Efficacy and Safety of Pulpal Anesthesia Strategies during Endodontic Treatment of Permanent Mandibular Molars with Symptomatic Irreversible Pulpitis: A Systematic Review and Network Meta-analysis

REVIEW ARTICLE Maryam Zanjir, DDS,* Nima Laghapour Lighvan, HBSc,* Carilynne Yarascavitch, BSc, DDS, MSc, Dip. ADBA,*†

Efficacy and Safety of Pulpal Anesthesia Strategies during Endodontic Treatment of Permanent Mandibular Molars with Symptomatic Irreversible Pulpitis: A Systematic Review and Network Meta-analysis

Joseph Beyene, BSc, MSc, PhD,‡ Prakesh S. Shah, MSc, MBBS, MD, DCH, MRCP, FRCPC,§k¶ and Amir Azarpazhooh, DDS, MSc, PhD, FRCD(C)*¶#

SIGNIFICANCE

ABSTRACT Introduction: Several strategies have been investigated for achieving successful pulpal anesthesia during endodontic treatment of mandibular molars with symptomatic irreversible pulpitis. However, comprehensive evaluation and identification of the most efficacious and safe intervention are lacking. We aimed to determine this using network meta-analysis. Methods: MEDLINE, Embase, Cochrane Central, CINAHL, and Scopus databases were searched. Study selection and data extraction were performed in duplicate. Eligible randomized controlled trials were meta-analyzed to estimate the treatment effects (odd ratios [ORs]; 95% credible interval (CrI) and surface under the cumulative ranking curve (SUCRA)]. CINeMA software (University of Bern, Bern, Switzerland) was used to assess the quality of results. Results: Thirty-seven interventions from 46 studies were identified. Compared with the common practice of an inferior alveolar nerve block with 2% lidocaine, a supplemental intraosseous injection was ranked the most efficacious with very low to moderate confidence (2% lidocaine 1 preoperative nonsteroidal anti-inflammatory drugs [NSAIDs] 1 acetaminophen [OR 5 74; 95% CrI, 15–470; SUCRA 5 97%], 2% lidocaine 1 preoperative NSAIDs [OR 5 46; 95% CrI, 8–420; SUCRA 5 94%], 2% lidocaine [OR 5 33; 95% CrI, 14–80; SUCRA 5 93%], 2% lidocaine 1 preoperative opioids 1 acetaminophen [OR 5 20; 95% CrI, 4.4–98; SUCRA 5 86%], and 4% articaine [OR 5 20; 95% CrI, 6.3–96; SUCRA 5 87%]) followed by supplemental buccal and lingual infiltrations using 4% articaine 1 preoperative NSAIDs (OR 5 18; 95% CrI, 6–56; SUCRA 5 86%; very low confidence). No major safety concerns were reported. Conclusions: Very low- to moderate-quality evidence suggests intraosseous injection using 2% lidocaine with 1:100,000 epinephrine or 4% articaine with 1:100,000 epinephrine or buccal and lingual infiltrations of 4% articaine with 1:100,000 epinephrine are superior strategies to achieve pulpal anesthesia during endodontic treatment of mandibular molars with symptomatic irreversible pulpitis. Preoperative NSAIDs or opioids with or without acetaminophen may increase the efficacy of these injections. (J Endod 2019;-:1–30.)

KEY WORDS Endodontic treatment; efficacy; irreversible pulpitis; local anesthetics Symptomatic irreversible pulpitis is a condition in which inflamed pulp results in sharp pain that may be referred, unprovoked, or provoked by thermal stimulus, lingering often 30 seconds or longer after stimulus removal and indicating the need for endodontic treatment1. Obtaining successful pulpal

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A supplemental intraosseous injection using 2% lidocaine or 4% articaine followed by supplemental buccal and lingual infiltrations of 2% articaine is a superior injection technique to achieve pulpal anesthesia during the endodontic treatment of mandibular molars with symptomatic irreversible pulpitis.

From the *Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada; † Department of Dentistry, Sunnybrook Sciences Health Centre, University of Toronto, Toronto, Ontario, Canada; ‡ Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada; §Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; kDepartment of Pediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada; ¶Clinical Epidemiology and Health Care Research, Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; and #Department of Dentistry, Mount Sinai Hospital, Toronto, Ontario, Canada Address requests for reprints to Dr Amir Azarpazhooh, 455–124 Edward Street, Toronto, Ontario M5G 1G6, Canada. E-mail address: amir.azarpazhooh@ dentistry.utoronto.ca 0099-2399/$ - see front matter Copyright © 2019 American Association of Endodontists. https://doi.org/10.1016/ j.joen.2019.09.002

