DR.

SAYNA SHAMSZADEH (Orcid ID : 0000-0001-6688-3430)

Accepted Article
Article type : Review

Title: The efficacy of non-narcotic analgesics on postoperative endodontic

pain: A systematic review and meta-analysis

Subtitle: The efficacy of non-steroidal anti-inflammatory drugs and/or paracetamol on

postoperative endodontic pain

Armin Shirvani1, Sayna Shamszadeh2*, Mohammad Jafar Eghbal2, Saeed Asgary1

1- Iranian Center for Endodontic Research, Research Institute of Dental Sciences, Shahid Beheshti University

of Medical Science, Tehran, Iran

2- Dental Research Center, Research Institute of Dental Sciences, Shahid Beheshti University of Medical

Science, Tehran, Iran

Correspondence: Dr. Sayna Shamszadeh,

Dental Research Center, Research Institute of Dental Sciences, Shahid Beheshti University of Medical Science,

Evin, Postal code: 1983963113, Tehran, Iran.

Tel: +98 21 22413897, Fax: +98 21 22427753

Email: saynashams@gmail.com

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/joor.12519
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 Summary

The objective of this review was to evaluate the efficacy of non-narcotic analgesics including non-
Accepted Article
steroidal anti-inflammatory drugs (NSAIDs) and/or paracetamol in the treatment of postoperative

endodontic pain. Additionally, we aimed to examine the possible association of study covariates on

the pain scores using meta-regression analysis. An electronic search was performed in 2016. After

data extraction and quality assessment of the included studies (n=27, representing 2188 patients),

meta-analysis was performed using a random-effect inverse-variance method. Meta-regression

analysis was conducted to examine the associations between effect sizes and study-level covariates

(P<0.05). The results showed that administration of non-narcotic analgesic was more effective than

placebo in the management of postoperative pain, resulting in a lower pain scores with a standardized

mean difference of -0.50 (95% CI= -0.70, -0.30), -0.76 (95%CI= -0.95, -0.56), -1.15 (95% CI= -1.52,

-0.78), -0.65 (95% CI= -1.05, -0.26) for immediately after the procedure, 6-, 12-, and 24 h

postoperative follow-ups (test for statistical heterogeneity: P=0.000,P=0.000,P=0.000,and P= 0.001),

respectively. Our meta-regression analysis provided the evidence for association between some study

covariates with treatment effect, each at different follow-ups. We concluded that the clinicians can

manage postoperative endodontic pain by administration of NSAIDs and/or paracetamol. However,

analgesics regimens should be considered as important determinants when prescribing a

pharmacological adjuvant.

Key words: endodontic, meta-analysis, non-narcotic analgesics, postoperative pain.

Introduction

Postoperative pain is a common complication of root canal therapy and its prevalence is estimated to

be around 25 to 40% (1). This complication is related to the exacerbation of inflammatory response

and release of inflammatory mediators such as prostaglandins that activate sensitive nociceptor in

periapical tissues (2).

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 Non-narcotic analgesics including non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol

(acetaminophen) are considered as an important class of pharmacological agent in the treatment of

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endodontic pain, where they are known to reduce inflammation. The beneficial action of NSAIDs

have been linked to their ability to inhibit synthesis of prostaglandin at sites of inflammation (3). In

patients with known sensitivity to NSAIDs, and in those who have gastrointestinal ulcerations,

paracetamol could be considered for treatment of endodontic pain; it is a weak inhibitor of peripheral

prostaglandin synthesis and this action may be via the inhibition of central hyperalgesia induced by

pain-producing neurotransmitter such as substance P (4). There is also some evidence of its impact on

the cyclooxygenase-dependent mechanism (5).

Several clinical studies have evaluated the use of non-narcotic analgesics to manage postoperative

endodontic pain. However, the results of such studies have resulted in conflicting conclusions. Some

studies have suggested that the use of non-narcotic analgesics can decrease the incidence of

postoperative endodontic pain (6, 7). In contrast, others have concluded no beneficial effect of the

non-narcotic analgesics administration to manage such complications (8, 9).

Previous systematic review in 2002 has evaluated the efficacy of NSAIDs on postoperative

endodontic pain (10). Their conclusion, however, was limited by lack of analysis. Since the

publication of that review, several RCTs have been published (11-15).

