Accepted Article

PROF. SUZAN ABDUL WANEES AMIN (Orcid ID : 0000-0002-6229-9277)

Article type : Original Scientific Article

Postoperative pain on endodontic irrigation using 1.3% versus 5.25% sodium hypochlorite in
mandibular molars with necrotic pulps: A randomized double-blind clinical trial

M E H A A Mostafa, Y A I El-Shrief, W I O Anous, M W Hassan, F T A Salamah, R M El Boghdadi, M A A

El-Bayoumi, R M Seyam, K G Abd-El-Kader, S A W Amin

Department of Endodontics, Faculty of Dentistry, Cairo University, Cairo, Egypt

Running Title: NaOCl Concentration and Postendodontic Pain

Keywords: Analgesic intake; irrigation; non-vital pulp; postendodontic pain; randomized clinical trial;
sodium hypochlorite.

Corresponding author:
Suzan Abdul Wanees Amin, BDS, MSc, PhD
Department of Endodontics, Faculty of Dentistry, Cairo University, 11 ElSaraya Str., ElManyal, Cairo,
11553, Egypt
E-mail: suzan.wanis@dentistry.cu.edu.eg.

This article has been accepted for publication and undergone full peer review but has not been through the
copyediting, typesetting, pagination and proofreading process, which may lead to differences between this
version and the Version of Record. Please cite this article as doi: 10.1111/IEJ.13222

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 Abstract
Accepted Article
Aim This randomized, prospective, double-blind, clinical trial assessed the effect of 1.3% and 5.25%
sodium hypochlorite (NaOCl) as irrigants on postendodontic pain and medication intake following root canal
treatment of mandibular molars with non-vital pulps.
Methodology Three hundred and eight patients, each with one symptomatic or asymptomatic molar, were
randomly assigned, using the permuted-block method, into two equal groups according to NaOCl
concentration: 1.3% or 5.25% (n=154). For both groups, syringe irrigation was performed using a 27-gauge
needle advanced into the canal to a depth of 3mm from the working length; 3 mL were used between every
2 consecutive instruments. All root canal treatments were carried out in two visits, with no intracanal
medication, by trained postgraduate students. The canals were prepared using the Protaper Universal
rotary system during the first visit. In the second visit 7days later, the same irrigant per group was used and
the canal walls were reprepared with the final instrument before filling the canal using the modified single-
cone technique with an epoxy resin-based sealer. Patients assessed their postoperative pain using the 0-
10 numerical rating scale (NRS) immediately after instrumentation, 3h, 24h, 48h and 7d after the first visit
and immediately following root canal filling. The incidence of rescue-medication intake (Sham or analgesic)
was, also, recorded; patients received a sham capsule to be used first, but, if pain persisted, an analgesic
was prescribed. Outcome data were analysed using Mann-Whitney U-test, Friedman’s test, Wilcoxon’s
rank test and Chi2 (χ2) test. Relative risk reduction (RRR) and its 95% confidence interval (CI) were
calculated for binary data.
Results The incidence and intensity of postoperative pain was significantly lower with 1.3% NaOCl than
5.25% NaOCl at all timepoints (p<0.05). Postoperative-pain intensity exceeded preoperative pain at 3h and
24h with 5.25% NaOCl only (p<0.05). The relative risk reduction in pain incidence was 38% (95% CI: 17%,
54%) immediately after instrumentation, 41% (95% CI: 31%, 49%) at 3h, 42% (95% CI: 32%, 51%) at 24h,
59% (95% CI: 45%, 69%) at 48h, 62% (95% CI: 27%, 80%) at 7d and 81% (95% CI: 68%, 89%) post root
filling. RRR was 38% (95% CI: 1%, 61%) for sham intake and 69% (95% CI: 37%, 85%) for analgesic
intake.
Conclusions Using 1.3% NaOCl was associated with less intense and less frequent postendodontic pain
than 5.25% NaOCl in mandibular molars with non vital pulps treated in two visits. The incidence of pain was
reduced by up to 60% within the week postinstrumentation and 80% post root canal filling and the rescue
analgesic intake by about 70% on using 1.3% NaOCl compared to 5.25% NaOCl.

