe inflammatory reaction on exposure to oral biofilm and require a prolonged healing phase after biofilm removal when compared to soft-tissues surrounding natural teeth. 8 The primary mode of treatment of peri-implant diseases consists of mechanical debridement. Surgical therapy may be utilized for peri-implantitis, however, the treatment has not been popular. 9 Adjunctive therapies like chlorhexidine (CHX), minocycline, sodium hypochlorite, herbal mouthwashes, probiotics, air polishing, laser therapy, photodynamic therapy, and systemic antibiotics are also used. 10 Of these, CHX is an easy-to-use topical antimicrobial that helps in the control and prevention of biofilm formation due to its high substantivity, bactericidal activity, and a broad spectrum of action. 11 Recently, Liu et al 12 in a systematic review assessed evidence on adjunctive CHX with non-surgical treatment of peri-implant disease but with small number of studies. With publication of several new studies, there is a need for updated evidence. Hence, this updated review aimed to answer the following clinical question: Does adjunctive topical CHX improve outcomes of peri-implant mucositis or peri-implantitis treated by non-surgical therapy?

The
PRISMA statement 13 (Preferred Reporting Items for Systematic Reviews and Meta-analyses) and recommendations of the Cochrane Handbook for Systematic Reviews of Intervention 14 were followed. The PROSPERO registration no of the review was CRD42022315308. Literature search: Two reviewers (M.Y. & W.L) conducted an electronic search of PubMed, Embase, Science Direct, CENTRAL, and Google Scholar databases up to 10 th March 2022. Any non-English language studies were translated to English using Google Translate. The search terms "chlorhexidine", "peri-implantitis", "peri-implant mucositis", "dental implant", "anti-microbial", "anti-infective", and "nonsurgical" were used for all databases (Supplementary Table-I). Following the database search, we deduplicated the results. All the remaining studies were analyzed by their titles and abstracts. Articles relevant to the subject of our review were identified and their full texts were extracted. These articles were then examined for final inclusion in the review. The entire process was conducted by two reviewers (M.Y. & W.L). Any discrepancies in study selection were resolved by consensus. Eligibility criteria: We formulated the inclusion criteria based on PICOS (Population, Intervention, Comparison, Outcome, and Study design). Studies with the following criteria were eligible: 1. Population: Adult patients (>18 years) with peri-implant mucositis or peri-implantitis 2. Intervention: Using any form of topical CHX for treating peri-implant mucositis or peri-implantitis with mechanical debridement 3. Comparison: Mechanical debridement without CHX or use of placebo 4. Outcomes: Reporting at least probing depth, BOP, and/or clinical attachment levels (CAL) 5. Study design: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) All retrospective studies and in-vitro studies were excluded. We also excluded studies on zirconia implants, studies comparing CHX with any active treatment, studies combining CHX with surgical treatments, and those not reporting any of the relevant outcomes. Data extraction and quality assessment: Data extracted included the first author, publication year, study location, study type, study population, CHX protocol, control group protocol, sample size, demographic details, study results, and follow-up. The primary outcomes of the review were probing depth, BOP, and CAL. We pooled data for these outcomes only if sufficient information was available from at least three studies. A descriptive analysis was conducted for all other outcomes.
We used the Cochrane Collaboration risk assessment tool for RCTs to assess the risk of bias. 15 Studies were rated as low risk, high risk, or unclear risk of bias for: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. Statistical analysis: The meta-analysis was performed using "Review Manager" (RevMan, version 5.3; Nordic Cochrane Centre (Cochrane Collaboration), Copenhagen, Denmark; 2014). A random-effects model was used for the analysis. We used standardized Mean Difference (SMD) with a 95% confidence interval (CI) to pool continuous data. Since some studies on periimplantitis reported an only change of baseline scores, outcomes for peri-implantitis were pooled using such scores. A sensitivity analysis was also carried out. Heterogeneity was assessed using the I 2 statistic. Since <10 studies were available for each analysis, funnel plots were not used to assess publication bias.

