DO ROOT CANAL SEALERS’ COMPOSITION INFLUENCE POSTOPERATIVE PAIN

AFTER ENDODONTIC TREATMENT OF PERMANENT TEETH? A SYSTEMATIC

REVIEW WITH META-ANALYSES

Vania Moraes, DDS, MSc Student a*; Sandra Meyfarth, DDS, MSc, PhD Student b*;
Ludmila Silva Guimarães, DDS, MSc, PhD, Post-doctoral studentb*; Guido Marañon
Vasquez, DDS, MSc, PhD, Post-doctoral studentc*; Lívia Azeredo Alves Antunes, DDS,
MSc, PhDa,b,d; Leonardo Santos Antunes, DDS, MSc, PhDa,b,d

a
Postgraduate Program, School of Dentistry, Fluminense Federal University, Nova
Friburgo, RJ, Brazil;
b
Postgraduate Program, School of Dentistry, Fluminense Federal University, Niterói,
RJ, Brazil;
c
Postgraduate Program, School of Dentistry, Rio de Janeiro Federal University, Rio de
Janeiro, RJ, Brazil;
d
Specific Formation Department, School of Dentistry of Nova Friburgo, Fluminense
Federal University, Nova Friburgo, Rio de Janeiro, Brazil.
*
Sandra Meyfarth and Vania Moraes contributed equally to this study.

Running Title: Sealers’ composition and postendodontic pain.

Correspondence author: Dr. Leonardo Santos Antunes, Department of Specific

Formation, School of Dentistry, Fluminense Federal University, Rua Doutor Silvio
Henrique Braune, 22 Centro, Nova Friburgo, Rio de Janeiro 28625-650, Brazil; Phone
number: +55 22 2528 7168; E-mail: leonardoantunes@id.uff.br

ABSTRACT
The development of pain after endodontic treatment is a frequent problem
among patients. This systematic review with meta-analyses aimed to investigate the
current evidence regarding the influence of root canal sealers’ composition and sealers
extrusion on postoperative pain after endodontic treatment. This review was registered
at PROSPERO (CRD42020211297). The eletronic search was done in the following
data bases until September 29, 2021: PubMed, Scopus, WEB of Science, Cochrane,
and Latin American and Caribbean Health Sciences (LILACS). Manual reference and
grey literature was also searched. It was only included randomized controlled trials.
Two independent reviewers performed the data extraction, risk of bias through RoB2
tool and assessed the certainty of the evidence using the GRADE approach. A
random-effect meta-analysis was performed to summarize the results of postoperative
pain. The search resulted in 2354 records, of which 12 studies met the elegiblity criteria
and were selected for the narrative analyses. Nine studies had low risk of bias, 1 study
was considered at a high risk of bias, and 2 studies were judged to be at some
concerns. It was found a total of 2 studies evaluating sealer’s extrusion, 9 studies
sealer’s composition, and 1 study sealer’s composition and extrusion on postoperative
pain. The sealer’s extrusion was analyzed in narrative way and had no influence on
pos-operative pain. The meta-analysis demonstrated that the comparative pain
intensity between AH Plus and Calcium silicate-based sealers had no significant
difference between subgroups in none of the evaluation periods reported by the studies
(CI 95%; p value < 0.05) with moderate to very low level of certainty. The meta-
analysis of comparative pain intensity between AH Plus vs ZOE and AH Plus vs
Ca(OH)2-based sealers were not perform due to the heterogenity and lack of data. The
narrative sinteses showed contrasting results for AH Plus vs ZOE-based sealers with
low to moderate certainty of evidence. For AH Plus vs Ca(OH) 2-based sealers a single
study concluded that AH Plus presented lesser postoperative pain when compared to
Apexit Plus with low level of certainty. Currently available evidences showed no
difference in postoperative pain between AH Plus and Calcium silicate-based sealers.
Due to the moderate to very low certainty of the evidence, future well-designed RCTs
should be performed to better evaluate postoperative pain and ZOE/ Ca(OH)2-based
sealers. Sealer extrusion is a variable that requires further clinical studies.

Keywords: Postoperative pain; Sealer extrusion; Sealer composition; Root canal

treatment.

INTRODUCTION
The development of pain after endodontic treatment is a recurrent problem
among patients (Seltzer and Naidorf 2004). Despite frequent, minor transient pain
immediately after endodontic treatment has no impact on patient’s quality of life. (Yu,
2012; Ng,2004; Wang, 2010; Antunes, 2018; Leong, 2020). Generally, it ranges from
mild to moderate and occurs even after optimally performed procedures (AlRahabi,
2017) Even though, pain control is still a key point of endodontic procedures. (Seltzer
and Naidorf 2004)
Postendodontic pain is multifactorial in nature (Comparin, 2017) and it can be
provoked by mechanical, chemical, or microbiological injuries to periodontal tissues
(Genet, 1987). Endodontic sealers placed into the root canals may have an effect on
the periradicular tissues either by direct contact or by percolated components into the
surrounding tissues that are released through the root canal systems. (Zhang, 2015)
which may trigger an inflammatory response increasing the risk of postoperative pain
(Siqueira 2003). The endodontic sealers are developed to be inside the root canal
system, but frequently unintentional extrusion may occur (Willershausen, 2011),
causing symptoms such as pain, hyperesthesia and paresthesia. (González-Martín,
2010) that may vary from intensity depending on the amount of extruded sealer
(Hubbe, 2016).
Dysregulated cytokines produced during inflammatory processes at local sites
are potential contributors to the development of inflammatory diseases (Cohen, 2001;
Gabay, 2006). Interleukin-6 (IL-6) and (IL-8) released have been reported to play an
important role in the root canal sealers-induced periapical inflammation (Huang, Tsai et
al. 2005; Gabay, 2006).
Therefore, this systematic review aimed to investigate the current evidence
regarding the influence of root canal sealers’ composition on postoperative pain after
endodontic treatment. The clinical question was designed according to the Population,
Intervention, Comparator, Outcome, and Study (PICOS) and should answer the
following questioning: Do root canal sealers composition influence postoperative pain
after endodontic treatment of permanent teeth?