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 Introduction
Accepted Article
Preventing postendodontic pain is important for both patients and clinicians. Postoperative pain is common
after root canal treatment and is mainly attributed to mechanical, chemical and microbiological factors,
especially in teeth with non-vital pulps, usually occurring as a consequence of extrusion of infected debris
and fluids (Siqueira & Barnett 2004, Boutskiotis et al. 2013). The incidence of postoperative endodontic
pain has been reported to occur on average in 40±24% of cases, but, could reach up to 80% within the first
24h (Glennon et al. 2004, Ng et al. 2004, Wang et al. 2010, Pak & White 2011).
Several factors can influence postendodontic pain including pretreatment, intratreatment or posttreatment
factors (Genet et al. 1987, Glennon et al. 2004, Ng et al. 2004, Arias et al. 2013). Intratreatment factors
include the number of visits, the type of irrigant and/or intracanal medication, the root canal instrumentation
technique and the root filling technique (Ng et al. 2004, Arias et al. 2013). Methods to prevent
postendodontic pain, thus, include the selection of instruments, instrumentation techniques, devices and
chemicals used during treatment (Walton 2002, Glennon et al. 2004, Ng et al. 2004, Nagendababu &
Gutmann 2017).
Several irrigants have been used during root canal treatment of which sodium hypochlorite (NaOCl) is the
most-commonly used due to its numerous advantages including its antimicrobial activity, antibiofilm activity,
and organic-tissue-dissolution potency (Zehnder 2006). On the other hand, it is irritant to periapical tissues,
especially at high concentrations, and can induce an inflammatory reaction even at concentrations as low
as 0.5% which could suggest a higher likelihood of postoperative-pain occurrence especially in cases of
teeth with patent apices and non-vital pulps (Zehnder 2006, Boutsioukis et al. 2013). Various
concentrations of NaOCl are used by dental practitioners varying from 0.5% to ≈8% with a tendency
towards using higher concentrations (Dutner et al. 2012, American Association of Endodontists (AAE)
2018). The concentration of NaOCl affects its behaviour and higher concentrations may enhance the
effectiveness of the solution, especially the tissue-dissolving property, yet, impair its safety (Zehnder 2006,
Stojicic et al. 2010). It has, also, been reported that there is no rationale for using high concentrations of
NaOCl and that effectiveness could be compensated for by other more safe means e.g. higher volume,
temperature increase, agitation or using a surfactant (Zehnder 2006, Stojicic et al. 2010, AAE 2018).
Several studies have assessed the effect of irrigants or irrigation protocols on postoperative pain
(Torabinejad et al. 2005, Bashetty & Hegde 2010, Almeida et al. 2012, da Silva et al. 2015, Farzaneh et al.
2018). A systematic review has highlighted a lack in studies assessing the effect of different concentrations
of the same irrigant, including NaOCl, on patient-related outcomes (Fedorowicz et al. 2012). Postoperative
pain following irrigation using 2.5% or 5.25% NaOCl in patients with irreversible pulpitis in mandibular
molars that were treated in one visit with results favouring 5.25% NaOCl has been reported (Farzaneh et al.
2018). The effect of different NaOCl concentrations on teeth with non-vital pulps is, however, yet to be
assessed. The aim of the the present study, thus, was to compare the effect of two NaOCl concentrations,
1.3% and 5.25%, on postendodontic pain and rescue-medication intake in patients with non-vital pulps in
mandibular molars, undergoing root canal treatment over two visits.

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 Materials and Methods
Accepted Article
Study design, setting and sampling
The protocol of this prospective, two-arm, parallel-group, double-blind, single-center, randomized, clinical
trial and the informed-consent format were approved by the Research Ethics Committee of the Faculty of
Dentistry. The study protocol was registered on www.clinicaltrials.gov (ClinicalTrials.gov Identifier:
NCT03792217). Study reporting followed the Consolidated Standards of Reporting Trials (CONSORT)
guidelines (Moher et al. 2010). All included patients signed a written informed consent after the nature of
the study, its objectives, procedures, benefits and potential risks were explained.
The patients were enrolled from the outpatient clinic of the Department of Endodontics, Faculty of Dentistry
between July 2011 to January 2015. Of nine postgraduate students trained on the endodontic procedures
required for accomplishing the study, including using rotary instrumentation, needle irrigation and cold-
compaction canal filling, for at least three months and evaluated by five supervisors from the staff members
of the Department of Endodontics before study initiation, seven were eligible to participate as operators in
this study with grades exceeding 80%; all operators followed the same approved protocol.
Sample size calculation
Sample-size estimation was performed based on a type I error (α) of 0.05 and a power set at 90%
indicating that a total sample of 256 participants, 128 per group, would be required to detect a minimal
clinically-important difference of 20% in postoperative pain incidence between groups. Information obtained
from previous studies indicated an anticipated postoperative-pain incidence of approximately 65% in the
comparator group (Glennon et al. 2004, Wang et al. 2010). Considering a dropout rate of 20%, 308
participants were required. PS: Power and Sample Size Calculation software Version 3.1.2
(http://biostat.mc.vanderbilt.edu/wiki/Main/PowerSampleSize) was used to calculate sample size.
Eligibility criteria
Eligible patients for inclusion in this study were systemically-healthy subjects between the age of 25 and 45
years with a mandibular molar (first or second) with non-vital pulp with or without radiographic evidence of
apical periodontitis; symptomatic and asymptomatic patients were included. Patients were excluded if they
were pregnant or lactating females; had a history of sensitivity or adverse reactions to any of the
medications or materials used in this study; had acute periapical or periodontal abscess, or badly-decayed
crowns; were retreatment cases or had severely-curved root canals. Patients who took a preoperative
premedication that could alter pain perception (e.g. analgesics) within at least 12 hours before treatment
were, also, excluded.
Clinical procedures
Diagnosis
Diagnostic procedures included history taking and clinical and radiographic examination with all findings
being recorded in each patient’s notes. The included patients had a diagnosis of symptomatic or
asymptomatic mandibular molars with non-vital pulps, associated or not with radiographic evidence of
apical periodontitis. Patients recorded their preoperative pain on a 0-10 numerical rating scale (NRS)
(Hjermstad et al. 2011) with 0 indicating “No pain” and 10 indicating “The worst pain” after being trained to