Meta-analysis of clinical trials is a statistical methodology allowing quantification of the therapeutic

effect from multiple studies. However, where studies presented with heterogeneity, it is an extension

of meta-analysis to estimate intervention effect that are not directly observed, or observed intervention

effect estimates to be strengthened from indirect estimates. In the case, meta-regression analysis

attempts to explain the association between study-level characteristics and treatment effects in a

collection of studies (16).

This review was aimed to summarize current evidence on the efficacy of non-narcotic analgesics for

the treatment of postoperative endodontic pain and to explore whether study-level covariates is related

to the estimated treatment effect.

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 Materials and methods

The current review was performed in accordance with the recommendations of the PRISMA
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statement (17).

Search strategy

A computerized search of Medline, PubMed, the Cochrane Library, Scopus, Science direct, and

Google scholar was conducted using the following key: [endodontic OR root canal treatment OR root

canal therapy] AND [NSAIDs OR Non-Steroidal Anti Inflammatory Drugs OR analgesics OR

paracetamol] AND [postoperative pain]. There was no language or publication data restriction.

Additionally, the references of retrieved trial were hand searched for further relevant article. The

search was also supplemented by screening major thesis databases: Networked Digital Library of

Thesis and Dissertations, Pro-Quest Digital Dissertation and Index to Thesis.

Selection criteria

Randomized placebo-controlled trials that met the following inclusion criteria was selected:

(1) Adults aged 15 years or above with clinical diagnosis of irreversible pulpitis or pulpal necrosis.

(2) Subjects were underwent non-surgical primary root canal therapy,

(3) Treatment was undertaken in single vs. multiple sessions.

(4) Multiple or single doses of non-narcotic analgesics (NSAID and/or paracetamol) were

administrated preoperatively, intraoperatively, or postoperatively by any route.

(5) Outcome measure was postoperative pain intensity or pain relief within the first 24 h.

Trials were excluded if they had no placebo arm or if they did not report adequate statistical data for

estimation of effect sizes.

Two authors (A.S., S.S) independently screened all the references by titles and abstracts. Any that did

not meet the selection criteria were excluded. Reports of the remaining articled were read in full and

reviewed for eligibility. Any disagreement was resolved by discussion through all authors.

Data extraction

A data extraction form was used by the authors, who were abstracted data for the following features:

(1) trial identification information, (2) demographic and clinical characteristics of patients (3) design

characteristics, (4), dose regimens for study drugs, and (5) outcome measures at follow-up. If the

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 outcomes in the published articles were presented in a graph, Image J software Version 2.1.4.7 (Image

J software, National Institutes of Health, USA) was used to abstract data from the graph. Any
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disagreement regarding data extraction was resolved by discussion.

Risk of bias assessment

Risk of bias assessment was conducted using the Cochrane Collaboration “Risk of Bias” tool (18)on

the following domains: 1) randomization procedure (randomization generation and randomization

concealment), 2) blinding (participants and outcome assessors), 3) incomplete outcome data , 4)

selective outcome reporting, and 5) other sources of bias related to comparability of groups at base-

line, co-intervention, and timing of outcome assessment. Each domain was recorded as ‘Low’ (low

risk of bias), ‘High’ (high risk of bias), or ‘Unclear’ (unclear or unknown risk of bias). Assessments

were made independently by the 2 authors and disagreements resolved by consensus.

Data analysis

The outcome measure was expressed as standardized mean difference (SMD) by dividing the

difference in mean changes at the end of follow-up (immediately after the procedure, 6-, 12-, and 48 h

postoperatively) by the pooled SD of changes (19). We chose SMD because changes in pain intensity

scores were reported by different scales in trials, and the SMD can compare pain intensity scores in a

uniform manner. In case where variance data was not reported as standard deviation, it was estimated

with algebraic recalculations or various approximation methods (20). If eligible studies compared

different types or multiple dosages of non-narcotic analgesics to placebo, all types and dosages were

included as separate comparisons (i.e., 3-arm trials with 2 active interventions will generate 2

randomized comparisons with placebo). In this case, the numbers of participants in the placebo arms

were divided by the number of active treatment arms, thus avoiding double counting of participants

and yielding more conservative estimates. Data were pooled using the random-effect Inverse variance

method (P<0.05). The heterogeneity among the trials was determined by using a Q statistic test.

