Postoperative pain of patients with necrotic teeth with apical periodontitis following single visit endodontic treatment versus multiple visit endodontic treatment using triple antibiotic paste: a randomized clinical trial

Background: A randomized clinical trial was conducted to compare the postoperative pain following endodontic treatment of necrotic teeth with apical periodontitis. Treatments were performed in multiple visits with application of triple antibiotic paste interappointment dressing or single visit without interappointment dressing. Methods: In total 44 participants were assigned randomly into two groups. Group A: multiple visit endodontic treatment with triple antibiotic paste interappointment dressing; group B: single visit endodontic treatment without interappointment dressing. Postoperative pain of participants was assessed after 24, 48, 72 hours and one week using numerical rating scale. Results: No statistically significant difference was found in postoperative pain after 24, 48, 72 hours and one week between the two groups. Conclusion: Triple antibiotic paste as an interappointment dressing in multiple visits endodontic treatment was not proved to reduce the postoperative pain compared to a single visit in patients with necrotic teeth with apical periodontitis who did not have an interappointment dressing. Trial registration: clinicaltrials.gov, NCT02947763. Date: 28th October 2016.


Introduction
Apical periodontitis (AP) arises primarily by continuous bacterial irritation from the root canals 1 . AP significantly reduces the endodontic success rate 2 . Therefore, treatment of AP should aim to completely eliminate the underlying root canal infection 3 , either by chemomechanical preparation or placement of an interappointment dressing 4 .
Recent systematic reviews found that multiple visits with calcium hydroxide did not improve postoperative pain and flareup and radiographic healing compared to single visit endodontic treatment without interappointment dressing [5][6][7][8] . Consequently, the search for a better antimicrobial alternative is required 9 . Previously, triple antibiotic paste (TAP) has been shown to effectively reduce the bacterial load in necrotic teeth 10 .
The aim of the present study was to compare the postoperative pain following endodontic treatment, of necrotic teeth having apical periodontitis, either performed in single visit or in multiple visits with application of triple antibiotic paste interappointment dressing.

Trial design
The study was registered on clinical trials.gov and the registration number is NCT02947763.
The protocol was approved by the Committee of Ethics, Faculty of Dentistry, Cairo University, Egypt (approval no 16562). Participants were asked to sign a printed informed consent that explained the study aim, alternative treatments to endodontic treatment, and the investigator's instructions.
The trial design of this study was a parallel, randomized, clinical design with allocation ratio 1:1. This article follows the CONSORT 2010 statement and a copy of the CONSORT checklist can be found in the Data availability section.
The study began in November 2016 and was completed in February 2018.

Sample size calculation
Prior data 11 indicated that standard deviation of pain score was 20.3. If the true difference in the intervention and control is 20.6, we should study 16 in each group to be able to reject the null hypothesis that the population means of the intervention and control groups are equal with probability (power) 0.8. The Type I error probability associated with this test of this null hypothesis was 0.05. The size of the sample was increased to 22 per group to correct for non-parametric usage and to substitute for any drop-out.

Participants
In total, 44 adults, medically-free with an age range of 16-55 years were selected for the study. All had a necrotic tooth with a periapical lesion confirmed radiographically (minimum size 2 × 2 mm). The participants were enrolled by SA.
Exclusion criteria included teeth previously accessed or endodontically treated; vital or necrotic teeth without periapical lesion; patients allergic to metronidazole, ciprofloxacin, or doxycycline or those with significant medical conditions; patients who took analgesic tablets before treatment up to 12 hours previously; and pregnant women.

Treatment procedures
The teeth were tested with an electric pulp test (Denjoy DY310 Dental Pulp Tester; Denjoy, Henan, China) to determine pulp sensitivity. Radiographs were taken using a photo stimulable phosphor plate wireless sensor (SOREDEX, DIGORA) to detect periapical lesions.
Local anesthesia was administered if needed (Ubistesin™ Articaine HCl 4% & Adrenaline 1:100,000 3M Australia). Isolation of the tooth with rubber dam and preparation of access cavity was performed and the root canal was instrumented by hybrid technique. Coronal shaping was performed with Gates-Glidden drills (MANI, Japan) sizes 4, 3 and 2. Working length was measured using apex locator (J Morita USA) and ascertained using radiograph, where it was set 1 mm away from the radiographic apex. The apical part was instrumented using stainless steel K-files (MANI, Japan); the master apical file size was set 3-4 sizes larger than the initial file. The middle part was instrumented using 3-5 stainless steel H-files.
Irrigation was done using sodium hypochlorite 2.6% (Clorox®, Egypt), using plastic disposable syringe with needle gauge 27, between successive instruments. Lubrication was done using EDTA gel (QMETA, Korea). Final irrigation was done with 5 ml 17% EDTA solution to remove the smear layer (17% EDTA solution, Prevest DenPro Limited, India). The final wash was done using saline. Master cone-fit radiograph was taken to ensure proper length and preparation. The canals were dried with paper points.