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 use the scale. The pain scores were categorized into 4 categories as follows: 0=none, 1-3=mild, 4-
Accepted Article
6=moderate and 7-10= severe. Included patients had a negative response to electric pulp senstivity testing
(Denjoy DY310 Dental Pulp Tester, Denjoy, Henan, China) and cold thermal testing (Ethyl chloride spray,
Walter Ritter GmbH, Hamburg, Germany). Definitive pulp status was confirmed during access cavity
preparation through lack of bleeding. Patients with or without pain on percussion were included. Periapical
radiographs were taken to assess the status of the periapical structures; patients with normal structures or
periapical radiolucency were included.
Randomization and blinding
Random sequence generation was done using the permuted-block method with seven blocks, 44 patients
each; patients in each block were treated by the same operator. The random sequence was generated
using Microsoft Excel computer software. Each block was randomly and equally divided into the two
groups: 1.3% NaOCl or 5.25% NaOCl. The allocation ratio was 1:1. The irrigants were placed in opaque,
sealed, sequentially-numbered syringes according to the random sequence generated for allocation
concealment. The irrigants were prepared and packed by a dental assistant not involved in the trial.
Assignment to groups was done right after access preparation. Once allocated, the patient’s name was
written on the container and the number on the container was written on the patient's chart to allow
decoding during data management. The patients and operators were unaware of the assigned group
throughout the duration of the study.
Endodontic procedures
Root canal treatment was carried out in two visits. At the first visit, each tooth was anaesthetized using
1.8mL 2% mepivacaine HCl with levonordefrin 1:20000 (Mepecaine-L, Alexandria Co. for Pharmaceuticals,
Alexandria, Egypt) through an inferior alveolar nerve block technique.
After access preparation, each tooth was isolated using rubber dam then patients were randomly assigned,
according to the NaOCl concentration used, to either of the following groups: 1.3% NaOCl or 5.25% NaOCl.
The pulp chamber was filled with 3mL irrigant. The patency of canals was established and an initial glide
path was prepared using size10 and size15 K-files (Mani, Mani Inc., Tochigi, Japan). After coronal pre-
flaring, the working length (WL) was determined using an apex locator (Root ZX, J.Morita USA, Irvine, CA,
USA) and radiographically confirmed to be 0.5-1mm short of the radiographic apex.
Root canals were mechanically prepared using a nickel-titanium rotary system (Protaper Universal,
Dentsply Sirona, Ballaigues, Switzerland) in a torque-controlled endodontic motor (X-Smart, Dentsply
Sirona) according to the manufacturer's sequence and recommendations of speed and torque. Root canal
preparation started with S1 and SX instruments in a crown-down sequence to shape the coronal two-thirds
of the root canal. After working-length determination, the apical third was prepared using S1, S2, F1, F2 or
F3 to the full working length according to the resistance of a K-file corresponding to the tip size of F2 or F3.
A lubricant (Glyde file prep, Dentsply-DeTrey, GmbH, Konstanz, Germany) was used with each instrument.
Apical patency was maintained throughout preparation using size10 K-files before each rotary-instrument
change.

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 Syringe irrigation was done using 3mL irrigant with a 27-gauge, notched-tip needle (Monoject needle, Tyco
Accepted Article
healthcare group LP, Kendall, MA, USA) between each two consecutive instruments. Needle penetration
depth in the canal was 3mm shorter than the working length of the canal after preparing the canal to the
master apical instrument as adjusted by rubber stoppers. The final flush was done using 5mL saline.
At the end of the first visit, the canals were dried using paper points (Protaper Universal, Dentsply Sirona),
a dry cotton pellet was placed in the pulp chamber and the access cavity was sealed with a temporary
filling (Cavit, 3M ESPE, Germany) without intracanal medication. In the second visit 7 days later, a rubber
dam was placed and the temporary filling was removed. Root canals were irrigated using the same irrigant
concentration as in the first visit and the canal walls were re-prepared using the instrument size last used in
the first visit before the canals were dried. Canal filling was carried out using the modified single-cone
technique with matched-size gutta-percha cones (Protaper Universal, Dentsply Sirona) and an epoxy resin-
based sealer (AH Plus, Dentsply DeTrey). The tooth was temporized using a cotton pellet and temporary
filling. A postoperative periapical radiograph was taken for each patient that was evaluated for the following
features: the extent of root canal filling (‘adequate filling’ within ≤ 2mm from the radiographic apex,
‘underfilling’ or ‘overfilling’), the taper and width of filling (‘overinstrumentation’ was considered if the filling
was wide and/or showed overflaring; ‘underinstrumentation’ was considered if the filling was thin and/or
showed underflaring), and/or the presence of a fractured instrument, a ledge or a perforation; such data
were recorded for each patient.
Postendodontic pain assessment
Each patient received a pain diary to record their pain at the following timepoints: immediately after
instrumentation, 3, 24, 48 hours and 7 days after the first visit and, on the second visit, immediately post
root filling. Pain was assessed using the numerical rating scale (NRS). Patients were asked to mark the
number that represented their pain level. Patients were contacted by their operator at each timepoint to
check on them and remind them to record their pain. After the first visit, each patient was dismissed with a
capsule (A capsule containing powdered milk), as sham analgesic, to be taken in case of pain. If pain
persisted, the patient was instructed to contact the operator who would then prescribe an analgesic
(Ibuprofen 600mg, Abbott Laboratories Inc., Lake Bluff, Il, USA). The patients were asked to record
whether they took the sham only or the analgesic as well in the pain diary. The patients delivered their pain
charts in the second visit after 7 days.
Statistical analysis
All data were collected and tabulated in Microsoft-Excel sheets (Microsoft Corporation, Redmond, WA,
USA) and coded to allow statistician blinding. Descriptive analysis for all variables was performed. Data
were explored for normality using Kolmogorov-Smirnov test and Shapiro-Wilk test and postoperative pain
intensity demonstrated non-normal distribution (p<0.05). Normally-distributed, continuous variables were
analyzed using the Student’s t-test, while non-normally-distributed continuous variables, using the Mann–
Whitney U-test. Comparisons at various time intervals within each group were analysed using Friedman’s
test and, if statisitical significance was detected, multiple comparisons was done using Wilcoxon’s sign rank
test. Categorical variables were analysed using the Pearson’s Chi-square χ2 test. The relative risk

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 reduction (RRR) and the number-needed-to-treat (NNT) and their 95% confidence intervals (CI) for the risk
Accepted Article
of pain and medication-intake incidence were estimated.
A binary logistic regression (BLR) was used to assess the association between postoperative pain
incidence (No/Yes) as a dependent variable and the following variables as independent variables: Gender
(Female/Male), preoperative pain (No/Yes), pain on percussion (No/Yes), preoperative periapical
radiolucency (No/Yes), sham intake (No/Yes), and analgesic intake (No/Yes); the odds ratio (OR) and its
95% confidence intervals (CI) were estimated for each variable given that the other factors were held
constant. p-values less than 0.05 were considered statistically significant. Data were analyzed using the
Statistical Package for Social Science version 25.0 for Windows (SPSS, IBM Corporation, New York, USA).