RESULTS
The search resulted in the identification of 4,782 unique articles (Fig.1). The authors selected 23 articles for full-text analysis. Of these, five were excluded with reasons and finally, a total of fourteen studies were included in the review. 3,16,[17][18][19][20][21][22][23][24][25][26][27][28] Except for two studies which were CCTs, all remaining studies were RCTs (Table-I). Four trials were on peri-implantitis while the rest were on peri-implant mucositis. Five studies used CHX only in mouthwash form, two studies used CHX chips, two used CHX irrigation, one used CHX gel to fill the peri-implant pocket, one used CHX gel for Meta-analysis revealed no significant difference in change in probing depths between CHX and control groups (SMD: -1.18 95% CI: -0.04, 2.40 I 2 =96% p=0.06) (Fig.3). On the exclusion of the study of Crespi et al 18 and mechanical debridement alone (control, the results revealed a significantly greater change in probing depths with CHX as compared to control (SMD: 0.23 95% CI: 0.05, 0.42 I 2 =0% p=0.01).

BOP:
Seven studies reported BOP as a percentage of probing sites while three reported data as an average of probing sites. On meta-analysis of studies reporting data as a percentage of probing sites, we noted no statistically significant difference between CHX and control groups (SMD: -0.89 95% CI: -1.99, 0.21 I 2 =93% p=0.11). (Fig.4) Similarly, no difference was noted between CHX and control groups on a pooled analysis of studies reporting data as an average of probing sites (SMD: -0.11 95% CI: -0.68, 0.46 I 2 =53% p=0.71) Fig-4. These results were stable on sensitivity analysis. Sufficient data was not available for meta-analysis of the BOP for peri-implantitis.

Risk of bias analysis:
Risk of bias in the included studies as per author's judgement are presented in Supplementary Fig.1.

