**1. Introduction**

Postoperative pain (POP) after root canal filling (RCF) affects up to 40% of patients [1]. The intensity and duration of POP vary according to multiple prognostic factors [2–4]. The filling technique is considered among the most relevant, in which warm vertical and cold lateral compaction as well as single cone are most traditionally utilized with resin-based or zinc-oxyde eugenol sealers [5,6]. The intensity and duration of postoperative pain are subjective and can be affected by many factors. In particular, by the severity of preoperative pain according to the medical history of the present diagnosis, tooth type, age, gender, etc. [2]. The intraoperative factors are also various, such as physical properties of the endodontic instrument used for the initial treatment, features of the irrigation protocol such as chemical solutions and concentrations, microbiological stability and resistance, histopathological state of the tissues surrounding the tooth, etc. [1–4]. At the final stage of root canal treatment during the obturation step, the endodontic sealer locally and directly contacts with the altered periapical tissues through the apical foramen and additional lateral canals. Accordingly, the physical and chemical properties of the sealer, such as pH-level, consistency, etc., also affect the intensity of postoperative endodontic pain [1,2]. The gutta-percha/bioceramic sealer (BCS) filling technique has gained popularity among endodontists due to features that include biocompatibility (due to their similarity with biological hydroxyapatite) and bioactive stimulation of periapical healing [7]. The setting time (30 min for working time), sealing ability, and antimicrobial properties are all key to the performance of endodontic sealers [8]. Premixed injectable formulations, preloaded syringes, and moldable putty forms are all available, facilitating ease of use [9]. However, there are no robust data evaluating any potential impact of BCS vs. traditional filling techniques on POP among randomized controlled trials (RCTs). The aim of this systematic review and meta-analysis was to assess the effect of the BCS filling technique compared with traditional filling techniques on POP in adult patients following RCF.

#### **2. Materials and Methods**

#### *2.1. Study Design*

This analysis considered all the studies that evaluated POP in adult patients, following RCF with BCS or traditional filling techniques.

Review question: How does the BCS filling technique affect the intensity of POP compared with the resin-based sealers (RBS) filling technique in patients undergoing a root canal treatment?

This study complies with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Statement (PRISMA), and was carried out on the basis of the Cochrane PICOS formula, defined as follows: *Population*, adult patients of both genders (not receiving analgesic or antibiotic medications, without long-term use of medications, not pregnant) with pulpal and/or periapical disease (without procedural errors, e.g., overfilling), who received an endodontic treatment in permanent teeth; *Intervention*, RCF with BCS; *Comparison*, RBS; *Outcome*, the primary outcome was the quality of life measured by the self-reported POP score; and *Study type*, RCTs. The systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) a priori, ID: CRD42021227248.

#### *2.2. Search Strategy and Inclusion Criteria*

A comprehensive search strategy was designed to access biomedical databases (PubMed, Springer Link, DOSS, Scopus, Nature, Wiley Online Library, Web of Science Core Collection, BMJ, Cochrane Library, Oxford scholarship online, CINAHL complete, Access medicine, Science direct), grey literature (SIGLE—information on grey literature in Europe), and a clinical trials register (clinical trial.gov). A manual search of the main endodontic journals was also carried out (Journal of Endodontics, European Endodontic Journal, International Endodontic Journal). The search terms were "postoperative pain" AND "endodontic sealer" OR "root canal treatment" in studies published from January 2010 to January 2021 in English or German. The inclusion criteria were RCTs that assessed POP after RCF using the BCS filling technique in permanent teeth with pulpal and/or periapical disease. The selected studies compared the impact of BCS vs. TS on POP scores following RCF. POP scores could be reported using any self-recorded pain scale. We excluded the studies that did not compare the individual effect of endodontic sealer on the POP level; studies that additionally assessed the impact of anti-inflammatory medicines and laser applications; assessed the POP level after canal overfilling; or assessed the POP level after different root canal preparation techniques.

#### *2.3. Study Selection*

After the removal of duplicate records, the titles and abstracts of the identified studies were independently screened for eligibility by three reviewers (E.M., D.P., and M.D.F.). Consensus was achieved through discussion, where there was discordance in study selection.

#### *2.4. Data Extraction*

Three reviewers (E.M., D.P., and M.D.F.) independently extracted data from studies that met the inclusion criteria, using a standardized data collection table consisting of strings: References (title, authors, year of publication, country), study design, sample size, age/sex groups, inclusion and exclusion criteria, diagnosis, pre-op status, operator, quantity of visits, glidepath, instrumentation, irrigation protocols, obturation technique and materials, restoration, POP assessment time and scale, analgesics intake, flare-up, etc. If multiple treatment groups were presented, the data conforming to PICO were collected. Moreover, if any information was missed, the authors were contacted through personal communication via e-mail. Furthermore, if there was no response for up to 5 weeks, the study was not included in the meta-analysis.

#### *2.5. Quality Assessment*

The quality of each RCT was assessed according to the Cochrane Risk of Bias Tool. All the domains (random sequence generation, allocation concealment, performance bias, blinding of outcome, attrition bias, reporting bias) were rated as "high", "low" or "unclear" risk of bias. We set an additional risk of bias according to the "Operator" (expert endodontist: Low risk; undergraduate student: High risk). Studies were classified as overall high risk if they contained one or more domains rated as high risk; overall moderate risk if they contained no high-risk domain and one or more were judged as unclear; and overall low risk if all the domains were judged at a low risk of bias.