Results
Of 463 patients assessed for eligibility, 308 were included, randomized and their data analysed without
dropouts or exclusions (Fig. 1). Of the 308 included patients, 178 were females and 130 were males. The
age range was from 25 to 45 years with an overall mean age of 31.87±5.82y. The study included 235 first
and 73 second mandibular molars. 57% (175/308) of the patients had pain on percussion and 40.6%
(125/308) had a periapical radiolucency. Both groups were similar regarding baseline data (p>0.05, Table
1). An intention-to-treat analysis was adopted.
The 1.3%-NaOCl group was associated with significantly less pain intensity than the 5.25%-NaOCl group at
all the time points (p<0.05, Table 2). The pain trend over time for each group is shown in Figure 2. For both
groups, a significant decrease in pain intensity occurred immediately after treatment compared to
preoperative pain (p<0.05). With 5.25% NaOCl, a significant rise in pain intensity (p<0.05) compared to
preoperative pain occurred at 3h and continued till 24h (p>0.05) then a significant decrease occurred at
48h compared to 24h (p<0.05), yet, reached the preoperative pain level (p>0.05). A gradual decrease
compared to the preoperative pain then occurred up to 7d (p<0.05); a significant rise, however, occurred
post root filling compared to the 7d pain intensity (p<0.05). A significant rise in pain intensity with 1.3%
NaOCl at 3h compared to immediately after treatment (p<0.05), yet, it was significantly less than the
preoperative pain (p<0.05). Pain remained at the same intensity from 3h to 24h afterwhich it gradually
declined until it reduced at 7d compared to preoperative pain (p<0.05) with no rise in pain level post root
filling than at 7d (p>0.05).
The incidence of pain at the different pain categories (No, mild, moderate, severe) at the different
timepoints is shown in Table 3. Immediately after treatment, the relative risk reduction (RRR) of pain
incidence, regardless of its intensity, was 38% (95% confidence interval [CI]: 17%, 54%) on using 1.3%
NaOCl compared to 5.25% NaOCl. The number-needed-to-treat (NNT) was six (95% CI: 4, 14); that is, it
was necessary to use 1.3% NaOCl with six patients for one extra patient to benefit compared to using
5.25% NaOCl. At 3h, the RRR of pain incidence was 41% (95% CI: 31%, 49%). The NNT was three (95%
CI: 3, 4). At 24h, the RRR of pain incidence was 42% (95% CI: 32%, 51%). The NNT was three (95% CI: 3,
4). At 48h, the RRR of pain incidence was 59% (95% CI: 45%, 69%). The NNT was three (95% CI: 2, 4). At

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 7d, the RRR of pain incidence was 62% (95% CI: 27%, 80%). The NNT was nine (95% CI: 6, 24). Post root
Accepted Article
filling, the RRR of pain incidence was 81% (95% CI: 68%, 89%) and the NNT three (95% CI: 2, 4).
When considering patients with moderate-to-severe pain, the RRR and NNT values were as follows:
Immediately after treatment, RRR was 71% (95% CI: 15%, 90%) on using 1.3% NaOCl compared to 5.25%
NaOCl and the NNT was 16 (95% CI: 9, 77); that is, it was necessary to use 1.3% NaOCl with 16 patients
for one extra patient to benefit compared to using 5.25% NaOCl; at 3h, the RRR was 66% (95% CI: 43%,
80%) and the NNT was 5 (95% CI: 4, 9); at 24h, the RRR was 65% (95% CI: 44%, 78%) and the NNT was
5 (95% CI: 4, 8); at 48h, the RRR was 72% (95% CI: 46%, 86%) and the NNT was 6 (95% CI: 5, 11). At 7d
and post root filling, all patients had no-to-mild pain only.
The findings of the binary logistic regression (BLR) revealed that overall postoperative-pain incidence was
significantly associated with preoperative pain (p=0.000, OR [95%CI]: 1.788 [1.459, 2.192]), periapical
radiolucency (p=0.015, OR [95%CI]: 1.282 [1.049, 1.568] and analgesic intake (p=0.000, OR [95%CI]:
2.477 [1.614, 3.803]; the other studied factors (Gender, pain on percussion, sham intake) did not have an
impact (p>0.05, Table 4).
A total of 60 of 308 patients (23/154 in the 1.3% NaOCl group, and 37/154 in the 5.25% NaOCl group) took
the sham capsule. A total of 38 of 308 (9/154 in the 1.3% NaOCl group, and 29/154 in the 5.25% NaOCl
group) patients took the analgesic (600 mg ibuprofen). Thus, of the 60 patients who took the sham capsule,
22 (22/60, ≈37%) patients did not require further analgesia via analgesics. Using 1.3% NaOCl was
associated with significantly less incidence of sham intake (23/154) compared to 5.25% NaOCl (37/154)
(14.9% vs 24% respectively, p=0.044). The RRR of sham intake was 38% (95% CI: 1%, 61%) and the NNT
was 11 (95% CI: 6, 330). There was, also, significantly less incidence of analgesic intake with 1.3% NaOCl
(9/154) compared to 5.25% NaOCl (29/154) (5.8% vs 18.8% respectively, p=0.001). The RRR of analgesic
intake was 69% (95% CI: 37%, 85%) and the NNT was eight (95% CI: 5, 18).
For the 1.3%-NaOCl group, overinstrumentation in a canal occurred in 12 cases, underinstrumentation in 1
case, overfilling in 10 cases and underfilling in 1 case. For the 5.25%-NaOCl group, overinstrumentation
occurred in 4 cases, underinstrumentation in 2 cases, overfilling in 4 cases and underfilling in 2 cases. No
instrument fractures occurred in either group. No adverse effects were recorded by any patient throughout
the trial.