METHODOLOGY
This systematic review with meta-analysis was written according to the
Preferred Reporting Items for Systematic Reviews and Meta-analysis statement
(PRISMA statement)(Page, 2021) and was registered on PROSPERO database by the
protocol number CRD42020211297.

Eligibility criteria
Papers should answer the following PICOS question to be included in this
review:
PICOS: Population: patients undergoing nonsurgical root canal treatment in
permanent teeth; Intervention: root canal filling with AH Plus sealer with/without
extrusion; Comparison: root canal filling with other sealers with/without extrusion;
Outcome: postoperative pain; Study design: randomized controlled trials.

Exclusion criteria
 Duplicated articles, pilot studies, literature reviews, editorial letters, book
chapters, theses, guidelines, in vitro studies, animal studies, and descriptive studies
such as case reports and case series were excluded.

Search strategy
A comprehensive electronic search was conducted to identify the available
relevant papers for this review. No date restrictions was applied. It was selected only
english studies. The following databases were consulted up to September 29, 2021:
PubMed, Scopus, WEB of Science, Cochrane, and Latin American and Caribbean
Health Sciences (LILACS). The grey literature was also searched through OpenGrey
database. The following MeSH terms were used: “root canal therapy”, “teeth,
endodontically treated”, “endodontically-treated tooth”, “root canal preparation” , “root
canal filling materials”, “endodontic obturation”, “endodontic obturations”, “root canal
obturation”, “root canal obturations”, pain”, “pain, postoperative”, “ postoperative pain”,
“hyperemia”,” toothache”, “odontalgia”. MeSH synonyms, related terms, and free terms
were also included. These key words were selected from DeCS–Health Sciences
Descriptors and from the Medical Subject Headings (MeSH) of the U.S. National
Library of Medicine. These terms were combined to refine the search results as
presented in Table 1. A manual search in the reference of the included studies was
also performed. Contacts were made with experts to identify related unpublished and
ongoing studies. The records were exported to Mendeley Reference Manager program
(Mendeley Ltd., United Kingdom, England) and, duplicates were considered just once.

Study selection
Initially, potentially relevant publications, selected by reading the title and
abstract were screened by two independent reviewers (VM and SM) previously trained
to elliminate those ones that did not fulfill the inclusion criteria. Any differences between
the two reviewers were solved by consensus with a third senior reviewer (LSA). To
evaluate agreement between authors, 10% of the publications were randomly selected
and had their classification compared, and then a kappa statistic of 0.90 was
determined. Studies without available abstracts were fully assessed for inclusion.
Articles found in more than one database were removed by the software Mendeley and
considered only once. Subsequently, the full texts of all potentially eligible studies were
accessed, and the inclusion and exclusion criteria were applied again. Any other
disagreement was discussed and solved by consensus or discussion with the senior
reviewer (LSA). In addition, the reference lists of the included studies were also hand
searched to retrieve all possible eligible papers.
Data extraction
Data from the included studies were extracted by two independent authors (VM
and SM), and organized according to the following:

1. First author, year of publication

2. Sample (sample size, gender, systemic disorders, tooth type)
3. Endodontic treatment (teeth previously accessed, irrigation, instrumentation,
number of sessions, intracanal medication, obturation technique, type of sealer)
4. Preoperative symptoms
5. Pain assessment (pain scale, period in hours, and analgesic intake)
6. Postoperative symptoms
7. Results

Quality assessment and risk of bias

The RoB2 tool was used for assessing randomized controlled trials (Sterne,
2019). Two authors (GMV and SM) assessed the RoB (Risk of Bias) of the included
studies independently and in duplicate, according to the Cochrane Collaboration’s Tool
for Assessing Risk of Bias (RoB). Disagreements over RoB were resolved by
consensus or, if necessary, adjudicated by a third author (LSA). In case where relevant
data were missing, the authors were contacted to obtain the required extra information
as advised in the Cochrane Handbook section 16.1.2 The sources of bias assessed
were: bias arising from the randomization process, bias due to deviations from
intended intervention, bias due to missing outcome data, bias in measurement of the
outcome and bias in selection of the reported result. Each domain was classified as
having low (+), high (x), or some concerns (-) risk of bias. A study was considered to
have an overall high risk of bias if judged to be at “high risk of bias” in at least one
domain for the result or judged to have “some concerns” for multiple domains in a way
that substantially lowers confidence in the result. A study was considered to have an
overall some concerns of bias if judged to be at “some concerns” in at least one
domain for the result and, finally a study was considered to have an overall low risk of
bias if judged to be at low risk of bias for all domains for this result (Sterne, 2019).

Meta-analyses
Meta-analysis was performed to combine comparable results by subgroups.
Extraction data of the mean and the standard deviation with 95% confidence interval
(CI) related to the postoperative pain between the type of sealers groups in the time
intervals of 6, 12, 24, 48, and 72 hours were performed. A random-effects model was
used for the meta-analysis. The mean differences between the sealers’ groups were
performed by using the inverse variance meta-analysis. The I 2 was used to assess
statistical heterogeneity between studies where I2 values of 25%, 50%, and 75%
indicated low, medium, and high heterogeneity, respectively (Jenatschke, 2001). The
meta-analysis calculation and forest plot creation were performed with RevMan 5.4.
Sensitivity analyses with different methods of imputation of data and subgroup
analyses were planned.

GRADE

The Grading of Recommendations Assessment, Development and Evaluation

(GRADE) system for classify the certainty of the evidence were used to ensure the
accuracy of data analysis in this systematic review. The GRADE Pro GDT software
(http://gdt.guidelinedevelopment.org) was used to summarize the results. GRADE
describes the process of rating the quality of the best available evidence and rates the
certainty of evidence. The certainty can be downgraded due to risk of bias,
inconsistency, indirectness, imprecision, and publication bias (Atkins, 2004; Balshem,
2011). The level of certainty among the identified evidence can be characterized as
very low to high. (Balshem, 2011).

