Evaluation of postoperative pain in infected root canals after using double antibiotic paste versus calcium hydroxide as intra-canal medication: A randomized controlled trial

Background: Postoperative pain is defined as pain of any degree after initiation of endodontic treatment either intra-appointment or post-obturation and is considered an undesirable occurrence for both patient and dentist. It was suggested that bacterial injury is probably the major cause of pain. Intra-canal medicaments are widely used to kill any bacteria surviving after instrumentation and irrigation. The aim of this study was to assess the ability of double antibiotic paste versus calcium hydroxide used as intra-canal medication in reducing postoperative pain. Methods: 36 patients with single rooted necrotic premolars with apical periodontitis were randomly assigned into two groups according to the intra-canal medication used: calcium hydroxide group (CH) and double antibiotic paste group (DAP). Preoperative pain was recorded using numerical rating scale. After isolation, access cavity was performed followed by chemico-mechanical preparation using rotary Race files with 2.5% sodium hypochlorite irrigation. Subsequently, intra-canal medication was placed and postoperative pain was recorded at 6, 12, 24 and 48 hours postoperatively. Results: There was no statistically significant difference between both groups. Both groups resulted in an increase in median pain value from preoperative to 6 hours postoperative, followed by gradual decrease from 6 hours to 12, 24, 48 hours postoperatively with statistically significant difference. When comparing both groups, DAP group showed lower postoperative pain values than CH group at 12 and 24 hours, but this was not statistically significant. Conclusion: The use of intra-canal medication in necrotic teeth with apical periodontitis was efficient in reducing postoperative pain regardless of type of intra-canal medication used. Trial registration: PACTR201605001482394 (Date: 22 nd February 2016).


Introduction
Pain is the main symptom in many medical and dental conditions that can significantly alter the person's general functioning 1 . Post-endodontic pain remains a serious problem facing the dental profession. It may occur as a result of several factors, including chemical, mechanical or bacterial irritation to the periapical tissues 2 . It has been suggested that the presence of bacteria as a result of failure to properly disinfect the root canal is the major cause of pain 3 . Many studies have found a direct relationship between root canal infection and the level of pain after endodontic treatment 4 . Thus, endodontic treatment is primarily focused on utmost elimination of these bacteria. Antibacterial intra-canal medicaments have been advocated in efforts to kill any bacteria surviving after chemico-mechanical preparation.
Several intra-canal medications have been used, including calcium hydroxide which is the most widely used intra-canal medication. It is characterized by its initial bactericidal, bacteriostatic effect and its high pH 5 . It has been suggested that calcium hydroxide has pain preventive characteristics due to its antibacterial action or tissue altering effects. Moreover, it controls inflammation and has repair potential 6 . However, there is no clear evidence of its effect on post-endodontic pain 7 . Other studies found that calcium hydroxide was not very effective in decreasing post-treatment pain when used alone 8,9 .
Double antibiotic paste is a mixture of metronidazole and ciprofloxacin, which is used as intra-canal medication for disinfection of necrotic teeth. It has been reported to be effective at reducing bacterial counts in the infected root canals 10 . When commonly used medicaments fail in eliminating the symptoms, then antibiotic paste can be used for treatment of teeth with large periapical lesions 11 .
The objectives of the present study were to test the null hypothesis of whether the use of double antibiotic paste will be more effective in reduction of pain than calcium hydroxide, or if this paste will have disadvantages and complaints more than the traditional method used.

Methods
The article has been written in concordance with CONSORT guidelines (Supplementary File 1).

Study setting
The study design is a parallel randomized controlled trial with allocation ratio 1:1 and a Superiority Framework. The study was conducted in the duration between March 2016 and March 2017. The protocol of this study was approved by the Ethics Committee of the Faculty of Oral and Dental Medicine, Cairo University, Egypt (approval number 15918). The nature of this study, and associated risks were fully explained to the patients and informed consent forms were signed before initial treatment.

Sample size
Based on a previous study by Ehrmann et al. (2003), a medium effect size of approximately 0.25 is expected. A total sample size of 24 patients will be sufficient to detect an effect size of 0.25, a power of 80%, and a significance level of 5%. This number has been increased to a total sample size of 28, to adjust for using nonparametric tests. The number is again increased to a total sample size of 36 (18 in each of the two groups) to allow for losses of around 25%. Sample size was calculated using G*Power program (University of Düsseldorf, Düsseldorf, Germany). Minimal clinical difference 3.5 and 4.5 at 24 hrs and 48 hrs respectively.

Participants
In total, 36 participants were included in the study with maxillary or mandibular non-vital single rooted premolar teeth showing tenderness to percussion.
Exclusion criteria: pregnant women, patients who had received antibiotic treatment during the last 3 months, patients having more than one tooth requiring root canal treatment, teeth with periodontal probing depth >4mm, teeth that couldn't be isolated with a rubber dam, teeth with previous root canal treatment, or teeth with fluctuant facial swelling where emergency management should include incision and drainage.
Patients were randomly assigned into two groups (n=18/group) according to the intra-canal medication used, using a computer generated random number table at the Center of Evidence-based Dentistry (EBD), Cairo University. The assistant supervisor generated the random sequence and assigned the participants to the intervention or control groups.
Experimental group: double antibiotic paste (DAP); control group: calcium hydroxide paste (CH). All clinical procedures were performed by a single endodontist.