Additional analysis we also performed a meta-regression analysis to examine whether the treatment

effect differed by certain covariates adjusting for study differences. Meta-regression was conducted

using random-effect model, with the proportion of between study variance explained using the

Knapp-Hartung modification(21). The examined covariates were as follow: 1) effect of risk of bias in

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 included trials, defined as blinding of participants, adequately of intention-to-treat analysis, and use of

co-interventions; 2) characteristics of population (preoperative pulpal diagnosis); 3) study

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characteristics (number of visit); and 4) details of intervention (non-narcotic analgesic regimens).

We first, fit a basic regression model containing all covariates. Then, for stronger covariate (greater P-

values) we tested a multivariate meta-regression model with the covariate-by-treatment interaction

and study indicators versus the basic regression model using a backward stepwise approach to

determine if the interaction was significant. Adjusted P-values were computed using permutation test

based on Monte Carlo simulation. The level of significance was set at 0.05. All statistical analyses

were performed using the Stata version 12.0 software (Stata Corporation, College Station, Texas,

USA)

Results

Literature search

The literature search initially identified 105 relevant citations. After review of title and abstract, 52

articles identified as being potentially eligible for inclusion into this review (Figure 1).

After screening the full-text articles, 27 randomized placebo-controlled trials including 2188

participants were finally included in the current meta-analysis.

Study characteristics

The characteristics of the included studies are shown in Table 1. The total number of participants

included in this review was 2188 adults diagnosed either as irreversible pulpitis (6-9, 11-15, 22-32) or

pulpal necrosis (9, 22, 27, 30, 33, 34) and underwent single-(6-8, 11-15, 26-32, 35) vs. multiple-visit

(9, 23, 25, 33, 36) root canal therapy.

The Participants were randomly allocated in 2 groups: 1 group received different types of non-

narcotic analgesics, and the other received placebo. Non-narcotic analgesics were given

preoperatively in 8 trials (6, 11-13, 15, 22, 25-27, 32), as intraoperative doses in 2, and as

postoperative dose in 9 trials (7-9, 14, 24, 28-30, 33-36). The drug dosing scheme varied between the

included trials: 24 trials administrated drugs as a single-dose (6-9, 11-15, 23, 24, 26, 28-34, 36),

whereas 3 trials administrated drugs as a multiple-dose (22, 25, 35). Monotherapy was administrated

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 in 22 trials (6, 8, 9, 11-15, 22, 23, 25-27, 29-34, 36), whereas in 3 trials analgesics were administrated

as combination therapy (22, 24, 27, 28, 35). Non-narcotic analgesics were delivered via different
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routes: orally (7-9, 11, 12, 14, 15, 22, 24-35), intracanal (23), or intraligamentary (6, 13). All studies

reported pain intensity score as the main outcome measure from the immediately after the procedure

until 24 h post-op.

Risk of bias Assessment

The methodological quality of the trials was generally satisfactory (Table 2). All studies were

randomized placebo-controlled trials and did not clearly report the allocation concealment. Studies

adopted patients blinding. But, blinding of outcome assessor was not adopted in 5 studies. Five

studies was considered quality in high, and studies reported use of co-interventions including the use

of rescue medication and supplementary anesthesia thus the quality of them was in moderate. The

effect of risk of bias in included trials on the treatment effect was examined by the meta-regression

analysis.

Pain scores

Pain scores at immediately after the procedure. Eight studies (19 comparisons) provided data on pain

scores at immediately after the procedure (Figure 2); pooled results showed a statistically significant

reduction in pain scores (SMD= -0.50; 95% CI= -0.70, -0.30; P=0.000) in analgesic-treated groups.

Regarding the high heterogeneity of these results (Q 64.294; P= 0.000), meta-regression was

performed (Table 3); the meta-regression found no association.

Pain scores at 6 h. twenty studies (36 comparisons) provided data on pain scores at 6 h (Figure 3).