RESULTS

Search and Study selection

The electronic search identified a total of 2354 studies. Of these, 288 were
duplicated and were removed by automation tool. After screening of titles and abstracts
1922 articles were excluded due to the following reasons: out of theme (n=1474), Case
report/ retrospective study/ literature reviews/ study with animals (n=448). Thirty-two
papers were potentially eligible, and had their text read in full. Three studies were
included from citation searching. A total of 12 studies were included in this systematic
review (Figure 1). Appendix 1 shows the studies excluded in the full-text analyses with
reasons.

Quality assessment and risk of bias

Risk of bias of the selected articles were evaluated using the Rob2 tool (Sterne,
2019). Nine studies had low risk of bias (Drummond, 2021; Shim, 2021; Tan, 2021;
Cunha, 2020; Aslan, 2020; Ferreira, 2020; Ambiga, 2020; Fonseca, 2019; Atav, 2018,
Graunaite, 2018), 1 study was considered at a high risk of bias due to bias in the
randomization process and due to deviations from the intended interventions (Paz,
2018), and 2 studies were judged to be at some concerns due to bias arising from the
randomization process, since the authors did not inform how it was performed (Shim,
2021; Gudlavalleti, 2020). Details regarding downgrading are provided in Figure 2. The
most frequent domain causing downgrading was bias due to randomization process
and bias due to deviations from intended intervention. No study had attrition bias
because of missing outcome data measurement of the outcome, and selection of the
reported results.

Narrative analysis

Data extraction from the selected articles is described in Table 2 and Table 3.
A total of 12 studies evaluated the effect of the sealer’s composition on post endodontic
pain (Ambiga, 2018; Paz, 2018; Graunaite, 2018; Atav, 2018; Fonseca, 2019; Aslan,
2020; Ferreira, 2020; Gudlavalleti, 2020;Tan, 2021; Shim, 2021; Drummond, 2021) A
total of 2 studies evaluated sealer’s extrusion and postoperative pain (Fonseca, 2019;
Drummond, 2021), 9 studies assessed sealer’s composition and pain (Ambiga, 2018;
Paz, 2018; Graunaite, 2018; Aslan, 2020; Ferreira, 2020; Gudlavalleti, 2020; Cunha,
2020; Tan, 2021; Shim, 2021) and, 1 study assessed sealer’s composition and
extrusion on post-endodontic pain (Atav, 2018)
One study used single-rooted teeth (Fonseca, 2019), 4 studies multi-rooted
teeth (Aslan, 2020; Gudlavalleti, 2020; Cunha, 2020; Drummond, 2021), 5 studies
multi-rooted and single-rooted teeth (Atav, 2018; Graunaite, 2018; Ferreira, 2020; Tan,
2021; Shim, 2021), and, 2 studies did not inform the type of teeth (Paz, 2018; Ambiga,
2018). The average number of teeth per study was 111,5 with a minimum of 30 and a
maximum of 330.

Regarding the irrigation solution, 10 studies (Atav, 2018; Graunaite, 2018; Paz,
2018; Fonseca, 2019; Aslan, 2020; Gudlavalleti, 2020; Ferreira, 2020; Cunha, 2020;
Tan, 2021; Shim, 2021) used sodium hypochlorite as an auxiliary chemical, varying
only in the concentration (from 1,5% to 5%), 1 study did not inform the irrigation
solution used (Ambiga, 2018) and, 1 study used 2% chlorhexidine gel with saline
solution as irrigant. (Drummond, 2021)
 Concerning the number of sessions, 7 studies were carried out in a single
session (Atav, 2018; Graunaite, 2018; Ambiga, 2018; Fonseca, 2019; Aslan, 2020;
Gudlavalleti, 2020; Drummond, 2021), and 5 studies in one or more sessions (Paz,
2018; Ferreira, 2020; Cunha, 2020; Tan, 2021; Shim, 2021).

Postoperative pain was assessed by all studies of which 6 studies evaluated

postoperative symptoms through a visual analogue scale (VAS) (no, mild, moderate,
and severe pain) (Aslan, 2020; Fonseca, 2019; Graunaite, 2018; Gudlavalleti, 2020;
Ambiga, 2018; Shim, 2021), 1 study used a modified VAS form (no, slight, moderate,
severe pain) (Paz, 2018), 1 study used a descriptive scale (no, slight, moderate, severe
pain) (Ferreira, 2020), 1 study used Likert Scale (no pain; very mild pain; severe pain)
(Tan, 2021), 1 study used a modified visual rating scale (Drummond, 2021), 1 study did
not use a scale, evaluating pain as present or absent (Cunha, 2020) and, 1 study used
Huskisson VAS form to assess pain (Atav, 2018).

Six studies did not inform if any patients took analgesics (Drummond, 2021;
Shim, 2021; Cunha, 2020; Gudlavalleti, 2020; Ambiga, 2018; Paz, 2018). Only 2
studies (Atav, 2018; Aslan, 2020) assessed NSAID intake at 6 and 12 hours after the
procedure. Analgesic intake was higher in the first 6 hours in the two studies. In both
time intervals, there were no statistical differences in the analgesic intake between
groups. Six eligible studies (Atav, 2018; Aslan, 2020; Fonseca, 2019; Graunaite, 2018;
Ferreira, 2020; Tan, 2021) assessed NSAID intake 24 hours after endodontic
treatment. There were no statistical differences in the analgesic intake for any of the
groups in all of them. At 48 hours, 2 studies (Ferreira, 2020; Aslan, 2020) reported that
very few patients took analgesics, but with no differences among groups. The same
was observed at 72 hours, in which 2 studies (Atav, 2018; Tan, 2021) reported very
few analgesic intakes with no differences among groups.