Efficacy and Safety of Pulpal Anesthesia Strategies

1

anesthesia during endodontic treatment of teeth with symptomatic irreversible pulpitis is important for patients’ pain and stress management; however, this can be especially challenging for patients with symptomatic irreversible pulpitis in mandibular teeth because of the failure of the inferior alveolar nerve block (IANB) to always provide profound anesthesia2–5. Increased acidity in the inflamed pulp reduces the amount of basic anesthetic that penetrates the nerve’s membrane, thus delaying or preventing pulpal anesthesia6. Additionally, increased expression of tetrodotoxin-resistant sodium channels occurs because of the increase of prostaglandins and the overexpression of sodium channels7,8. Several randomized controlled trials (RCTs) have investigated interventions to overcome the difficulty of achieving pulpal anesthesia in mandibular teeth for patients with symptomatic irreversible pulpits. Interventions such as changing the local anesthetic solution type9, supplemental injection techniques10–12, premedication with oral analgesics13,14, and increasing the volume of anesthetics15,16 have been assessed; however, available systematic reviews and meta-analyses are inconclusive regarding the most effective intervention. Although some sources concluded that 4% articaine was more successful than 2% lidocaine in patients with irreversible pulpitis17–20, others concluded that the type of anesthetic does not affect efficacy21,22. These pairwise meta-analyses compared the efficacies of only 2 interventions at a time rather than all the interventions available in RCTs, making it challenging to determine the superiority of one intervention over another17– 23 . With the introduction of network metaanalysis (NMA), it is now possible to compare and rank multiple sets of treatments for a particular condition regardless of whether or not the treatments were directly compared in RCTs24. For instance, 1 NMA compared the effect of oral premedication on the success rates of IANB as a primary injection25, but none compared the effect of all the primary and supplemental injection techniques. Thus, the objective of this review was to identify the most efficacious and safe intervention to achieve pulpal anesthesia in adult patients undergoing nonsurgical endodontic treatment for mandibular molars with symptomatic irreversible pulpitis. Our research question was as follows: What is the most efficacious and safe local anesthetic agent and injection technique to achieve successful pulpal anesthesia in adults undergoing endodontic treatment of mandibular molars with symptomatic irreversible pulpitis when compared with IANB using 2% lidocaine?

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Zanjir et al.

MATERIALS AND METHODS The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension statement for NMA was followed when reporting results (Supplemental Table S1 is available online at www.jendodon.com)26.

Inclusion Criteria RCTs of adults undergoing nonsurgical endodontic treatment for permanent mandibular molars with the pulpal diagnosis of symptomatic irreversible pulpitis were included. Interventions included any local anesthetic types and injection techniques combined with any oral preoperative medication to achieve anesthesia during nonsurgical endodontic treatment. In order to render results applicable to routine daily practice, studies using pharmacologic agents that require mixing/extra preparation or their use is restricted to those who meet special qualifications were excluded.

Outcomes The primary outcome was successful pulpal anesthesia during nonsurgical endodontic treatment measured by any form of verbal or visual analog scales. The secondary outcome was safety of the interventions. Any study not reporting the primary outcome was excluded.

Search Method The electronic databases MEDLINE, Embase, Cochrane Central, CINAHL, and Scopus were searched from inception until February 23, 2018, with no restriction on publication language (Supplemental Table S2 is available online at www.jendodon.com). Completed and ongoing trials were searched using the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registries. Unpublished and gray literature was searched through ProQuest, OpenGrey, and Google Scholar (first 100 hits). Abstracts from the annual meetings of the American Association of Endodontists, the International Federation of Endodontic Association, and the European Society of Endodontology were searched. We manually scanned reference lists from the identified research syntheses and 3 major textbooks7,27,28. An attempt to contact the authors was made in case of missing information from any of the studies.

Screening and Data Extraction Two review authors (M.Z. and N.L.L.) independently reviewed and selected trials from searches. Disagreements were resolved through discussion and consensus or by consulting a third reviewer (A.A.). Any reason for exclusion was reported (Supplemental

Table S3 is available online at www.jendodon. com). The information outlined in Table 1 was extracted from each study to verify inclusion criteria and to conduct NMA.

Assessment of Risk of Bias Two review authors (M.Z. and N.L.L.) independently used the Cochrane risk of bias tool68 to evaluate the quality of included trials across 6 domains (random sequence generalization, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting and other bias). The possible judgment for these domains could be “high risk,” “low risk,” or “unclear risk” of bias. A final judgment for each study was given based on the following: low risk if all the domains were judged to be of low risk, moderate risk if any domain was to be of unclear risk, and high risk if any domain was judged to be of high risk. Disagreements were resolved through discussion and consensus or by consulting a third reviewer (P.S.).