Discussion
Pain management during endodontic procedures and the postoperative stages is one of the most important
goals of clinicians (Nagendrababu & Gutmann 2017). One of the intra-operative factors contributing to
postoperative pain is irrigant used (Torabinejad et al. 2005, Bashetty & Hegde 2010, Almeida et al. 2012,
da Silva et al. 2015, Farzaneh et al. 2018); however, few reports have assessed the effect of different
concentrations of an irrigant (Farzaneh et al. 2018). NaOCl has been used in various concentrations
ranging from 0.5%-≈8% (Dutner et al. 2012, AAE 2018); a common consensus on the optimal
concentration for clinical use, however, is yet to be reached (Zehnder 2006, Fedorowicz et al. 2012). A
previous clinical study revealed that NaOCl concentration (0.5% or 5%) was not associated with its

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 antimicrobial efficacy (Byström & Sundqvist 1985). These results were supported by a later study (Siqueira
Accepted Article
et al. 2000) that demonstrated that NaOCl concentration had no effect of its antibacterial effect against
Enterococcus faecalis. The present study revealed that using 1.3% NaOCl was associated with a lower
incidence and intensity of postendodontic pain than 5.25% NaOCl with less need for medication intake in
mandibular molars with non-vital pulps treated in two visits. NaOCl is associated with a dose-dependent
anti-microbial and tissue-dissolving effect that increases with higher concentrations, yet, is accompanied by
higher cytotoxicity and liability to extrude periapically (Zehnder 2006, Parirokh et al. 2012, Boutsiokis et al.
2013, AAE 2018). Thus, a low concentration can be safer to use especially in cases when irrigant extrusion
is anticipated, e.g. perforations, apical resorption or open apices, while compensating for higher
concentration by frequent exchange, higher volumes and agitation (Salzgeber & Brilliant 1977, Zehnder
2006, Boutsiokis et al. 2013, AAE 2018).
This study is a randomized, double-blind, clinical trial with patient-reported outcome measures for the best
possible chance to decrease selection bias and in which the participants, who are also the outcome
assessors, were blinded to the interventions used, thus, minimizing performance and detection bias; the
lack of dropouts or exclusions prevents attrition bias (Moher et al. 2010). Block randomization was used to
ensure that each operator would treat an equal number of patients in both groups (Moher et al. 2010). The
participation of several operators in the present study could contribute to an enhanced external validity of
the study results with a more pragmatic approach simulating real-life clinical practices (Menhinick et al.
2004, Thorpe et al. 2009). Patient-oriented outcome measures, e.g. pain relief, are recommended since
they matter to patients (De-Deus & Canabarro 2017).
Several factors (pre-treatment, intra-treatment or post-treatment) influence postendodontic pain acting as
confounders. Pre-treatment factors include age, gender, tooth type and preoperative pain. Intra-treatment
factors include the number of visits, irrigant or intracanal medication used, canal instrumentation technique
and sealer type, while analgesic intake represent post-treatment ones (Imura & Zuolo 1995, Walton 2002,
Glennon et al. 2004, Ng et al. 2004, Arias et al. 2013, Nagendrababu & Gutmann 2017). Minimizing the
effect of known and unkown factors on the study findings can be achieved by specifiying eligibility criteria,
standardizing the study protocol and randomly assigning patients to groups (Moher et al. 2010).
To eliminate the effect of pretreatment analgesics on diagnosis and postendodontic pain, patients who took
no pain-perception-altering medications in the last 12h before treatment were included. Only non-vital pulps
were included since they represent a common indication for using full-concentration NaOCl (Zehnder
2006). Mandibular molars were selected as these teeth have the highest incidence of postoperative pain
(Ng et al. 2004, Arias et al. 2013), thus, representing the worst-case scenario.
Standardizing study protocols can help eliminate the effects of intraoperative variables on results. A two-
visit root canal treatment was used in this study with no intracanal dressing to eliminate the chemical
effects of intracanal medication and canal filling, especially with overfilling or extrusion, and the variables
related to them that could influence pain findings (Pascon et al. 1991, Glennon et al. 2004, Ng et al. 2004,
Nagendrababu & Gutmann 2017). To decrease the risk of inadvertent extrusion of debris and irrignt, the