When evaluating sealers’ composition, 7 studies compared pain intensity

between AH Plus (Dentsply Maillefer, Konstanz, Germany) and calcium silicate-based
sealers and, found no statistically significant difference between the groups regarding
the level of pain (Aslan 2020; Atav, 2018; Ferreira, 2020; Graunaite, 2018; Cunha,
2020; Tan, 2021; Shim, 2021). On the other hand, 2 studies found statistically
significant differences in post-operative pain intensity between groups (Paz, 2018;
Ambiga, 2018). Paz et al reported that AH Plus sealer group referred post-operative
pain less frequently than Bioroot sealer (Septodont, SaintMaur-des-Fosses, France)
group. However, Ambiga et al reported that AH Plus presented more postoperative
pain when compared to MTA Fillapex (Angelus, Londrina, Brazil) and Endo Sequence
BC (Brasseler, Savannah, GA, USA) sealers during all time intervals.
 Regarding the studies that compared pain intensity between AH Plus and Zinc
oxide and eugenol based sealers (ZOE) (Ferreira, 2019; Gudlavaletti, 2020), Ferreira
et al found no significant differences between AH Plus and Endofill (Dentisply,
Petrópolis, Brazil). Contrastingly, Gudlavalleti et al concluded that AH Plus presented
lesser postoperative pain when compared to Tubliseal (SybronEndo, Glendora, CA,
USA).

The single study that compared pain intensity between AH Plus and Calcium
hidroxyde based sealers (Ca(OH)2) (Gudlavaletti, 2020) concluded that AH Plus
presented lesser postoperative pain when compared to Apexit Plus (Ivoclar, Vivadent,
De Trey, Germany.

The studies that evaluated sealer’s composition with extrusion and

postoperative pain (Atav, 2018; Fonseca, 2019; Drummond, 2021) showed no
association between the extrusion and the occurrence of pain. Atav et al showed that
AH Plus had more extrusion than iRoot SP (Innovative BioCeramix Inc., Canada), but
there was no association between extrusion of root canal sealer-pain intensity and
analgesic intake. Fonseca et al found that despite Sealer Plus BC (MK Life, Porto
Alegre, RS, Brazil) had presented a significantly incidence of extrusion than AH Plus,
their findings showed no association with sealer extrusion and pain. Drummond et al
found that the occurrence of unintentional apical extrusion of AH Plus sealer presented
similar postoperative pain results compared with EndoSequence BC (Brasseler,
Savannah, GA, USA) and Bio-C Sealers (Angelus, Londrina, PA, Brazil).

Meta-analyses

Homogeneous data from the included studies in the narrative analysis were
compared through the meta-analysis.

Two eligible studies were excluded from the analyses (Aslan, 2020; Cunha,
2020). The study of Aslan et al was not possible to extract data. The corresponding
author was contacted by email, but missing data was not provided. The other study
reported the total number of patients that developed pain after endodontic treatment as
present or absent, and did not inform by the sealers group. (Cunha, 2020).

The meta-analysis that assessed the intensity of pain between AH Plus and
Calcium Silicate-based sealers (Atav, 2018; Graunaite, 2018; Fonseca, 2019;
Drumond, 2021; Shim, 2021) that included continuous data showed no significant
difference in mean pain intensity among patients at 6 hours (MD: -0.16; 95% CI =
-0.96, 0.64; p = 0.70; I2= 0%), 12 hours (MD: 0.10; 95% CI = -0.63, 0.82; p = 0.79; I 2=
0%), 24 hours (MD: -0.05; 95% CI = -0.13, 0.03; p = 0.19; I 2= 0%), 48 hours (MD: 0.19;
95% CI = -0.04, 0.42; p = 0.10; I2= 35%), and 72 hours (MD: -0.00; 95% CI = -0.00,
0.00; p = 0.69; I2= 0%) (Figure 3).

The meta-analyses of the studies that included binary data (Ambiga, 2018; Paz,
2018; Ferreira, 2020; Tan, 2020) found no statistically significant difference in pain
intensity among patients who were treated with different types of sealers in none of the
reported periods: 24 hours (RR: 1.14 95% CI = 0.45, 2.89, p = 0.78), 48 hours (RR:
0.29 95% CI = 0.07, 1.25, p = 0.10) and, 72 hours (RR: 1.03 95% CI = 0.36, 2.93, p =
0.96). The subgroups tests showed that the size-effect between AH Plus and Calcium
Silicate-based sealers were the same at 24, 48 and, 72 hours (p=0.27) (Figure 4).It is
important to highlight that the study

Regarding the studies that compare pain intensity between AH Plus and ZOE-
based sealers (Ferreira, 2019; Gudlavaletti, 2020), the meta-analysis could not be
performed, because the studies reported their outcomes in different ways.

The meta-analysis to assess the intensity of pain between AH Plus and

Ca(OH)2-based sealers could not be performed, because only 1 study presented data.
(Gudlavaletti, 2020)

It is important to highlight that the study of Atav et al also evaluated devital teeth
with AH Plus and iRoot SP sealers, Paz et al assessed teeth with AH Plus and two
different obturation techniques, and Shim et al evaluated AH Plus and Endoseal MTA
in multirooted teeth.Therefore, additional meta-analyses were performed including
those data, but no statistical difference was observed. (Appendix 2 and 3)

Evidence synthesis (GRADE)

The overall certainty varied from moderate to very low to all the synthesis. All
analyses were downgraded due to imprecision (low number of participants) and some,
due to risk of bias (Table 4).
For each outcome the analyses of certainty of evidence were performed based
on the time intervals investigated.
For the imprecision (pain intensity), we used a threshold of 1 point in the 10-
point VAS (Bodian, 2001; Dawdy, 2017) and 400 as a minimum sample.
Regarding the synthesis performed between AH-Plus vs ZOE-based sealers
most of them were affected by risk of bias and all were affected by imprecision.
 The synthesis of the continuous data between AH-Plus vs Calcium silicate-
based sealers only in the time intervals 96, 120, 144 and, 168 hours were downgraded
due to risk of bias. All the synthesis were affected by imprecision. The synthesis of the
binary data all the outcomes were downgraded due to imprecison and only the time
interval of 168 hours were not affected by risk of bias.
The analyses of certainty of evidence performed between AH-Plus vs Ca(OH) 2-
based sealers were downgraded due to imprecision and risk of bias in all time intervals
investigated.