Quality of Evidence Two review authors (M.Z. and N.L.L.) used the CINeMA Web application (University of Bern, Bern, Switzerland) to judge the confidence in the NMA results considering 6 domains: within- and across-studies bias, indirectness, imprecision, heterogeneity, and incoherence. Each domain was judged as having no concerns, major concerns, or minor concerns. The latter would downgrade the level of evidence. An overall final judgment of either high, moderate, low, or very low confidence was given to each result69. Consensus was reached by consulting a third reviewer (P.S.).

Data Synthesis and Analysis NMA was conducted using the program R (Version 3.5.0; R Project for Statistical Computing, Vienna, Austria) with the gemtc version 0.8.2 and rjags packages, which interface with Just Another Gibbs Sampler software (Version 4.0.0; developed by Martyn Plummer) for Markov chain Monte Carlo modeling. A Bayesian NMA was preformed using a hierarchical random effects framework and unified generalized linear model with binominal likelihood along with the logit link function to compare the interventions with one another70–72. The treatment effects were estimated as odd ratios (ORs) with associated 95% credible intervals (CrIs) and the surface under the cumulative ranking curve (SUCRA). Heterogeneity was assessed using the I2 statistic. The node splitting method and its Bayesian P value were used to calculate the inconsistency of the model73. Posterior

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TABLE 1 - Characteristics of the Included Studies

Identification number 1

2

3

Efficacy and Safety of Pulpal Anesthesia Strategies

4

5

Author, year, country Aggarwal, 2009, India29

Aggarwal, 2010, India11

Aggarwal, 2010, India13

Aggarwal, 2011, India30

Aggarwal, 2017, India9

Interventions as reported in studies 1.8 mL 2% lidocaine/ 1:200,000/IANB 1.8 mL 2% lidocaine/ 1:200,000/IANB 1 1.7 mL 4% articaine/ 1:100,000/BI 1 1.7 mL 4% articaine/ 1:100,000/LI 1.8 mL 2% lidocaine/ 1:200,000/IANB 1 1.7 mL 2% lidocaine/ 1:100,000/BI 1 1.7 mL 4% articaine/ 1:100,000/LI 1.8 mL 2% lidocaine/ 1:200,000/IANB 1.8 mL 2% lidocaine/ 1:200,000/IANB 1 300 mg ibuprofen 1.8 mL 2% lidocaine/ 1:200,000/IANB 1 10 mg ketorolac capsule 2.2 mL 4% articaine/ 1:100,000/IANB 2.2 mL 4% articaine/ 1:100,000/GowGates 2.2 mL 4% articaine/ 1:100,000/VaziraniAkinosi 1.1 mL 4% articaine/ 1:100,000/BI 1 1.1 mL 4% articaine/ 1:100,000/LI 1.8 mL 2%lidocaine/ 1:200,000/IANB 1.8 mL 2% lidocaine/ 1:200,000/IANB 1 1.8 mL 4% articaine/ 1:100,000/BI 1.8 mL 2% lidocaine/ 1:200,000/IANB

Age in years (mean ± SD/range if available)

Sample size (male/ female ratio)

28 6 9/24–37

24 (14/10)

29 6 8/26–37

30 (15/15)

30 6 6/23–36

30 (16/14)

20 first molars, 10 second molars

26 6 9/21–35

24 (14/10)

30 6 8/23–38

22 (10/12)

12 first molars, 12 second molars 10 first molar, 12 second molars

29 6 8/24–37

23 (12/11)

11 first molars, 12 second molars

26 6 6/21–32

22 (12/10)

27 6 5/22–32

25 (13/12)

12 first molars, 10 second molars 14 first molars, 11 second molars

25 6 6/21–31

24 (12/12)

13 first molars, 11 second molars

10

26 6 5/21–31

26 (14/12)

13 first molars, 13 second molars

7

30 6 4/24–34

23 (12/11)

Heft-Parker VAS*

31 6 5/26–35

24 (11/13)

11 first molars, 12 second molars 14 first molars, 14 second molars

37 6 8.3/31–47

31 (22/9)

19 first molars, 12 second molars

Heft-Parker VAS*

Mandibular tooth type 15 first molars, 9 second molars 19 first molars, 11 second molars

Evaluation scale used Heft-Parker VAS*

Safety Not reported

Success 8 20

14

Heft-Parker VAS*

Not reported

7 6

9

Heft-Parker VAS*

Not reported

8 13

Not reported

9 13

Not reported

7

(continued on next page )

3

4

TABLE 1 - Continued

Zanjir et al.