Pooled results showed a significant reduction in pain scores at 6 h (SMD= -0.76; 95% CI= -0.95, -

0.56; P= 0.000) with the administration of non-narcotic analgesics. Regarding the high heterogeneity

of these results (Q= 107.283; P=0.000), meta-regression analysis was performed; the meta-regression

found intraligamentary injection of drug (P=0.004), supplementary anesthesia (P=0.01), different

types of NSIDs [ibuprofen (p=0.05), and indomethacin (P=0.000)], and use of rescue medication

(P=0.01) to be a significant predictor of pain score at 6 h (Table 3).

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 Pain scores at 12 h. fifteen studies (26 comparisons) provided data on pain scores at 12 h (Figure 4).

The pooled analysis showed a significant reduction in pain scores at 12 h (SMD= -1.15; 95% CI= -
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1.52, -0.78; P=0.000) with the administration of non-narcotic analgesics. There was an evidence for

the high heterogeneity (Q= 176.730; P=0.000) and thus, meta-regression analysis was performed; the

meta-regression found preoperative delivery of drug (p=0.02), diagnosis of irreversible pulpitis

(P=0.03), type of NSAIDs [Indomethacin (P=0.002)], use of rescue medication (P=0.05) and

supplementary anesthesia (P=0.02) to be a significant predictor of pain scores at 12 h (Table 3).

Pain scores at 24 h. fifteen studies (26 comparisons) provided data on pain scores at 24 h for

postoperative pain treatment (Figure 5). The pooled analysis showed a significant reduction in pain

scores at 24 h (SMD= -0.55; 95% CI= -1.05, -1.05; P= 0.001) with the administration of non-narcotic

analgesics.

Regarding the high heterogeneity (Q= 192.405; p=0.000), meta-regression analysis was performed

and found diagnosis of irreversible pulpitis (P=0.005), multiple-dose regimens (P=0.005), oral route

(P=0.000), supplementary anesthesia (P=0.005), postoperative drug delivery (P=0.002), and use of

rescue medication (P=0.01) to be a significant predictor of pain scores at 24 h (Table 3).

Discussion

Postoperative pain is an unpleasant experience after root canal therapy, which might be perceived as

the main source of patient’s discomfort. Such pain arises as a consequence of peri radicular damage

and release of inflammatory mediators such as prostaglandins. Peripheral and central sensitization as a

consequence of acute tissue damage and progenitor of acute and chronic pain has been demonstrated

in a variety of animal models and experiments in human subjects (37, 38). Based on data suggesting

the potential involvement of anti-inflammatory process in the patho-physiology of endodontic pain,

non-narcotic analgesics including NSAIDs and/or paracetamol have been studied as a candidate

adjunctive pharmacological therapy in endodontic patients who suffered from post-op pain.

The current review of 27 RCTs investigating the use of non-narcotic analgesics in adults undergoing

root canal therapy provides the level 1 evidence. The main conclusion that can be drawn from this

review is that there is a significant advantage to use analgesic over placebo for managing

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 postoperative endodontic pain. The clinical results of our review were consistent to prior systematic

review in which NSAIDs were effective in reducing postoperative endodontic pain when compared to
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placebo (10). However, we have added more evidence by including additional RCTs.

Since the results showed a significant statistical trend, the results were heterogeneous. This can result

from differences in the patient’s characteristics, and from the interventions applied. On ground of this

heterogeneity, the meta-regression analysis was applied to assess the association between different

covariates and treatment effect. Meta-regression may partially compensate for the comparisons where

there is heterogeneity between different trials, but the differences within the groups of trials are small.

This study deals with just such a situation (39).

From our analysis, one of the strong predictor of improved analgesia (and hence a lower pain score)

after root canal therapy is a type of NSAIDs used. NSAIDs are widely used for the management of

inflammatory-induced pain; however, there is a discrepancy between the extents to which NSAIDs

are more useful in control of post-op (40). Postoperative pain appears to be more decreased with use

of indomethacin and Rofecoxib at 24h. Why differences in efficacy should exist between NSAIDS in

not clear. Although both indomethacin and Rofecoxib had a similar mechanism of action, small

differences in their chemical structure could influence their efficacy and pharmacological properties

(41). However,

Due to the low number of comparative trials, there is little scientific reason to prefer one NSAID over

the other.