DISCUSSION

Many patients still see the endodontic treatment with fear and anxiety (Virdee
2016) due to the development of pain after this procedure (Seltzer and Naidorf 2004).
Postoperative pain rate may vary from 3 to 69.3% after root canal treatment (Sathorn,
Parashos et al. 2008) (AlRahabi 2017) The literature suggests several factors as
etiology of postoperative pain, such as apical sealer extrusion (Seltzer and Naidorf
2004 ;Peng, 2007; Alonso-Ezpeleta, 2012), and sealers’ composition (Zhang and Peng
2015).
Two systematic reviews (Sponchiado Jr.; Mekhdieva, 2021) evaluated calcium
silicate-based and epoxy resin-based sealers regarding the risk and intensity of
postoperative pain. Both studies presented contrasting results. Sponchiado Jr et al had
shown no statistical difference between these two sealers’ composition and
postoperative pain. However, the small number of articles retrieved and participants
included in the meta-analyses limited the body of the evidence. Mekhdieva, 2021 et al
concluded that calcium silicate-based was associated with significantly lower post-
operative pain as compared to epoxy resin-based sealers. This study presented as
limitation the absence of GRADE performance for classify the certainty of the evidence
to ensure the accuracy of data analysis of the selected studies.
There is a wide variety of root canal sealers in the market. ZOE-based, calcium-
hydroxide-based and, resin-based sealers are currently used. Bioceramic sealers were
recently launched. Therefore, this systematic review aimed to investigate the current
scientific evidence regarding the influence of all available root canal sealers’
composition with or without extrusion on postoperative pain after root canal obturation.
In this review, a total of 12 studies were included. Most of them focused on the
influence of the sealers’ composition on postoperative pain. (Ambiga, 2018; Paz, 2018;
Graunaite, 2018; Atav, 2018; Aslan, 2020; Ferreira, 2020; Gudlavalleti, 2020; Cunha,
2020; Shim, 2021), whereas only 3 assessed the effect of sealers extrusion on post-
endodontic pain (Atav, 2018; Fonseca, 2019; Drumond, 2021).
Randomized control trials are considered the golden standard among all the
investigations methods, as they are capable to produce direct scientific evidence with
less probability of error for clarifying a cause-effect relationship between two events.
Despite of that, they are not free of bias. (Pereira, 2008) The Cochrane Collaboration
tool allows a careful evaluation of the clinical studies. In terms of quality assessment, 9
studies had low risk of bias (Atav, 2018; Ambiga, 2018; Ferreira, 2020; Aslan, 2020;
Fonseca, 2019; Graunaite, 2018; Cunha, 2020; Tan, 2021; Drummond, 2021), 2
studies were judged to be at some concerns in at least one domain (Gudlavalleti, 2020;
Shim, 2021) and, 1 study was considered at a high risk of bias. (Paz, 2018).
A correct randomization process ensures that no pattern will exist between the
assignment of subjects into groups and any characteristics of those subjects. Every
subject will as likely as any other to be assigned to the treatment (or control) group.
Allocation concealment is also important so that the operator cannot identify which
group the patient will be placed into. In relation to the selection bias, 3 studies
presented unclear randomization process and allocation concealment was not informed
(Paz, 2018; Gudlavalleti, 2020; Shim, 2021). There was no attrition bias due to missing
data. Some authors acknowledged the missing data and reported the reasons;
however, there was not a substantial loss of study participants without imbalanced
attrition between the groups.
Another relevant aspect of quality assessment is blinding of participants,
personnel, operator and, examiner in relation to the treatment and outcome
assessment avoiding performance bias (Ammari, 2014). Blinding of participants and
personnel was done by 10 studies (Atav, Aslan, Ferreira, Fonseca, Graunaite,
Sigadam, Drumond, Shim, Tan, Cunha). Blinding of the operator was not performed in
all the studies, due to the color and consistency of the sealers. However, being aware
that the blindness of the operator is not always possible, examiner masking should be
considered a minimum. (Ammari, 2014). The outcome assessment was done blindly by
4 studies (Atav; Sigadam, Cunha, Drummond, Tan). Selective reporting was done by
all the studies so all the authors reported their limitations.
Post endodontic pain is a major issue in daily clinical practice. Its control is still
a key point of endodontic procedures. Some pain-causing conditions can be attributed
to endodontic factors (Siqueira, 2002), while others can be due to non-endodontic
causes. (Silva Borges, 2017) Nevertheless, all these aspects may influence the
intensity and duration of postoperative pain. The individual results of the eligible studies
showed no association between cases of sealer extrusion and the occurrence and
intensity of postoperative pain (Atav, 2018; Fonseca, 2019; Drummond, 2021). In all
the studies of this systematic review, there was not a significant amount of sealer
extruded. When slight extrusion occurs, the treatment outcome is not significantly
affected by the type of sealer. (Riccuci, 1998) The larger the volume of extruded sealer,
the larger the surface of contact between the filling material and the tissue, increasing
the intensity of chemical damage to the periradicular tissues and the risk of pain.
(Siqueira, 2005) Another issue that must be pointed out is that in the methodology of
the selected articles that assessed postendodontic pain and apical sealer extrusion,
there was no control group (no sealer extrusion). Therefore, this design cannot
determine that any deviation in results from the treatment group is indeed a direct
result of the variable. Thus, sealer extrusion is a variable that requires further clinical
studies.
Regarding sealers’ composition, AH Plus (Dentsply, De Trey, Konstanz,
Germany) was chosen as the control group. AH-Plus is a resin-based sealer and
represents the gold standard in clinical practice and is the reference material for other
types of sealers in in vitro and in vivo studies. (Geethapriya, 2019)
Usually, the biocompatibility of materials is evaluated by ex vivo cytotoxicity and
in vivo implantation techniques. (Geurtsen, 2001; Zmener, 2004) Some in vitro studies
showed conflicting results on biocompatibility. (Zang, 2010; Rodríguez-Lozano, 2017;
Loushine, 2011) Nonetheless, these results should be interpreted with caution. The
meta-analysis is a useful statistical tool for linking data from individual studies and
increases the statistical precision and accuracy of effect estimates analysis. (Silva
Borges, 2017) The results of our meta-analysis between AH Plus vs Calcium silicate-
based sealers confirmed the results of the selected studies in which there was no
statistical differences in pain intensity between the groups in any time interval. The
contrasting results between the in vitro studies and our meta-analyses can be
attributed to the fact that except for the paraformaldehyde-containing materials, most of
the contemporary root canal sealers are either biocompatible or show cytotoxicity only
prior to setting. (Siqueira, 2005) which may not be enough to develop an intense
inflammatory reaction. This may justify the nonclinical relevance in terms of
postoperative pain presented by patients.
Regarding the studies that compare pain intensity between AH Plus vs ZOE-
based and AH Plus vs Ca(OH)2-based sealers a meta-analyses could not be
performed. The individual results of the elegible studies that assessed AH Plus vs
ZOE-based sealers presented constrasting results. Gudlavalleti et al concluded that AH
Plus presented lesser post-therapy pain when compared to Tubliseal, while Ferreira et
al found no significant difference between AH Plus and Endofill sealer. In relation to AH
Plus vs Ca(OH)2-based sealers only one study was retrieved and showed that AH Plus
presented lesser post-therapy pain when compared to Apexit-Plus. Thus, further RCTs
evaluating post-endodontic pain using ZOE-based and Ca(OH)2-based sealers should
be performed.
Previous studies showed that the NSAIDs intake after endodontic treatment has
a significant effect on reducing postoperative pain. (Morse et al. 1990, Mehrvarzfar et
al. 2012). The studies included in this systematic review reported that the
analgesics/anti-inflammatory consumption was low with no statistical difference
between groups with regard to the pain level and analgesics intake. No significant
difference in analgesic consumption may be indicative of the fact that despite the
occurrence of postoperative pain, it may not be clinically relevant.
Despite this systematic review follows a rigorous methodology and attempt to
reduce all biases and errors by following strict criteria, the findings of this review should
be viewed considering some limitations. Although all efforts were made to retrieve all
relevant studies, publication bias could not be ruled out. Besides, unclear risk of bias
for some of the included studies could not be verified because of authors’ non-
response.