Identification number

6

7

8

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9

Author, year, country

Aggarwal, 2018, India31

Allegretti, 2016, Brazil32

Ashraf, 2013, Iran33

Claffey, 2004, United States5

Interventions as reported in studies 1.8 mL 4% articaine/ 1:100,000/IANB 1.8 mL 0.5% bupivacaine/ 1:200,000/IANB 1.8 mL 2% lidocaine/ 1:80,000/IANB 1.8 mL 2% lidocaine/ 1:80,000/IANB 1 0.4 mL 2%lidocaine/ 1:80,000/PDL 1.8 mL 2% lidocaine/ 1:80,000/IANB 1 1.2 mL 2% lidocaine/ 1:80,000/PDL 3.6 mL 2% lidocaine/ 1:100,000/IANB 3.6 mL 4% articaine/ 1:100,000/IANB 3.6 mL 2% mepivacaine/ 1:100,000/IANB 1.5 mL 2% lidocaine/ 1:100,000/IANB 1 0.3 mL 2% lidocaine/ 1:100,000/BI 1.5 mL 2% lidocaine/ 1:100,000/BI 1 0.3 mL 2% lidocaine/ 1:100,000/BI 1 1.8 mL 2% lidocaine/ 1:100,000/BI 1.5 mL 4% articaine/ 1:100,000/IANB 1 0.3 mL 4% articaine/ 1:100,000/BI 1.5 mL 4% articaine/ 1:100,000/IANB 1 0.3 mL 4% articaine/ 1:100,000/BI 1 1.8 mL 4% articaine/ 1:100,000/BI 2.2 mL 2% lidocaine/ 1:100,000/IANB

Age in years (mean ± SD/range if available)

Sample size (male/ female ratio)

34 6 6.5/27–41

30 (16/14)

38 6 4.25/29–45

30 (19/11)

NA

Mandibular tooth type

Molars

29 6 7/19–38

39 (16/23)

Molars

30 6 9/21–43

39 (24/15)

Molars

30.3/18–49

22 (9/13)

28.7/18–47

22 (12/10)

33.9/19–50

22 (6/16)

11 first molars, 11 second molars 10 first molars, 12 second molars 13 first molars, 9 second molars 25 first molars, 26 second molars

51 (23/28)

Safety

20 first molars, 10 second molars 22 first molars, 8 second molars

97 (40/38)

32.5 6 8.7

Evaluation scale used

Success 10 5

Heft-Parker VAS*

VAS†

There was a slight nonsignificant increase in the heart rate after 30 s to 1 min of PDL injections measured by finger pulse oximeter. Not reported

19 25

33

12 14 16

Heft-Parker VAS*

Not reported

9

17

37.9 6 10.0

51 (24/27)

17 first molars, 43 second molars

8

41

31 6 8.0/20–48

35 (12/23)

3 second premolars, 20 first molars, 12 second molars

Heft-Parker VAS*

Not reported

8

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TABLE 1 - Continued

Identification number

Author, year, country

Interventions as reported in studies 2.2 mL 4% articaine/ 1:100,000/IANB

10

11

Efficacy and Safety of Pulpal Anesthesia Strategies

12

Click, 2015, United States34

Cunha, 2011, Brazil35

Dou, 2013, China36

3.6 mL 2% lidocaine/ 1:100,000/GowGates 1 0.9 mL 2% lidocaine/1:100,000/ BI 3.6 mL 2% lidocaine/ 1:100,000/GowGates 1 1.8 mL 4% articaine/1:100,000/BI 3.6 mL 2% lidocaine/ 1:100,000/VaziraniAkinosi 1 0.9 mL 2% lidocaine/1:100,000/ BI 3.6 mL 2% lidocaine/ 1:100,000/VaziraniAkinosi 1 1.8 mL 4% articaine/1:100,000/BI 3.6 mL 2% lidocaine/ 1:100,000/IANB 3.6 mL 4% articaine/ 1:100,000/IANB 3.6 mL 3% prilocaine/ 0.03 IU felypressin/ IANB 3.6 mL 2% mepivacaine/ 1:100,000/IANB 4 mL 2% lidocaine/ 1:100,000/IANB 1 0.9 mL 4% articaine/ 1:100,000/BI 4 mL 2% lidocaine/ 1:100,000/IANB 10.9 mL 4% articaine/ 1:100,000/BI 1 0.9 mL 4% articaine/ 1:100,000/LI

Age in years (mean ± SD/range if available) 31 6 8.3/21–53

33/18–58

Sample size (male/ female ratio)

Mandibular tooth type

37 (13/24)

1 first premolar, 3 second premolars, 21 first molars, 12 second molars 3 second premolars, 37 first molars, 21 second molars

60 (17/43)

Evaluation scale used

Safety

Success 9

Heft-Parker VAS*

Not reported

21

20

34/20–64

38 (17/21)

22 first molars, 16 second molars

6

12

19–57

60 (41/19)

Molars

Heft-Parker VAS*

Not reported

3 7 7

8 38.0 6 10.3/20–59

40 (22/18)

40.8 6 8.9/21–55

40 (26/14)

First or second molars

Heft-Parker VAS*

Not reported

28

32

(continued on next page ) 5

6

TABLE 1 - Continued

Zanjir et al.