There is good evidence that preoperative administration of NSAIDs seems to be more effective that

postoperative drug administration in oral surgery (42, 43) though some studies have reported no

difference between preoperative or postoperative administration of non-narcotic analgesics (44, 45).

We found that preoperative administration resulted in better analgesia at 12 h. From the biological

view, the reduction in prostaglandin synthesis would attenuate the central and peripheral nervous

system responses to the adverse stimuli; this could diminish the central and peripheral sensitization

phenomena – and therefore patient response to subsequent painful stimuli (46). However,

postoperative administration of non-narcotic analgesics appears to improve analgesia at 24; this can

happened due to this fact that intensity of pain is reduced by time. Consideration can therefore be

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 given to either preoperative administration or start the dosing immediately after the treatment session,

before the offset of local anesthesia.

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It is a common belief that parental NSAIDs would be more effective that the oral route. A prior meta-

analysis evaluated the efficacy of NSAIDs delivered by various routes in acute and chronic pain. The

authors concluded that there is a lack of evidence for any difference in analgesic efficacy of NSAIDs

delivered by different routes. In contrast to this results, our meta-regression analysis showed that

postoperative pain at 6 h appears to be more decreased when NSAID were delivered via

intraligamentary route. Parental route can provide a greater predictable response due to faster rate of

drug absorption and onset of analgesia. It should not be expected that the response of different

patients to oral administration of the drug be the same and predictable. Hence, it is recommended that

when the patients are intolerant of oral analgesics such as those with gastritis or asthma, the clinician

use an injectable product. However, regarding the low sample size, these results must be interpreted

with caution.

Our meta-regression analysis found that supplementary injection was more effective at 24h when

compared with no administration of supplementary anesthesia, especially in patients with inflamed

pulp. If we look deeply, supplementary anesthesia is often requested in patients with irreversible

pulpitis whose teeth are difficult to anesthetize and presented more advanced level of inflammatory

stage (47). On the other hand, the clinical and histological findings of pulpal inflammatory stage are

inconsistence and hence, the need for supplementary anesthesia could be considered as the better

predictor; we interpreted that such patients might need more analgesic, due to the increased duration

of inflammation.

We found that pulp vitality can be a strong predictor for pain relief at 12-, and 24h post-op. It has

been reported that pulpal status can influence the postoperative pain intensity. Non-narcotic analgesics

are administrated to reduce inflammatory pain, and, that can be why our results showed greater

magnitude of treatment effect in patients with irreversible pulpitis.

The strength of this study was the use of an approximation method by differential equation to include

more trials and increase the power of the evidence. As already stated, the analgesics regimens in

included trials were variable, although the statistical technique of meta-regression partially

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 compensates for this. Since we found the source of heterogeneity by meta-regression analysis, but the

results should be interpreted cautiously. This review does have weakness; there was no consistent
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reporting of every covariate assessment in all follow-ups and hence, it can affect our interpretation.

Conclusions

In conclusion, we provide evidence on the potency of non-narcotic analgesics in treatment of

postoperative endodontic pain. The definitive answer on how best to manage such pain can be

summarized as follow: I) administration of multiple-dose regimens of non-narcotic analgesics during

the postoperative period can reach the most efficacy, II) Various types of analgesics have different

efficacy which might be influenced by other treatment strategies, and III) the need for supplementary

anesthesia can be an appropriate predictor of duration of pain. Hence, we can use some alternatives

such as combination therapy and Intraligamentary injection, to reduce the duration of inflammation.

Disclosure/Acknowledgements

Ethical approval

There is no necessary ethical approval.

Source of funding

There is no source of funding.