CONCLUSIONS

The quality of evidence available to support a relationship between root canal

sealers’ composition and postoperative pain varied from moderate to very low.
Currently available evidence has shown no significant difference between AH-Plus and
Calcium silicate-based sealers and the occurrence of postoperative pain. Further
randomized clinical trials with high methodological evidence are needed to assess
postoperative pain with others sealers’ composition. Sealer extrusion is also a variable
that requires further clinical studies. Future well-designed RCTs should be performed
to evaluate the influence of sealers extrusion on postoperative pain using a
comparative group without sealer extrusion.

CONFLICT OF INTEREST
The authors deny any conflicts of interest related to this study.

ACKNOWLEDGMENTS

Vania Moraes and Sandra Meyfarth contributed equally to this study. Vania
Moraes has a CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico)
scholarship. The work was supported by individual scholarships (FAPERJ –Fundação
de Amparo à Pesquisa do Estado do Rio de Janeiro (#E-26/010.100995/2018; #E-
26/202.805/2019; #E-26/010.002195/2019) and (CNPq – Conselho Nacional de
Desenvolvimento Científico e Tecnológico).

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TABLE 1 – Electronic Databases and Search Strategy
TABLE 2 – Evidence table summarizing the characteristics of the included studies
Sample Endodontic treatment
Author Sample Gender Systemic Tooth Tooth Previous Irrigation Instrumentation N° of Medication Obturation Sealers Pre
Year size disorders diagnosis type access solution sessions technique operative
symptom

Ambiga, S. 90 NI No NI NI No NI NI 1 No NI *Endosequence NI
(2018) BC
* MTA
*AH Plus
Paz, A. 30 NI NI Asymptomatic NI No 2.5% NaOCl ProTaper Next 1 or 2 NI Cold lateral * BioRoot RCS NI
(2018) irreversible condensation * AH Plus
pulpitis

Graunaite, I. 61 25 No Asymptomatic Single Yes 2% NaOCl ProTaper Gold 1 No Warm *AH Plus No
(2018) males apical /multi- vertical *Total Fill BC
36 periodontitis rooted condensation
females
Atav, A. 160 67 No Pulp necrosis Single No 2.5% NaOCl One Shape 1 No Herofill™ * iRoot SP Yes
(2018) males and vital /multi- Soft-Core *Innovative
89 teeth rooted obturator BioCeramix
females * AH Plus

Fonseca, B. 64 26 No Pulp necrosis Single No 2.5% NaOCl Reciproc VDW 1 No Single cone *AH Plus No
(2019) males rooted *Sealer
38 Plus BC
females
Aslan, T. 96 34 NI Asymptomatic Multi- No 5% NaOCl Reciproc VDW 1 No Single cone *AH Plus No
(2020) males irreversible rooted *Endoseal MTA
50 pulpitis *Endosequence
females BC

Ferreira, 60 19 No Pulp necrosis Single No 2.5% NaOCl Wave One Gold 2 Ca (OH)2 Single cone *AH Plus No
N.S. males /multi- and vertical *EndoFill
(2020) 41 rooted compaction *MTA Fillapex
females technique

Gudlavalleti, 99 45 No Chronic Multi- No 3% NaOCl Protaper 1 No Cold lateral *Tubli-Seal Yes

B. males irreversible rooted Universal condensation EWT
(2020) 54 pulpitis *Apexit Plus
females *AH Plus
 Cunha, S.A. 69 33 No Symptomatic Multi- No 2.5% NaOCl Protaper Next 2 to 4 Ca (OH)2 Single cone + *AH Plus Yes
(2020) males irreversible rooted accessory *Sealer 26
27 pulpitis and cones
females pulp necrosis