Identification number 13

14

Author, year, country Fan, 2009, China10

Fullmer, 2014, United States37

Interventions as reported in studies

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1.7 mL 4% articaine/ 1:100,000/IANB 1 0.4 mL 4% articaine/ 1:100,000/BI 1.7 mL 4% articaine/ 1:100,000/IANB 1 0.4 mL 4% articaine/ 1:100,000/PDL 1.8 mL 2% lidocaine/ 1:100,000/IANB 1 0.9 mL 2% lidocaine/ 1:100,000/BI 1 placebo 1.8 mL 2% lidocaine/ 1:100,000/IANB 1 0.9 mL 2% lidocaine/ 1:100,000/BI 1 1.8 mL 4% articaine/ 1:100,000/BI 1 placebo 1.8 mL 2% lidocaine/ 1:100,000/IANB 1 0.9 mL 2% lidocaine/ 1:100,000/BI 1 1.8 mL 4% articaine/ 1:100,000/BI 1 1.8 mL 2% lidocaine/ 1:100,000/IO injection 1 placebo 2% lidocaine 1.8 1:100,000/IANB/2% lidocaine 1 0.9 mL 2% lidocaine/ 1:100,000/BI 1 1000 mg acetaminophen/ 10-mg hydrocodone capsules 1.8 mL 2% lidocaine/ 1:100,000/IANB 1 0.9 mL 2% lidocaine/ 1:100,000/BI 1 1.8

Age in years (mean ± SD/range if available)

Sample size (male/ female ratio)

32.93 6 5.67/23–43

27 (15/12)

First molars

34.93 6 7.62/18–46

30 (19/11)

First molars

36 6 13/18–61

50 (27/23)

2 first premolars, 4 second premolars, 28 first molars, 14 second molars, 2 third molars

35 6 12/20–67

50 (19/31)

Mandibular tooth type

7 second premolars, 26 first molars, 17 second molars

Evaluation scale used Heft-Parker VAS*

Safety Not reported

Success 22

25

Heft-Parker VAS*

In the acetaminophen/ hydrocodone group, 76% of the patients reported side effects from the medication. The majority reported euphoria; a few reported sleepiness, and a few reported nausea.

14

15

16

16

17

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Identification number

15

Efficacy and Safety of Pulpal Anesthesia Strategies

16

Author, year, country

Ianiro, 2007, United States38

Jena, 2013, India39

Interventions as reported in studies mL 4% articaine/ 1:100,000/BI 1 1000 mg acetaminophen/ 10-mg hydrocodone capsules 1.8 mL 2% lidocaine/ 1:100,000/IANB 1 0.9 mL 2% lidocaine/ 1:100,000/BI 1 1.8 mL 4% articaine/ 1:100,000/BI 1 1.8 mL 2% lidocaine/ 1:100,000/IO injection 1 1000 mg acetaminophen/10mg hydrocodone capsules 3.6 mL 2% lidocaine/ 1:100,000/IANB 1 sugar placebo 3.6 mL 2% lidocaine/ 1:100,000/IANB 1 acetaminophen 1000 mg 3.6 mL 2% lidocaine/ 1:100,000/IANB 1 1000 mg acetaminophen 1 600 mg ibuprofen 1.8 mL 2% lidocaine/ 1:100,000/IANB 1 sugar-coated pills (placebo) 1.8 mL 2% lidocaine/ 1:100,000/IANB 1 600 mg ibuprofen 1.8 mL 2% lidocaine/ 1:100,000/IANB 1 10 mg ketorolac 1.8 mL 2% lidocaine/ 1:100,000/IANB 1 400 mg etodolac and 500 mg paracetamol 1.8 mL 2% lidocaine/ 1:100,000/IANB 1

Age in years (mean ± SD/range if available)

Sample size (male/ female ratio)

Mandibular tooth type

Evaluation scale used

Safety

Success

12

Mandibular posterior teeth

10-cm VAS‡

33.7

13 (7/6)

Not reported

6

38.5

14 (5/9)

10

36.6

13 (4/9)

10

34 6 12.49

20 (13/7)

38.80 6 12.01

20 (14/6)

11

33 6 10.33

20 (11/9)

14

37.45 6 13.61

20 (13/7)

10

39.55 6 11.37

20 (12/8)

11

First or second molar

Heft-Parker VAS*

Not reported

8

7

(continued on next page )

TABLE 1 - Continued 8 Zanjir et al.