Conflict of interest

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

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pharmacological activity, and pharmacokinetic evaluation of indomethacin-loaded poly (d, l-
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Table 1: Characteristics of included studies

Reference Patient Preop pulpal N of non-narcotic analgesic(s) Dose Method of Time of

(n) status visit used delivery delivery
Ryan, 2008(22) 43 Vital /non-vital 2 Ibuprofen, Multiple oral preop
Pentazocine/naloxone
Attar, 2008 (9) 39 Vital /non-vital 2 Ibuprofen Single oral postop
Nekoofar,2003 (8) 51 Vital 1 Meloxicam Single oral postop
Piroxicam
Rashka,2013(6) 52 Vital 1 Diclofenac sodium Single IL preop
Negm,1989 (36) 267 Vital /non-vital 2 Piroxicam, Single oral postop
Diclofenac sodium
Mehrvarzfar,2012(35) 100 Vital 1 Tramadol Multiple oral postop
Novafen,
Naproxen
Salarpoor,2014 (7) 100 Vital 1 Indomethacin, Single oral postop
Ibuprofen
Negm,1994(23) 393 Vital 2 Diclofenac sodium, Single Intracanal Intraop
Diclofenac sodium / Hyaloronidase medicament
ketoprofen,
ketoprofen/ Hyaloronidase,
Hyaloronidase
Negm,1994 (23) 367 Vital 2 Diclofenac sodium Single Intracanal Intraop
Diclofenac sodium / Hyaloronidase medicament
ketoprofen
ketoprofen/ Hyaloronidase
Hyaloronidase
Makkar,2014(24) 30 Vital 2 Diclofenac sodium /Paracetamol Single oral postop
Paracetamol/ Ibuprofen
Flath,1987 (25) 60 Vital 2 Flurbiprofen Multiple oral preop
Saatchi,2009 (26) 90 Vital 1 Ibuprofen Single oral preop
Diclofenac sodium
Yaghooti,2011 (12) 48 Vital 1 Ibuprofen Single oral preop
Sulindac
Menhinick,2004 (27) 57 Vital /non-vital 1 Ibuprofen Single oral preop
Ibuprofen/Acetaminophen
Kaviani,2011 (11) 36 Vital 1 ketamine Single oral postop

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 Baradaran,2014 (28) 45 Vital 1 Ibuprofen Single oral postop
Ibuprofen/Alprazolam
Ashraf,2002(29) 60 Vital 1 Rofecoxib Single oral postop
Ibuprofen
Menke,2000 (30 36 Vital /non-vital 1 Etodolac Single oral postop
Accepted Article
Ibuprofen
Mirzai,2011 (31) 90 Vital 1 Celecoxib Single oral postop
Ibuprofen
Gopikrishna,2003 (32) 45 Vital 1 Ibuprofen, Single oral preop
Rofecoxib
Ashraf,2013 (14) 30 Vital 1 Celecoxib Single oral postop
Douglas, 2004 (34) 60 Necrosis 2 Rofecoxib Single oral postop
Diclofenac sodium
Ehsani,2012(33) 80 Necrosis 2 Ibuprofen, Single oral postop
N-acetyl cysteine
Atbaei, 2012 (13) 65 Vital 1 Piroxicam Single , IL, preop
Andrew, 1999 36 Vital /non-vital 2 Flurbiprofen Multiple, oral postop
Tramadol
Mokhtari, 2016 (15) 66 Vital 1 Indomethacin Single oral preop
Ibuprofen

IL, Intraligamentary; Intraop, dosing started between the treatment sessions; N, numbers; NSAIDs, non-steroidal anti-
inflammatory drugs; Pre, dosing started before procedure; Post, dosing started after procedure.