Intervention
All patients accepted two-visit root canal treatment. Preoperative pain was recorded before any intervention.
First visit: Teeth were anaesthetized using nerve block or infiltration technique by local anesthesia (Articaine HCI 4% & Adrenaline 1:100,000) and properly isolated with rubber dam. After access cavity preparation, the working length was checked using apex locator and confirmed by a radiograph. The root canals were prepared using rotary Race files (Fkg Dentaire, Switzerland) along with 2.5% sodium hypochlorite irrigation. The canals were dried and filled with intra-canal medication plugged into the canal by using Lentulo spiral according to the randomly selected group (DAP group -combination of 500 mg ciprofloxacin and 500 mg metronidazole ground then mixed with saline to obtain creamy consistency; CH group). The access cavities were properly filled with glass ionomer to ensure proper sealing with no leakage of any oral fluids inside the root canal, which might disturb the action of the intra-canal medication.
Patients were instructed to record their postoperative pain level (see below) after 6, 12, 24 and 48 hours.
Second visit: After 7 days, all the patients returned the pain charts and the root canals were obturated using lateral condensation technique and resin-based root canal sealer.

Outcomes
Primary outcome measure is postoperative pain.
A pain chart using numerical rating scale (NRS) was used to record the patients' pain level. The NRS (0-10 scale) consists of a line anchored by two extremes "No pain" and "the worst pain". Patients were asked to choose the mark that represented their level of pain from 0 to 10. Pain level was assigned as follow: 0, "no pain"; 1-3, "mild pain"; 4-6, "moderate pain"; 7-10, "severe pain".

Blinding
The study was double-blinded (the participants and the assessor). Participants did not know which group they were treated with; they chose a folded paper inside an opaque envelope which contained the numbers of each random sequence for both groups. The assessor, who assessed all outcome data, did not know which group the participants were related to.

Statistical analysis
Data was analyzed using IBM SPSS 21 (SPSS Inc., Chicago, IL, USA). The level of pain was described as median and range. Pain score was compared between the two groups using Mann-Whitney U test. Friedman test was performed to test the significance between the 4-time periods within each group. Chi square test was used to compare qualitative pain score. The level of significance was set at P < 0.05. All tests were two tailed.

Results
In total, 36 patients were included in this study; Table 1 shows their baseline characteristics. A CONSORT flow diagram can be found in Supplementary File 2.
The overall highest incidence of pain values in both groups was at 6 hours postoperatively, whereas the lowest incidence of pain values was at 48 hours postoperatively with no statistically significant difference between them. The DAP group showed lower postoperative pain values at 12 and 24 hours compared with the CH group, but with no statistical significance difference (

Discussion
Effective control over the intra-canal microbial load before root canal obturation is a key element that increases the success rate of endodontic treatment 12 . Necrotic pulp with periapical periodontitis was selected for assessment of postoperative pain, as the highest frequency of postoperative pain occurred in patients with necrotic pulp and apical periodontitis 4,13 that harbored large number of bacteria due to its polymicobial nature as reported in previous studies [14][15][16][17][18] . In the present study, pain was recorded using a numerical rating scale (NRS), which is considered a consensus-based, standardized assessment method and reports better compliance compared to other scales 19 . The literature shows that the NRS provides sufficient distinctive power for chronic pain patients for describing their pain intensity 20 . As well, it was preferred by the majority of patients in different regions 21,22 . In the present study, the Rotary Race system was chosen for root canal preparation, owing to the fact that rotary NiTi instruments result in minimal debris extrusion compared to hand instrumentation 23 , which in turn would result in less postoperative pain. This was attributed to their rotary action, as well as copious irrigation associated with these instruments 24 .
In the present study, in patients with necrotic teeth with apical periodontitis, the use of double antibiotic paste showed no difference regarding postoperative pain compared to CH. DAP showed lesser postoperative pain at 12 and 24 hours than the CH group but this didn't reach a level of statistical significance. This might be attributed to the combined spectrum of antimicrobial activity and synergetic or additive action of antibiotics found in DAP. In accordance with the results of this study, Pai et al. 25 reported no statistically significant difference in postoperative pain between calcium hydroxide and triple antibiotic paste (TAP), although TAP was more effective that calcium hydroxide but this was not statistically insignificant. As reported in other studies 7-9,26,27 , there was no statistically significant difference in postoperative pain between calcium hydroxide paste and no intra-canal medication. In contrast, some studies counteracted our findings 28,29 , suggesting that CH had pain-preventive properties because of its antimicrobial as well as its tissue-altering effects. These properties could be referred to the chemical, physical, and antimicrobial effects of calcium hydroxide due to the diffusion of its hydroxyl (OH−) ions produced from ionization in aqueous solution, which leads to a highly alkaline environment. This is not conducive for the survival of microorganisms inside root canals 3,30 , and most of the microorganisms cannot sustain that high a pH (15.5).

Conclusion
The use of intra-canal medication for 7 days in necrotic teeth with apical periodontitis was efficient in reducing postoperative pain regardless of the type of intra-canal medication used.

Grant information
The author(s) declared that no grants were involved in supporting this work. The objective of this study was to assess the ability of double antibiotic paste versus calcium hydroxide used as intra-canal medication in reducing postoperative pain. Post-operative pain is currently a relevant subject in the dental practice. Overall, the study was well written and designed. Additionally, it fits in a Randomized Control Trial, which increases the significance of the research. The results are well described, and no differences were observed between the groups; however, clinically, the antibiotic pastes present some disadvantages compared to calcium hydroxide. The sample size is adequate for this kind of research. I recommend the manuscript for indexing.

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? Yes
No competing interests were disclosed.

Competing Interests:
Referee Expertise: endodontics, endodontic microbiology, endotoxins I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.