Identification number

17

18

19

Author, year, country

Kanaa, 2012, United Kingdom40

Madani, 2013, Iran41

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Mahajan, 2017, India42

Interventions as reported in studies 100 mg aceclofenac and 500 mg paracetamol 2 mL 2% lidocaine/ 1:80,000/IANB 2 mL 2% lidocaine/ 1:80,000/IANB 1 2 mL 2% lidocaine/ 1:80,000/IANB 2 mL 2% lidocaine/ 1:80,000/IANB 1 2 mL 4% articaine/ 1:100,000/BI 2% lidocaine/1:80,000/ IANB/2% lidocaine 1 0.36 mL 2% lidocaine/ 1:80,000/PDL 2 mL 2% lidocaine/ 1:80,000/IANB 1 1 mL 2% lidocaine/ 1:80,000/IO 1.8 mL 2% lidocaine/ 1:80,000/IANB 1 500 mg glucose (placebo) 1.8 mL 2% lidocaine/ 1:80,000/IANB 1 400 mg ibuprofen 1.8 mL 2% lidocaine/ 1:80,000/IANB 1 325 mg acetaminophen 1.8 mL 2% lidocaine/ 1:80,000/IANB 1 400 mg ibuprofen 1.8 mL 2% lidocaine/ 1:100,000/IANB 1 lactose powder capsules (placebo) 1.8 mL 2% lidocaine/ 1:100,000/IANB 1 600 mg ibuprofen 1.8 mL 2% lidocaine/ 1:100,000/IANB 1 50 mg tramadol 1.8 mL 2% lidocaine/ 1:100,000/IANB 1

Age in years (mean ± SD/range if available)

Sample size (male/ female ratio)

Mandibular tooth type

Evaluation scale used

31.9 6 10/18–66

182 (133/49)

93 first molars, 62 second molars, 7 third molars

Patient reports; if pain free or not, without the use of any scale

Safety

Not reported

Success

42 6

11

3

11

22.80 6 8.53

15 (8/7)

28.80 6 10.91

15 (8/7)

7

24.53 6 7.44

15 (9/6)

2

26.47 6 10.58

15 (5/10)

10

18–25

15 (9/6)

18–25

15 (8/7)

7

18–25

15 (8/7)

9

18–25

15 (7/8)

8

Molars

First or second molar

Heft-Parker VAS*

Heft-Parker VAS*

Not reported

Not reported

3

5

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TABLE 1 - Continued

Identification number

20

21

22

Author, year, country

Monteiro, 2015, Brazil43

Noguera-Gonzalez, 2013, Mexico44

Efficacy and Safety of Pulpal Anesthesia Strategies

Oleson, 2010, United States45

Interventions as reported in studies acetaminophen 325 mg 1 ibuprofen 400 mg 1.8 mL 4% articaine/ 1:100,000/BI 1 0.6 mL 4%articaine/ 1:100,000/LI 1.8 mL 4% articaine/ 1:100,000/BI 1 0.6 mL 4% articaine/ 1:100,000/LI 1 0.9 mL 4%articaine/ 1:100k/PDL 1.8 mL 2% lidocaine/ 1:100,000/IANB 1.8 mL 2% lidocaine/ 1:100,000/IANB 11.8 mL 4% articaine/ 1:100,000/BI 1.8 mL 2% mepivacaine/ 1:100,000/IANB 1 gelatin (placebo) 1.8 mL 2% mepivacaine/ 1:100,000/IANB 1 600 mg ibuprofen 3.6 mL 2% lidocaine/ 1:100,000/IANB 1 0.9 mL 2% lidocaine/ 1:100,000/BI 1 placebo 3.6 mL 2% lidocaine/ 1:100,000/IANB 1 0.9 mL 2% lidocaine/ 1:100,000/BI 1 1.8 mL 4%articaine/ 1:100,000/BI 1 placebo 3.6 mL 2% lidocaine/ 1:100,000/IANB 1 0.9 mL 2% lidocaine/ 1:100,000/BI 1 1.8 mL 4% articaine/ 1:100,000/BI 1 1.8

Age in years (mean ± SD/range if available)

28 6 13.8

Sample size (male/ female ratio)

30 (5/25)

Mandibular tooth type

17 first molars, 13 second molars

Evaluation scale used

VAS/did not specify categories

Safety

Not reported

Success

12

21

33.5 6 16.5

30 (4/16)

13 first molars, 7 second molars

2 16

34

25 (8/17)

33

25 (10/15)

33 6 12

51 (25/26)

First or second molars

Heft-Parker VAS*

Not reported

9

18

4 first premolar, 9 second premolars, 17 first molars, 19 second molars, 2 third molars