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 Table 2: Risk of bias assessment of included trials
Accepted Article
Study (year) Randomization blinding Selective Incomplete
Gene concealment Outcome Patient reporting outcome data
ration assessor
Rayan, 2008 (22) Low risk Unclear Low risk Low risk Low risk Low risk
Attar, 2008 (9) Low risk Unclear Low risk Low risk Low risk Low risk
Nekoofar,2003(8) Low risk Unclear Low risk Low risk Low risk Low risk
Rashka,2013(6) Low risk Unclear Unclear Low risk Low risk Low risk
Negm,1989 (36) Low risk Unclear Low risk Low risk Low risk Low risk
Mehrvarzfar,2012 (35) Low risk Unclear Low risk Low risk Low risk Low risk
Salarpoor,2014 (7) Low risk Unclear Low risk Low risk Low risk Low risk
Negm,1994 (23) Low risk Unclear Unclear Low risk Low risk Low risk
Negm,1994(23) Low risk Unclear Unclear Low risk Low risk Low risk
Makkar,2014(24) Low risk Unclear Low risk Low risk Low risk Low risk
Flath,1987 (25) Low risk Unclear Low risk Low risk Low risk Low risk
Saatchi,2009 (26) Low risk Unclear Low risk Low risk Low risk Low risk
Yaghooti,2011 (12) Low risk Unclear Low risk Low risk Low risk Low risk
Menhinick,2004 (27) Low risk Unclear Low risk Low risk Low risk Low risk
Kaviani,2011 (11) Low risk Unclear Low risk Low risk Low risk Low risk
Baradaran,2014 (28) Low risk Unclear Low risk Low risk Low risk Low risk
Ashraf,2002 (29) Low risk Unclear Low risk Low risk Low risk Low risk
Menke,2000 (30) Low risk Unclear Unclear Low risk Low risk Low risk
Mirzai,2011(31) Low risk Unclear Low risk Low risk Low risk Low risk
Gopikrishna,2003 (32) Low risk Unclear Low risk Low risk Low risk Low risk
Ashraf,2013 (14) Low risk Unclear Low risk Low risk Low risk Low risk
Douglas, 2004 (34) Low risk Unclear Low risk Low risk Low risk Low risk
Ehsani,2012 (33) Low risk Unclear Low risk Low risk Low risk Low risk
Atbaei, 2012(13) Low risk Unclear Unclear Low risk Low risk Low risk
Andrew, 1999 Low risk Unclear Low risk Low risk Low risk Low risk
Mokhtari, 2016 (15) Low risk Unclear Low risk Low risk Low risk Low risk

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 Table 3: Association between study covariates and treatment effect estimates
Accepted Article
Follow-up Study covariates Meta-regression P-value Comparisons variance Model
coefficient (95 % in this model, n explained, P-value
confidence interval) %
Immediately after the -
- - - - -
procedure
6h Rescue medication -0.67 (-1.19, -0.15) 0.01
Ibuprofen -0.34 (-0.60, -0.003) 0.05
Indomethacin -1.99 (-2.80, -1.17) 0.000
Injection route -1.17 (-1.93, -0.41) 0.004 34 83.89 0.000
Supplementary injection -0.62 (-1.1, -0.13) 0.01
Intention to treat analysis 1.14 (0.71, 1.56) 0.000
Cons -0.72 (-1.1, -0.34) 0.001
12 h Vital teeth 1.45 (0.15, 2.75) 0.03
Preoperative administration 1.61 (0.29, 2.94) 0.02
Combination therapy -0.88 (-2.05, 0.28) 0.1
Rescue medication -1.09 (-2.23, 0.04) 0.05
Indomethacin -3.63 (-5.79, -1.48) 0.002 26 62.39 0.004
Supplementary injection -1.48 (-2.71, -0.24) 0.02
Blinding -0.71 (-1.64, 0.20) 0.10
Intention to treat analysis 0.70 (-0.12, 1.53) 0.003
Cons -2.26 (-3.66, -0.86) 0.003
24 h Vital teeth 0.91 (-0.66, 1.89) 0.005
Postoperative administration -4.27 (-6.59, -1.69) 0.002
Combination therapy -0.66 (-1.53, 0.19) 0.1
Multiple dose 2.75 (0.97, 4.54) 0.005
Oral route 4.24 (2.62, 5.86) 0.000
Rescue medication -0.92 (-1.59, -0.25) 0.01 24 80.9% 0.001
Indomethacin -0.94 (-2.65, 0.76) 0.2
Supplementary injection -1.42 (-2.33, -0.52) 0.005
Blinding -0.98 (-1.80, -0.16) 0.02
Intention to treat analysis 0.64 (-1.44, 1.43) 0.1
Cons -3.98 (-5.83, -2.12) 0.000

N/A, not applicable.

Figure legends:

Figure 1: flow chart of search strategy

Figure 2: A) forest plot analysis of pain score at the immediately after the procedure

Figure 3: forest plot analysis of pain score at 6 h postoperatively.

Figure 4: A) forest plot analysis of pain score at 12 h postoperatively

Figure 5: forest plot analysis of pain score at 24 h postoperatively.

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Accepted Article

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Accepted Article

This article is protected by copyright. All rights reserved.

Accepted Article

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Accepted Article

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Accepted Article

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