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 needle penetration depth was kept at 3mm from the WL (Boutsiokis et al. 2010). A rotary system used
Accepted Article
according to the manufacturer’s instructions was used with all patients.
Lubricants help reduce applied stresses on rotary instrumentation (Peters et al. 2005, Boessler et al. 2007,
Chandler & Chellappa 2019). Paste-type lubricants, e.g. Glyde (glycol-based), have gained popularity to
which chelating agents to remove the inorganic component of the smear layer are usually incorporated
(Chandler & Chellappa 2019). From a chemical perspective, the use of paste-like chelator preparation
containing EDTA and peroxide, e.g. Glyde, is highly questionable if NaOCl is used as an irrigant as can
decrease the available chlorine mainly responsible for soft-tissue dissolving and antibacterial properties of
hypochlorite solutions (Zehnder et al. 2002, 2005, Girard et al. 2005) . Paste-type lubricants, however, are
commonly used by clinicians and can easily be placed on instruments before insertion into the root canal
(Al-Nahlawi et al. 2016, Elzaki et al. 2016, Chandler & Chellappa 2019). The antibacterial effect of
lubricants introduced on files may have clinical significance (Wong et al. 2014, Chandler & Chellappa
2019). In the present study, Glyde was used as a lubricant to simulate common clinical situations; its use
can also facilitate standardizing clinical procedures among the seven operators and aid in disinfecting
canals.
In the present study, calcium hydroxide (CH) was not used as an intracanal medication to avoid its potential
effect on postoperative pain (Abbott 1990, Ghoddusi et al. 2006, Singh et al. 2013), thus, influencing the
effects of the NaOCl concentrations on postoperative pain. Even though it was observed that microbial
regrowth could occur between visits (Byström & Sundqvist 1985), a randomized clinical trial failed to detect
a difference in microbial growth or treatment outcome with or without the use of CH (Waltimo et al. 2005).
Several randomized clinical trials assessing the effect of irrigants or irrigation devices on postoperative
pain, also, avoided using ICM (Torabinejad et al. 2005, Bashetty & Hegde 2012, Ramamoorthi et al. 2014).
A systematic review (Manfredi et al. 2016) has shown that one-visit and multiple-visit root canal treatments
are comparable regarding most clinical and radiographic outcomes, regardless of pulp status, yet, patients
treated in one visit can be more likely to experience pain within the first week postoperatively and require
painkillers. In this study, thus, the two-visit approach without the use of intracanal medication was used to
exclude as many intraoperative factors as possible that could influence postoperative pain.
In clinical trials assessing acute pain, rescue medication should be administered in case of pain after
treatment regardless of the quality of the intervention (Moore et al. 2011). In this study, a sham capsule
was initially administered to avoid masking the initial levels of postoperative pain and avoid the patients’
intake of analgesics for fear of experiencing pain rather than actual pain occurrence itself, thus,
confounding pain from the interventions (Walton 2002, Nagendrababu & Gutmann 2017). With pain
persistence, however, an analgesic was prescribed without excluding such patients to avoid attrition bias
and to preserve study power (Moher et al. 2010).
Various methods are used for measuring pain (Hjermstad et al. 2011, Farzaneh et al. 2018). In this study,
an 11-point NRS was used being easier to use than visual analogue scales (VASs) and more sensitive than
verbal rating scales (VRSs) (Hjermstad et al. 2011). Patients were trained to use the scale to allow proper
outcome data collection (Moher et al. 2010). Since postendodontic pain is usually felt within the first 48h

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 after treatment (Ng et al. 2004, Pak & White 2011), four timepoints were selected within this duration from
Accepted Article
immediately after treatment to 48h. Pain was, also, assessed at 7 days to be able to compare results with
other similar studies (Torabinejad et al. 2005, Bashetty & Hegde 2010, Almeida et al. 2012, Farzaneh et al.
2018). The periapical inflammatory reactions caused by 5.25% NaOCl can remain for up to a month after
treatment (Gomes-Filho et al. 2008); thus, it was of interest to assess if this would impact post canal filling.
Patients in the present study had an overall mean age of approximately 32y representing a rather young
population. Several previous studies, however, demonstrated the lack of an association between age and
postoperative pain (Genet et al. 1987, Glennon et al. 2004, Ng et al. 2004); the findings of this study may,
thus, be applicable to a wider age range of patients. The effect of gender on postoperative pain has been
contradictory, with some studies reporting more pain with females (Genet et al. 1987, Ng et al. 2004, Arias
et al. 2013), while others showing no association (Glennon et al. 2004, Middha et al. 2017, Vera et al.
2018). The presence of preoperative pain is the most-established predictor for postendodontic-pain
occurence (Genet et al. 1987, Glennon et al. 2004, Ng et al. 2004, Arias et al. 2013). In this study, both
groups had similar baseline characteristics indicating successful randomization (Table 1).
In this study, the use of 1.3% NaOCl caused less pain incidence and intensity than 5.25% NaOCl at all
timepoints within the week between the two visits and immediately post root filling (Tables 2&3 and Fig. 2).
The RRR of postoperative pain ranged from 38% immediately after treatment to 81% postroot filling with
1.3%NaOCl compared to 5.25% NaOCl. The NNT ranged from 3-9 within the trial duration which indicates
the number of patients to be treated using 1.3%NaOCl to observe "no pain" with one more person than with
5.25% NaOCl; the smaller the NNT, the more effective the intervention is. Such findings, however, disagree
with a recent study that compared 2.5% and 5.25% NaOCl concentrations where patients experienced
more pain with the lower concentration in patients with irreversible pulpitis treated in one visit (Farzaneh et
al. 2018). This could mainly be attributed to the different populations selected relative to the pulp and
periapical status in each study and their interplay with the NaOCl concentrations used (Salzgeber & Brilliant
1977, Vier & Figueiredo 2002, Parirokh et al. 2012). In the previous study (Farzaneh et al. 2018), teeth with
irreversible pulpitis having no preoperative spontaneous pain and no apparent periapical changes were
selected compared to mandibular molars with non-vital pulps that were either symptomatic or asymptomatic
and with or without periapical pathosis in the present study.
The nature of pulp and periapical status could modulate postendodontic pain response (Genet et al. 1987,
Walton 2002, Arias et al. 2013). Postendodontic pain, especially severe flare-ups, has been associated with
pulp necrosis, symptomatic apical periodontitis, and the presence of preoperative periapical radiolucency
(Imura & Zuolo 1995, Walton 2002). Preoperative periapical radiolucency was also associated with pain
lasting more than two days (Arias et al. 2013). Teeth with non-vital pulps associated with periapical lesions
have 83.2% prevalence of foraminal resorption (Vier & Figueiredo 2002) and disruption of the apical
constriction causes more periapical extrusion (Tinaz et al. 2005). Intact periapical tissues can act as a
barrier against irrigant and material extrusion (Psimma et al. 2013). Teeth with necrotic pulps were more
likely to allow irrigant extrusion into the periapical area than those with vital pulps (Salzgeber & Brilliant