Heft-Parker VAS*

Not reported

18

17

15

9

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10

TABLE 1 - Continued

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Identification number

23

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24

Author, year, country

Parirokh, 2010, Iran46

Parirokh, 2010, Iran47

Interventions as reported in studies mL 2% lidocaine/ 1:100,000/IO injection 1 placebo 3.6 mL 2% lidocaine/ 1:100,000/IANB 1 0.9 mL 2% lidocaine/ 1:100,000/BI 1 800 mg ibuprofen 3.6 mL 2% lidocaine/ 1:100,000/IANB 1 0.9 mL 2% lidocaine/ 1:100,000/BI 1 1.8 mL 4% articaine/ 1:100,000/BI 1 ibuprofen 800 mg 3.6 mL 2% lidocaine/ 1:100,000/IANB 1 0.9 mL 2% lidocaine/ 1:100,000/BI 1 1.8 mL 4% articaine/ 1:100,000/BI 1 1.8 mL 2% lidocaine/ 1:100,000/IO injection1 ibuprofen 800 mg 1.8 mL 2%lidocaine/ 1:80,000/IANB 1.8 mL 2% lidocaine/ 1:80,000/IANB 1 600 mg ibuprofen 1.8 mL 2% lidocaine/ 1:80,000/IANB 1 75 mg indomethacin capsule 1.8 mL 2% lidocaine/ 1:80,000/IANB 3.6 mL 2% lidocaine/ 1:80,000/IANB 1.8 mL 2% lidocaine/ 1:80,000/IANB 1 1.8 mL 2% lidocaine/ 1:100,000/BI

Age in years (mean ± SD/range if available)

32 6 8

Sample size (male/ female ratio)

Mandibular tooth type

49 (20/29)

3 first premolars, 7 second premolars, 28 first molars, 8 second molars, 3 third molars

Evaluation scale used

Safety

Success

20

12

15

25.9 6 6.0

50 (22/28)

26.2 6 9.5

50 (26/24)

26.2 6 5.7

50 (23/27)

26.0 6 6.9

27 (10/17)

28.4 6 8.1

28 (8/20)

11

27.7 6 7.9

27 (7/20)

17

First or second molars

Heft-Parker VAS*

None of the patients reported any side effects for up to 48 hours

16 39

31

Molars

Heft-Parker VAS*

Not reported

4

(continued on next page )

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TABLE 1 - Continued

Identification number 25

26

27

Efficacy and Safety of Pulpal Anesthesia Strategies

28

29

30

Author, year, country 48

Paul, 2011, India

Poorni, 2011, India3

Prasanna, 2011, United States49

Qiu, 2010, China50

Saatchi, 2018, Iran51

Saha, 2016, India52

Interventions as reported in studies 3.6 mL 2% lidocaine/ 1:100,000/IANB 1 0.9 mL 2% lidocaine/ 1:100,000/BI 1 placebo with sugarcoated pills 3.6 mL 2% lidocaine/ 1:100,000/IANB 1 0.9 mL 2% lidocaine/ 1:100,000/BI 1 100 mg aceclofenac 1.8 mL 4% articaine/ 1:100,000/IANB 1.8 mL 2% lidocaine/ 1:100,000/IANB 1.8 mL 4% articaine/ 1:100,000/BI 1.8 mL 2% lidocaine/ 1:200,000/IANB 1 cellulose powder 1.8 mL 2% lidocaine/ 1:200,000/IANB 1 8 mg lornoxicam capsule 1.8 mL 2% lidocaine/ 1:200,000/IANB 1 50 mg diclofenac capsule 1.2 mL 4% articaine/ 1:100,000/IANB 1.2 mL 4% articaine/ 1:100,000/PDL 3.6 mL 2% lidocaine/ 1:80,000/IANB 3.6 mL 2%lidocaine/ 1:80,000/Gow-Gates 1.8 mL 2% lidocaine/ 1:80,000/IANB 1 1.8 mL 2% lidocaine/ 1:80,000/Gow-Gates 1.8 mL 2% lidocaine/ 1:200,000/IANB 1 placebo

Age in years (mean ± SD/range if available)

Sample size (male/ female ratio)

Mandibular tooth type

Evaluation scale used

Safety

Success

31.76 8.933

20 (11/9)

14 first molars, 6 second molars

30.4 6 9.832

20 (12/8)

12 first molars, 8 second molars

24.40 6 4.19

52 (28/24)

Molars

24.13 6 4.21

52 (32/20)

34

23.46 6 3.7

52 (30/22)

34

28 6 7

38 (18/20)

20 first molars,18 second molars

26 6 9

38 (22/16)

19 first molars, 19 second molars

28

30 6 6

38 (15/23)

22 first molars, 16 second molars

24

18–55, 38

50 (01/49)

Molars

Heft-Parker VAS*

Not reported

7

13

Heft-Parker VAS*

Heft-Parker VAS*

VAS§,ǁ

Not reported

Not reported

Not reported

50

36

10

44 45

18–64

50 (21/29)

Molars

18–55

50 (16/34)

20

18–56

50 (15/35)

35

18–65

42 (22/20)

18 first molars, 24 second molars

Heft-Parker VAS*

Heft-Parker VAS*

Not reported

Not reported

22

12

(continued on next page ) 11

12

TABLE 1 - Continued

Zanjir et al.