Tan, H.S.G. 171 76 No Pulp necrosis Single Yes 1,25% NaOCl Rotatory files 1 or Ca (OH)2 Single cone *AH Plus Yes
(2020) males and vital /multi- more and Warm *TotalFill BC
87 teeth rooted vertical
females Compaction

Shim, K. 108 36 No NI Single No 2.5% NaOCl Protaper Next 2 to 4 NI Single cone *AH Plus Yes
(2021) males /multi- and *Endoseal MTA
31 rooted Continuous
females wave

Drummond, 330 36 No Asymptomatic Multi- No 2% Wave One Gold 1 No Single cone *AH Plus No
J.P.S.C. males irreversible rooted chlorhexidin and Warm *BC Sealer
(2021) 31 pulpitis e gel vertical *Bio-C Sealer
females Compaction
NI= not informed
TABLE 3 - Summary of the parameters and results collected for each study
Pain assessment
Author Pain scale Period Analgesic Postoperative Results
Year (hours) intake symptoms
Ambiga VAS 24, 72, 120, NI Pain None of the patient reported postoperative pain after 3rd day. No patient reported severe pain at any time interval.
(2018) 168 Postoperative pain during the 1h and 1, 3 days intervals was significantly different (p <0.05) between groups.

Paz Modified VAS 24, 48, 72, Ibuprofen Pain Bioceramic referred post-operative pain more frequently than resin sealer. There were statistically significant differences
(2018) 96, 120, 144, 600 mg in post-operative pain intensity only between Day 1 and Day 6 and between Day 1 and Day 7 (p = 0.002) respectively.
168

Graunaite VAS 24, 48, 72, Nonsteroid Pain There was no statistically significant difference between the tested root canal sealers regarding postoperative pain at any
(2018) 168 analgesics time points assessed (P > .05).

Atav Huskisson VAS 6, 12, 24, 72 Ibuprofen Pain There was no significant difference between groups in the incidence of postoperative pain; however, iRoot SP sealer was
(2018) 200 mg associated with less analgesic intake compared to AH Plus sealer. No correlation between sealer extrusion-pain intensity
and analgesic intake.

Fonseca (2019) VAS 24, 48, 72 Ibuprofen Pain No statistically significant difference between the groups with regard to pain level and intake of analgesics (p > 0.05).
600 mg Sealer Plus BC presented a statistically significant more extrusion (59.37%) than AH Plus (28.12%). Sealer extrusion was not
associated with pain.

Aslan VAS 6, 12, 24, 48 Ibuprofen Pain There were no significant differences among the groups in terms of postoperative pain at any time points assessed
(2020) 400 mg (P>0.05) nor for analgesic intake of patients among the groups (P>0.05).

Ferreira Descriptive 24, 48, 168 Ibuprofen Pain No significant differences were detected among the groups in terms of either incidence or intensity of postoperative pain,
(2020) 600 mg or need for analgesic intake, at any time point (p>0.05).

Gudlavalleti VAS 8, 24, 48 Ibuprofen Pain There was statistically significant difference seen in all three groups (p=0.0001) at all the time points (8h, 24h and 48h).
(2020) 200 mg
Tan Ibuprofen* Pain There was no significant difference in pain experience between teeth filled using AH Plus or TotalFill BC Sealer 1, 3, and 7
(2020) Likert 24, 72, 168 days after obturation.

Cunha (2020) NI + NI Pain No effect of sealer composition was observed. Apical repair incidences and asymptomatic teeth were, respectively, 90.5
and 89.3, 96.8 and 90.0% during 1 and 2 years of follow-up.
Shim (2021) VAS 24, 48, 72, NI Pain Endoseal MTA and AH Plus had equivalent effects on postoperative pain incidence and intensity.
96, 120, 144,
168
Drumond Modified VRS 6, 12, 24, 48, Acetaminoph Pain The occurrence of unintentional apical extrusion of calcium silicate–based root canal sealers present similar postoperative
(2021) 168 en 500 mg pain results compared with resin-based sealers with low-intensity pain.
NI= not informed; + period of 1 and 2 years.
TABLE 4: GRADE – Quality of evidence and strength of recommendations of the selected studies