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 1977, Farzaneh et al. 2018). Cases with pulp necrosis and periradicular radiolucency were associated with
Accepted Article
higher incidence of NaOCl accidents as well (Boutsiokis et al. 2013).
NaOCl concentration affects its biological properties where higher concentrations of NaOCl (e.g. 2.5% and
5.25%) can have more adverse, longer-lasting inflammatory reactions in connective tissue compared to
lower concentrations (e,g, 0.5%) (Gomes-Filho et al. 2008) in addition to the higher potential of
5.25%NaOCl to extrude periapically (Parirokh et al. 2012). Such effects can clinically manifest as more pain
with higher concentrations.
Immediately after instrumentation, pain was at its lowest intensity for both groups mainly because of the
still-ongoing effect of local anesthesia. Within the trial duration, pain intensity exceeded preoperative pain
within the first 2 days with 5.25%NaOCl only. This is in accordance with other studies reporting higher
levels of postendodontic pain within the first 48-72h postoperatively (Genet et al. 1987, Torabinejad et al.
2005, Bashetty & Hegde 2010, Pak & White 2011, Farzaneh et al. 2018). Post root filling pain intensity
increased than before obturation with 5.25%NaOCl only which could be explained by the possible
aggravation of the already-existing inflammatory reponse with such concentration together with the
irritational effect of filling materials (Pascon et al. 1991).
In the present study, the presence of preoperative pain or a preoperative periapical radiolucency and
analgesic intake was associated with postoperative pain. A well-established association exists between
preoperative pain and postoperative pain (Genet et al. 1987, Glennon et al. 2004, Ng et al. 2004, Siqueira
& Barnett 2004, Arias et al. 2013). The association of postoperative pain with the presence of periapical
radiolucency supports results of previous studies (Genet et al. 1987, Imura & Zuolo 1995, Walton 2002)
which was discussed earlier. Postoperative-pain incidence was, also, associated with a higher intake of
analgesics which is in accordance with previous studies (Imura & Zuolo 1995, Walton 2002, Nagendrababu
& Gutmann 2017).
Fewer patients, in the present study, required medication intake (Sham, analgesic) with 1.3% NaOCl than
with 5.25% NaOCl. These findings, however, were in contrast to those of a previous study where the use of
2.5%NaOCl resulted in more analgesic intake than 5.25%NaOCl (Farzaneh et al. 2018); this could be
rendered to the differences in the pulp and periapical status in the patients of each study. The relative risk
of sham intake was reduced by 38% and that of analgesic intake by nearly 70%. The higher overall
incidence of sham intake (60/308 [19.5%]) compared to that of analgesic intake (38/308 [12.3%]) may
indicate that sham can be effective in reducing the unnecessary use of analgesics which could mask the
differences in pain levels caused by the trial interventions (Ramamoorthi et al. 2014).
Placebos have been commonly used in the field of medicine for clinical research and practice (Moore et al.
2011, Colloa et al. 2015). In clinical research, the use of placebos is essential to facilitate blinding as well
as eliminate the placebo effect of taking a tablet (Torabinejad et al. 1994, Moher et al. 2010, Moore et al.
2011). Despite some ethical concerns on their use, the beneficial effects of therapeutic placebos are based
on valid empirical evidence especially in certain conditions e.g. pain (Colloa et al. 2015, Castelnuovo et al.
2018). In the present study, placebos were primarily administrated as a rescue analgesic to allow the
discrimination of patients with no-to-mild pain who might not really need analgesics (Ramamorthi et al.

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 2014) from those patients with rather moderate-to-severe pain who would really need analgesics. Of the 60
Accepted Article
patients who took placebos, 37% (22/60) did not require further analgesia and, thus, did not have to be
unnecessarily exposed to NSAIDs’ side effects.
A limitation of this trial may be the inclusion of only patients with non vital pulps, thus, including a broader
spectrum of patients could increase the generalizability of the trial findings. Future studies are
recommended to assess the effects of different concentrations of other irrigants on the short- and long-term
outcomes.

Conclusions
Using 1.3% NaOCl was associated with less intense and less frequent postendodontic pain than 5.25%
NaOCl in mandibular molars with non vital pulps treated in two visits. The incidence of pain was reduced by
up to 60% within the week postinstrumentation and 80% post root canal filling and the rescue analgesic
intake by about 70% on using 1.3% NaOCl compared to 5.25% NaOCl.

Acknowledgements
Thanks are due to Safaa Hashim, BDS, MSc and Shahinaz Alfaki, BDS, MSc, for their contribution.

Conflict of Interest statement

The authors have stated explicitly that there are no conflicts of interest in connection with this article.

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 Figure Legends
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Figure 1 CONSORT flowchart showing flow of participants along the study.
Figure 2 Pain intensity level for the 1.3% and the 5.25% sodium hypochlorite (NaOCl) groups pre-
operatively (PreOP), immediately after treatment (POPimm), 3h (POP3h), 24h (POP24h), 48h (POP48h),
7d (POP7d) after treatment and postobturation (POPobt). Different lower-case letters within each column
represent a statistically significant difference of each postoperative timepoint from the preoperative
timepoint within each group (Wilcoxon’s sign rank test); Different upper-case letters within each column
represent a statistically significant difference of each timepoint from the one preceding it within each group
(Wilcoxon’s sign rank test).

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 Table 1 Baseline characteristics of the included study participants in the 1.3% and the 5.25% sodium
Accepted Article
hypochlorite (NaOCl) groups.
SD,
1.3% NaOCl 5.25% NaOCl
Variables p-value
(n=154) (n=154)

Age (Years)
Mean ±SD 32.14 ± 5.79 31.60 ± 5.87
0.412
Range [25, 45] [25, 45]
Gender [n (%)]
Male 62 (40.3%) 68 (44.2%) 0.489
Female 92 (59.7%) 86 (55.8%)
Tooth [n (%)]
Mandibular first molar
111 (72%) 124 (80.5%) 0.082
Mandibular second
43 (28%) 30 (19.5%)
molar
Percussion [n (%)]
Yes 85 (55.2%) 90 (58.4%) 0.565
No 69 (44.8%) 64 (41.6%)
Radiolucency [n (%)]
Yes 58 (37.7%) 67 (43.5%) 0.296
No 96 (62.3%) 87 (56.5%)
Pre-operative pain
incidence [n (%)]
Yes 88 (57.1%) 90 (58.4%) 0.818
No 66 (42.9%) 64 (41.6%)

standard deviation.