DISCUSSION
The cause of both gingivitis and peri-implant mucositis has been attributed to the pathological effects of oral biofilm. 29 Indeed, while the host response to biofilm does not differ much between teeth and implants, BOP is more frequently observed around implants as compared to teeth. 30 Also, peri-implantitis presents with larger lesions along with a significantly higher destructive inflammatory profile and faster clinical progression. 31 Probing depths are higher with implants and there is a tendency of the probe to reach the alveolar bone relatively easily as compared to teeth. While biofilm reduction is an effective treatment for both types of diseases, root surfaces are easier to access and clean in teeth as compared to implants due to design features and surface roughness of the latter. 30 This has led to the use of several adjuncts to manage peri-implant diseases. 10 Barootchi et al 32 in a recent review including 14 RCTs concluded that adjunctive therapies had no significant impact on clinical outcomes as compared to non-surgical therapy alone. While the authors assessed the efficacy of CHX, only six RCTs could be included. Another metaanalysis by Ramanauskaite et al 33 assessed the efficacy of numerous adjunctive therapies with non-surgical therapy of peri-implant diseases only to conclude that adjunctive measures provided no beneficial effect in resolving peri-implant mucositis. Similar to the previous review, the studies on CHX were limited. On the other hand, Liu et al 12 reviewed only on adjunctive use of CHX and concluded that it has no beneficial effect with nonsurgical management of peri-implant diseases. However, it analyzed just seven studies. Therefore, our review represents a major update from the previous study 12 , by including seven more studies.
In case of peri-implant mucositis, our meta-analysis revealed statistically significant reduction in probing depth with the use of CHX adjunct. This is in contrast with the results of Liu et al 12 who noted no difference in probing depths with CHX but with only four trials. The difference in our results could be due to the inclusion of five more trials. However, our results were not stable on sensitivity analysis. On sequential exclusion of three studies the results turned statistically non-significant. Also, on the forest plot, it can be noted that the studies of Alqutub et al 28 and Ahmedbeyli et al 26 were outliners reporting a large difference between the study and control groups. The cause of such large difference in these two studies is difficult to contemplate as both trials used CHX mouthwashes for just 10-14 days.     Similar protocol was used by other trials but without any difference in probing depths between CHX and control groups. Also, in our analysis, we noted no difference in BOP in peri-implant mucositis patients with and without adjunctive CHX. In the overall analysis, only one study of Alzoman et al 22 reported a significant reduction of BOP sites with the use of CHX mouthwash. None of the remaining studies noted any difference between the study and control groups. Also, on descriptive analysis of other outcomes, most did not differ between the study and control groups.
A limited number of trials have examined the efficacy of CHX for peri-implantitis as only four studies were available. We noted that adjunctive use of CHX did not significantly impact probing depths in patients with peri-implantitis. However, it is important to note that the 95% CI were wide ranging from -0.04 to 2.40, with the lower end very close to zero, indicating a greater change of probing depths with CHX. On examination of the forest plot it can be seen that the study of Crespi et al 18 and mechanical debridement alone (control reported significantly better outcomes with CHX as compared to other trials. This variation may be explained by the difference in the method of CHX application between the trials. Crespi et al 18 and mechanical debridement alone (control used a combination gel of 3% chlortetracycline hydrochloride and CHX which was placed around the implant surface, while the other trials used CHX irrigation or only CHX chips.
Use of the gel may have reduced the bacterial load and detoxified the implant surface in their study resulting in better outcomes. The authors also left the granulation tissue in the soft tissue pocket hypothesizing that it would result in proliferation of cells with embryonic stem cell properties thereby leading to better healing of tissues. 34 they can be used for subsequent surgery on the same patient. Fifteen human periodontal granulation tissue samples were obtained from intrabony defects during surgery. Immunohistochemistry (IHC This may be the reason that Crespi et al 18 and mechanical debridement alone (control noted statistically significant improvement in all outcomes in the CHX group as compared to the control group.
There was significant heterogeneity in all our metaanalyses. This was expected and is in line with previous reviews 12 due to the different CHX protocols used by the included studies. The authors used CHX in chips, mouthwashes, gels, irrigating solutions, sprays and even in combinations. Furthermore, there was no homogeneity in the timing and duration of CHX use. The difference in patient populations, severity of illness, and other implantrelated factors could have also led to this substantial interstudy heterogeneity. Future studies should standardize the CHX protocol and also compare different forms of CHX to generate quality evidence.
Overall, our results do not clearly prove the added efficacy of CHX for peri-implant diseases. Such lack of effect of CHX may be due to the variation in substantivity of the drug between tooth and implant surfaces. In contrast to tooth surface wherein CHX has high substantivity with long-lasting effect, the adhesion of CHX on implant surfaces depends on surface texture and the drug concentration. 35 Research indicates that adsorbed CHX is rapidly released of non-treated implant surfaces, while prepared implant surfaces (sand blasting/ acid etching) may have better CHX uptake. 36 There are also concerns regarding the alteration of implant surfaces by anti-microbial agents. Kotsakis et al 37 have noted that CHX can affect the biocompatibility of implant surface and recommend against the use of CHX on implant surface.
Limitations: Firstly, most of the studies were of small sample size and could have been underpowered to detect significant differences. Secondly, as discussed earlier, there was vast heterogeneity in the method and timing of CHX application. Thirdly, the studies also varied in the type of outcomes reported which resulted in lower number of studies in the meta-analysis. Lastly, the number of studies on peri-implantitis were too few to derive strong conclusions.

Strength of the study:
The strength and uniqueness of the review is that it is the largest meta-analysis till date assessing the efficacy of adjunctive CHX for non-surgical treatment of peri-implantitis/peri-implant mucositis. A comprehensive detailed literature search was conducted wherein we doubled the number of studies from the previous review 12 . We believe that by combining data from published studies this review provides high quality evidence to clinicians involved in the management of peri-implant diseases. The results of this review will allow informed decisions and provide impetus to further research on CHX. Based on the results of the study, at this point it is unclear if CHX should be routinely used as an adjunct to managing peri-implant diseases. However, due to conflicting results, it is advised that clinicians may evaluate each case on its merit and recommend the usage of CHX till further data is available.

CONCLUSION
Evidence on the efficacy of adjunctive CHX for periimplant mucositis is conflicting. Similarly, strong conclusions on the effect of CHX for peri-implantitis cannot be drawn due to limited number of studies. Overall, there seems to be a trend of non-significant impact of CHX on outcomes of peri-implant mucositis as well as peri-implantitis. Further research is needed assessing the efficacy of specific delivery of CHX on outcomes of peri-implant diseases.