N° of participants or Absolute or relative effects Overall

Certainty assessment    
Events/total (95% CI) certainty
N° of Study Risk of Indirectnes Other
Inconsistency Imprecision   Intervention Comparator  
datasets design bias s considerations
AH-Plus vs. ZOE-based (8 hours)
⊕⊕◯◯
1 RCT Seriousa Not serious Not serious Seriousb None 33 33 No difference between groups*
LOW
AH-Plus vs. ZOE-based (24 hours)
⊕⊕◯◯
2 RCT Seriousa Not serious Not serious Seriousb None 53 53 No difference between groups*
LOW
AH-Plus vs. ZOE-based (48 hours)
⊕⊕◯◯
2 RCT Seriousa Not serious Not serious Seriousb None 53 53 No difference between groups*
LOW
AH-Plus vs. ZOE-based (72 hours)
⊕⊕⊕◯
1 RCT Not serious Not serious Not serious Seriousb None 20 20 No difference between groups*
    MODERATE
AH-Plus vs. Calcium silicate-based (6 hours) - Continuous data
No difference between groups ⊕⊕⊕◯
2 RCT Not serious Not serious Not serious Seriousb None 52 52
MD: -0.16 [-0.96, 0.64] MODERATE
AH-Plus vs. Calcium silicate-based (8 hours) - Continuous data
⊕⊕⊕◯
1 RCT Not serious Not serious Not serious Seriousb None 13 13 No difference between groups*
MODERATE
AH-Plus vs. Calcium silicate-based (12 hours) - Continuous data
No difference between groups ⊕⊕⊕◯
2 RCT Not serious Not serious Not serious Seriousb None 52 52
MD: 0.10 [-0.63, 0.82] MODERATE
AH-Plus vs. Calcium silicate-based (24 hours) - Continuous data
Not No difference between groups ⊕⊕⊕◯
5 RCT Not serious Not serious Seriousb None 156 158
serious† MD: -0.05 [-0.13, 0.03] MODERATE
AH-Plus vs. Calcium silicate-based (48 hours) - Continuous data
No difference between groups ⊕⊕⊕◯
2 RCT Not serious Not serious¥ Not serious Seriousb None 89 89
MD: 0.19 [-0.04, 0.42] MODERATE
AH-Plus vs. Calcium silicate-based (72 hours) - Continuous data
Not No difference between groups ⊕⊕⊕◯
2 RCT Not serious Not serious Seriousb None 54 56
serious† MD: 0.00 [-0.00, 0.00] MODERATE
AH-Plus vs. Calcium silicate-based (96 hours) - Continuous data
1 RCT Seriousa Not serious Not serious Seriousb None 15 17 No difference between groups* ⊕⊕◯◯
 LOW
AH-Plus vs. Calcium silicate-based (120 hours) - Continuous data
⊕⊕◯◯
1 RCT Seriousa Not serious Not serious Seriousb None 15 17 No difference between groups*
LOW
AH-Plus vs. Calcium silicate-based (144 hours) - Continuous data
⊕⊕◯◯
1 RCT Seriousa Not serious Not serious Seriousb None 15 17 No difference between groups*
LOW
AH-Plus vs. Calcium silicate-based (168 hours) - Continuous data
⊕⊕◯◯
2 RCT Seriousa Not serious Not serious Seriousb None 28 30 No difference between groups*
    LOW
AH-Plus vs. Calcium silicate-based (24 hours) - Binary data
No difference between groups ⊕◯◯◯
4 RCT Seriousa Serious c Not serious Seriousb None 37/143 30/140
RR: 1.14 [0.45, 2.89] VERY LOW
AH-Plus vs. Calcium silicate-based (48 hours) - Binary data
No difference between groups ⊕⊕◯◯
2 RCT Seriousa Not serious Not serious Seriousb None 2/30 7/30
RR: 0.29 [0.07, 1.25] LOW
AH-Plus vs. Calcium silicate-based (72 hours) - Binary data
No difference between groups ⊕⊕◯◯
3 RCT Seriousa Not serious Not serious Seriousb None 13/123 12/120
RR: 1.03 [0.36, 2.93] LOW
AH-Plus vs. Calcium silicate-based (168 hours) - Binary data
⊕⊕⊕◯
2 RCT Not serious Not serious Not serious Seriousb None 3/103 6/100 No difference between groups*
    MODERATE
AH-Plus vs. Ca(OH)2-based (8 hours) - Continuous data
⊕⊕◯◯
1 RCT Seriousa Not serious Not serious Seriousb None 33 33 No difference between groups*
LOW
AH-Plus vs. Ca(OH)2-based (24 hours) - Continuous data
⊕⊕◯◯
1 RCT Seriousa Not serious Not serious Seriousb None 33 33 No difference between groups*
LOW
AH-Plus vs. Ca(OH)2-based (48 hours) - Continuous data
⊕⊕◯◯
1 RCT Seriousa Not serious Not serious Seriousb None 33 33 No difference between groups*
    LOW
CI, confidence interval; MD, mean difference; RR, relative risk

a. Datasets provide results with risk of bias for some criteria, and likely to seriously alter the results.

b. Limited amount of data included in the synthesis (number of subjects evaluated less than the threshold suggested by GRADE of 400).

c. I2 value greater than 50% (P<0.05).

† The subgroup test showed that the study with a high risk of bias did not affect the direction or significance of the effect; therefore, it was kept in the synthesis and it was considered that the evidence was not affected
for this topic.
¥ Since the imprecision item would be affected anyway, it was opted to exclude the study by Shim et al. and to make the evidence more consistent.
FIGURE 1- PRISMA flowchart of the manuscripts screened through the review process
FIGURE 2 - Quality assessment of selected studies (the Cochrane Collaboration tool
for assessing risk of bias – RoB2).
FIGURE 3: Forest plots of postoperative pain between AH Plus vs Calcium silicate-
based sealers groups (6, 12, 24, 48, and 72 hours). CI, confidence interval; SD,
standard deviation.
FIGURE 4: Forest plots of the relative risk (RR) for postoperative pain between AH
Plus vs Calcium silicate-based sealers groups (24, 48, and 72 hours).
APPENDIX 1: Studies excluded in the full-text analyses with reasons

Author, year Reason for exclusion Indexing in databases (DOI)/ INSS

1 Thakur, 2013 No RCTs 10.4103/0972-0707.120944
2 Shashirekha, 2018 10.4103/JCD.JCD_224_18
3 Yu, 2021 10.1007/s00784-021-03814-x
4 Alacam, 1985 AH-Plus not tested 10.1016/S0099-2399(85)80233-8
5 Goreva, 2004 15111950
6 Sadaf, 2014 25598754
7 Sharma, 2019 23952822
8 Javidi, 2020 10.30476/DENTJODS.2020.83231.1041
9 Nabi, 2020 15509702
10 Sadaf, 2021 10.9734/jpri/2021/v33i42A32418
11 NCT04935736 -
12 NCT03874949 -
13 Wang, 2003 No english version 10067248
14 Chen, 2006 16718852
15 Tang, 2009 10.3969/j.issn.1673-8225-2009.29.040
16 Xu, 2013 10.3724/SP.J.1008.2013.01029
17 Shu, 2018 10.19439/j.sjos.2018.06.017
18 CTRI / 2021/04/032815 Not finished -
19 NCT03732170 -
20 CTRI/2019/02/017745 -
21 CTRI/2018/10/015919 -
22 NCT04228913 No author reply -
23 NCT02981693 -
APPENDIX 2: Forest plots of postoperative pain between AH Plus vs Calcium silicate-
based sealers groups (6, 12, 24, 48, and 72 hours). CI, confidence interval; SD,
standard deviation.
APPENDIX 3: Forest plots of the relative risk (RR) for postoperative pain between AH
Plus vs Calcium silicate-based sealers groups (24, 48, and 72 hours)