Randomization
At this step, the participants were divided randomly into two groups with a table of random numbers from 1 to 44 generated by SMA using a freely available computer program with n=22/group. The allocation table was kept with an investigator not involved with participant enrollment (SIG). Numbers from 1 to 44 were written on 44 pieces of paper folded eight-times. Each paper was placed separately in a closed opaque envelope. Each participant was asked to pick one of the envelopes and the participant was assigned to the groups based on the number in the envelope.
Group A: multiple (two) visit endodontic treatment with triple antibiotic paste interappointment dressing; group B: single visit endodontic treatment without interappointment dressing.
For group A, triple antibiotic paste (ciprofloxacin, metronidazole, and doxycycline mixed with saline) was prepared and 1 mL of the mixed paste was placed into the canals with a 20-gauge needle of sterile plastic syringe. A sterile cotton pellet was placed, and glass ionomer was placed (Riva Self Cure, Australia). Preparation of the triple antibiotic paste followed the protocol of a previous study 14 , using ciprofloxacin 250 mg tablets (EPICO, Egypt), metronidazole 500 mg tablets (Aventis, Egypt) and doxycycline 100 mg capsules (Pfizer, Egypt). The powder content of doxycycline capsule was placed in a sterile mortar. In the same mortar, a tablet of metronidazole and a tablet of ciprofloxacin were crushed and all are mixed with saline to a creamy paste. A second appointment was scheduled after at least 7 days. Under rubber dam isolation, the interappointment dressing was removed by H-files and 2.6% sodium hypochlorite and 17% EDTA irrigation followed by saline final wash. Then, obturation was performed using cold lateral condensation technique with resin sealer (ADSEAL, META, Korea). After obturation, glass ionomer was placed to seal the access cavity till final restoration.
For group B, no interappointment dressing was applied and endodontic treatment was ended in the same visit without placement of interappointment dressing. Obturation and sealing of access cavity were performed as in group A.

Outcomes
Primary outcomes. Postoperative pain at 24, 48, 72 hours and one week after instrumentation (first visit of Group A and the single visit of Group B); recorded by the participants using NRS in a pain diary.
Secondary outcomes. Incidence of analgesic intake and number of tablets consumed in case of presence of moderate or severe postoperative pain. Participants were instructed to take one tablet of Ibuprofen 400 mg (NOVARITIS, Canada) every 6 hours and to report the number of tablets consumed.

Blinding
The operator was blinded until the end of instrumentation until she saw the number of the envelope, then the operator either administered the interappointment dressing in group A or ended the endodontic treatment in a single visit (group B). Blinding of the operator to the end of treatment was difficult as there was only a single operator (SA). The participant did not know whether endodontic treatment was done in multiple or single visit; as another appointment was given to all participants whether to complete the endodontic treatment in Group A or for follow-up in Group B. The data analyst was blinded to the group assignment.

Statistical analysis
All the data was collected and tabulated. Statistical analysis was performed by Microsoft Office 2013 (Excel) and statistical package SPSS version 22. The significance level was set at p-value ≤ 0.05. Non-parametric data was summarized as minimum, maximum and median. Chi-squared test was used to compare the incidence of studied parameters and Mann-Whitney test for analysis of severity of pain 15 .

Results
After enrollment of 78 patients, only 44 participants were included ( Figure 1). The age, gender, and preoperative pain did not differ significantly between the two groups; all participants in the two groups had preoperative no-to-mild pain ( Table 1).
The data of the postoperative pain are shown in Table 2. There was no statistically significant difference between the two tested groups, either in the intensity nor the incidence of different pain categories. In both groups, there was a significant decrease in the incidence of pain at different follow-up periods (p < 0.05; Table 3).
There was no statistically significant difference between the two tested groups regarding the incidence of analgesic intake and number of analgesics tablets taken by the participants (p > 0.05; Table 4).