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Accepted Article
Table 2 Pain intensity for the 1.3% and the 5.25% sodium hypochlorite (NaOCl) groups.
1.3% NaOCl 5.25% NaOCl
p-value
Time point (n=154) (n=154)
1†
Med IQR Min Max Mean (SD) Med IQR Min Max Mean (SD)

PreOP 1a, A 3 0 10 2.03 (2.72) 1a, A 3 0 10 2.14 (2.74) 0.674

POPimm 0b, B 1 0 8 0.58 (1.30) 0b, B 2 0 8 1.12 (1.83) 0.001*

POP3h 1b, C 2 0 8 1.25 (1.66) 2b, C 3 0 9 2.94 (2.16) 0.000*

POP24h 1b, C 2 0 8 1.21 (1.75) 2b, C 2 0 9 3.08 (2.29) 0.000*

POP48h 0b, D 1 0 9 0.62 (1.37) 1a, D 3 0 8 1.82 (2.05) 0.000*

POP7d 0b, E 0 0 2 0.08 (0.29) 0b, E 0 0 2 0.25 (0.57) 0.002*

POPobt 0b, E 0 0 2 0.10 (0.32) 0b, E 1 0 2 0.64 (0.77) 0.000*

p-value 2‡ <0.001* <0.001*

Med, median; IQR, interquartile range; Min, minimum; Max, maximum; SD, standard deviation; †, Mann-Whitney test comparing two independent groups in a row;
‡, Friedmann’s test comparing different timepoints within each group in a column; Different lower-case letters within each column represent a statistically significant
difference of each postoperative timepoint from the preoperative timepoint within each group (Wilcoxon’s sign rank test); Different upper-case letters within each
column represent a statistically significant difference of each timepoint from the one preceding it within each group (Wilcoxon’s sign rank test); *, statistical
significance (p<0.05); PreOP, pre-operative pain; POPimm, pain immediately after treatment; POP3h, pain after 3h; POP24h, pain after 24h; POP48h, pain after
48h; POP7d, pain after 7d; POPobt, postobturation pain.

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 Table 3 Incidence [n (%)] of pain at the different pain categories for the the 1.3% and the 5.25% sodium
Accepted Article
hypochlorite (NaOCl) groups.

1.3% NaOCl 5.25% NaOCl

Variables Pain category p-value
(n=154) (n=154)

No 66 (42.9) 64 (41.6)
Mild 59 (38.3) 56 (36.4)
PreOP 0.222
Moderate 9 (5.8) 19 (12.3)
Severe 20 (13.0) 15 (9.7)
No 109 (70.8) 81 (52.6)
Mild 41 (26.6) 59 (38.3)
POPimm 0.002*
Moderate 0 (0.0) 6 (3.9)
Severe 4 (2.6) 8 (5.2)
No 69 (44.8) 12 (7.8)
Mild 69 (44.8) 95 (61.7)
POP3h 0.000*
Moderate 12 (7.8) 30 (19.5)
Severe 4 (2.6) 17 (11.0)
No 75 (48.7) 18 (11.7)
Mild 60 (39.0) 82 (53.3)
POP24h 0.000*
Moderate 14 (9.1) 37 (24.0)
Severe 5 (3.2) 17 (11.0)
No 112 (72.7) 52 (33.8)
Mild 32 (20.9) 67 (43.5)
POP48h 0.000*
Moderate 9 (5.8) 29 (18.8)
Severe 1 (0.6) 6 (3.9)
No 143 (92.9) 125 (81.2)
POP7d 0.002*
Mild 11 (7.1) 29 (18.8)

No 140 (90.9) 80 (51.9)

POPobt 0.000*
Mild 14 (9.1) 74 (48.1)

*, statistical significance (p<0.05); PreOP, pre-operative pain; POPimm, pain immediately after treatment;
POP3h, pain after 3h; POP24h, pain after 24h; POP48h, pain after 48h; POP7d, pain after 7d; POPobt,
postobturation pain.

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 Table 4 Binary linear regression of the effect of different variables factors on postendodontic pain.
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S.E.,
95% CI
Variables (reference) S.E. OR p-value
Lower Upper
bound bound

Gender (Female) 0.099 1.095 0.902 1.329 0.360

Preoperative pain (no) 0.104 1.788 1.459 2.192 0.000*

Pain on percussion (no) 0.108 0.992 0.803 1.225 0.939

Periapical radiolucency
0.103 1.282 1.049 1.568 0.015*
(no)

Sham intake (no) 0.178 1.160 0.818 1.645 0.405

Analgesic intake (no) 0.219 2.477 1.614 3.803 0.000*

standard error; OR, odds ratio; CI, confidence interval.

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 iej_13222_f1.doc

Accepted Article
CONSORT 2010 Flow Diagram

Enrollment
Assessed for eligibility (n= 463)

Excluded (n= 155)

♦ Not meeting inclusion criteria (n=115)
♦ Declined to participate (n=40)
♦ Other reasons (n=0)

Randomized (n= 308)

Allocation
Allocated to intervention (n= 154) Allocated to intervention (n=154)
♦ Received allocated intervention (n=154) ♦ Received allocated intervention (n=154)
♦ Did not receive allocated intervention (give ♦ Did not receive allocated intervention (give
reasons) (n=0) reasons) (n=0)

Follow-Up
Lost to follow-up (give reasons) (n=0) Lost to follow-up (give reasons) (n=0)

Discontinued intervention (give reasons) (n=0) Discontinued intervention (give reasons) (n=0)

Analysis
Analysed (n=154) Analysed (n=154)
♦ Excluded from analysis (give reasons) (n=0) ♦ Excluded from analysis (give reasons) (n=0)

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