Discussion
Presence of AP decreases the endodontic success rate, regarding postoperative pain and radiographic healing, by about 10%-15% 2,16 . Maximum removal of the bacteria and irritants causing AP is essential to achieve better prognosis 17 . Placement of inter-appointment dressing has been previously recommended to completely disinfect the root canal system 4 .
TAP has been found to remain active for 30 days 18 and shows better antibacterial efficacy than calcium hydroxide in previous in-vitro studies 18-28 . TAP has been used clinically in case reports and series to treat cases with large periapical lesions, when the use of calcium hydroxide cannot eliminate the symptoms 29-32 . Moreover, previous randomized clinical trials found that TAP is better than calcium hydroxide, as an intracanal medicament, both clinically and radiographically 33-35 .
In the present study, the intensity and the incidence at different pain categories did not differ statistically to a significant level (age, gender and preoperative pain were similarly distributed among both groups). This finding is in accordance to the results of previous studies comparing single visit versus multiple visits with calcium hydroxide 36-41 . During a previous literature search, the authors found no similar studies comparing single visit versus multiple visits with TAP.
In our study, the median postoperative pain of multiple visits group (with TAP) at all follow-up periods was 0 and the incidence of moderate and severe pain ranged from 18.2% to 0%.     In the present study, nearly 95% of the participants were asymptomatic after 72 hours postoperatively. Previous studies found that severe postoperative pain is reduced to a mild pain during this period of time 43,44 .
Within the conditions of this study, it could be concluded that postoperative pain was similar after performing endodontic treatment in multiple visits with triple antibiotic paste interappointment dressing or in a single visit.

Grant information
The author(s) declared that no grants were involved in supporting this work. Stated as: "Triple antibiotic paste as an interappointment dressing in multiple visits endodontic treatment was not proved to reduce the postoperative pain compared to a single visit in patients with necrotic teeth with apical periodontitis who did not have an interappointment dressing." Suggested correction: There is no significant difference in the postoperative pain when endodontic treatment is carried out in patients for necrotic teeth with apical periodontitis either in multiple visits with an interappointment dressing of triple antibiotic paste or in a single visit without an interappointment dressing.

Introduction:
-It is clear and appropriate, but very brief. Therefore, it needs elaboration on the contents related to postoperative pain/flare-up, particularly following single visit vs. multiple visit endodontics, and triple antibiotic paste.

Methods:
Trial design: -CONSORT guidelines have been followed and CONSORT checklist for reporting has been mentioned.

Sample size calculation:
-Sample size calculation is clear, but the authors must state the percentage of anticipated drop-out rate.

Treatment procedures:
-The proportion or ratio of antibiotics used for the TAP should be specified. -All the outcomes measured in the study have been included in the results section.
-The name of the statistical test/tests applied for each table (i.e. Tables 1, 2, 3, and 4) should be stated as a foot note.
-The median value of pain intensity, which has been recorded using numerical rating scale (NRS), should be described together with 1 quartile (Q1) and 3 quartile (Q3).
-value 1 must be reported as 0.999 (Tables 2 and 4). -p -values must be reported to 3 decimal places (Tables 1 and 4). Stated as: "all participants in the two groups had preoperative no-to-mild pain (Table 1)." Suggested correction: all the participants in both the groups had preoperative no-to-mild pain ( Table 1). 2) Page no. 4, Paragraph no. 2, Sentence line no. 1: Stated as: "The data of the postoperative pain are shown in Table 2." Suggested correction: The data of the postoperative pain is shown in Table 2. 3) Page no. 4, Paragraph no. 2, Sentence line no. 3: Stated as: "either in the intensity nor the incidence of different pain categories." Suggested correction: either in the intensity or in the incidence of different pain categories.

Or st rd
Stated as: "Within the conditions of this study, it could be concluded that postoperative pain was similar after performing endodontic treatment in multiple visits with triple antibiotic paste interappointment dressing or in a single visit." Suggested correction: Within the limitations of this study, it could be concluded that there is no significant difference in the postoperative pain when endodontic treatment is carried out in patients for necrotic teeth with apical periodontitis either in multiple visits with an interappointment dressing of triple antibiotic paste or in a single visit without an interappointment dressing.

Is the work clearly and accurately presented and does it cite the current literature? Yes
Is the study design appropriate and is the work technically sound? Yes

If applicable, is the statistical analysis and its interpretation appropriate? Yes
Are all the source data underlying the results available to ensure full reproducibility? Yes

Are the conclusions drawn adequately supported by the results? Partly
No competing interests were disclosed.

Competing Interests:
Reviewer Expertise: Dr. A. R. Vivekananda Pai: Restorative dental materials, Restorative and Esthetic dentistry, and Endodontics.
We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above.
I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.
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