Identification number

31

32

33

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34

Author, year, country

Sampaio, 2012, Brazil53

Schellenberg, 2015, United States54

Shantiaee, 2017, Iran55

Shapiro, 2018, United States56

Interventions as reported in studies 1.8 mL 2% lidocaine/ 1:200,000/IANB 1 10 mg ketorolac 1.8 mL 2% lidocaine/ 1:200,000/IANB 1 50-mg diclofenac capsule 3.6 mL 2% lidocaine/ 1:100,000/IANB 3.6 mL 0.5% bupivacaine/ 1:200,000/IANB 2.8 mL 4% lidocaine/ 1:100,000/IANB 1 0.9 mL 2% lidocaine/ 1:100,000/BI 2.8 mL 4% lidocaine/ 1:100,000/IANB 1 0.9 mL 2% lidocaine/ 1:100,000/BI 1 1.8 mL 4% articaine/ 1:100,000/BI 1.8 mL 2% lidocaine/ 1:100,000/IANB 1.8 mL 2% lidocaine/ 1:100,000/IANB 1 7.5 mg meloxicam 1.8 mL 2% lidocaine/ 1:100,000/IANB 1 600 mg ibuprofen 2% lidocaine 1.8 1:100,000/IANB 1 placebo 1.7 mL 4% articaine/ 1:100,000/IANB 1.7 mL 4% articaine/ 1:100,000/IANB 1 1.7 mL 4% articaine/ 1:100,000/BI 1.7 mL 4% articaine/ 1:100,000/IANB 1 1.7 mL 2% lidocaine/ 1:100,000/BI

Age in years (mean ± SD/range if available)

Sample size (male/ female ratio)

Mandibular tooth type

Evaluation scale used

Safety

Success

18–65

42 (23/19)

30 first molars, 12 second molars

32

18–65

42 (20/22)

19 first molars, 23 second molars

23

32.3

35 (16/19)

VAS†

29.4

35 (16/19)

17 first molars, 18 second molars 20 first molars, 15 second molars

36/18–64

50 (21/32)

3 second premolars 25 first molars, 21 second molars, 1 third molars

Heft-Parker VAS*

Not reported

22 28

Not reported

20

11

29.26 6 5.93

23 (11/12)

32.78 6 9.55

23 (10/13)

16

31.70 6 8.04

23 (10/13)

20

32.22 6 8.87

23 (13/10)

8

39 6 15

199 (97/102)

37 6 13 for first molars and 41 6 16 for second molars

76 (41/35)

73 (23/41)

First molar

First and second molars

Heft-Parker VAS*

Heft-Parker VAS*

Not reported

None of the patients reported any side effects.

5

50 47

35

(continued on next page )

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TABLE 1 - Continued

Identification number

35

36

Author, year, country

Sherman, 2008, United States57

Simpson, 2011, United States58

Interventions as reported in studies

Efficacy and Safety of Pulpal Anesthesia Strategies

1.7 mL 4% articaine/ 1:100,000/IANB 1 1.7 mL 2% lidocaine or 4% articaine/ 1:100,000/BI 1 1.7 mL 4% articaine/ 1:100,000/IO injection 1.8 mL 2% lidocaine/ 1:100,000/GowGates 1.7 mL 4% articaine/ 1:100,000/GowGates 3.6 mL 2% lidocaine/ 1:100,000/IANB 1 0.9 mL 2% lidocaine/ 1:100,000/BI 1 placebo 3.6 mL 2% lidocaine/ 1:100,000/IANB 1 0.9 mL 2% lidocaine/ 1:100,000/BI 1 1.8 mL 4% articaine/ 1:100,000/BI 1 placebo 3.6 mL 2% lidocaine/ 1:100,000/IANB 1 0.9 mL 2% lidocaine/ 1:100,000/BI 1 1.8 mL 4% articaine/ 1:100,000/BI 1 1.8 mL 2% lidocaine/ 1:100,000/IO injection 1 placebo 3.6 mL 2% lidocaine/ 1:100,000/IANB 1 0.9 mL 2% lidocaine/ 1:100,000/BI 1 800 mg ibuprofen and 1000 mg acetaminophen 3.6 mL 2% lidocaine/ 1:100,000/IANB 1

Age in years (mean ± SD/range if available)

Sample size (male/ female ratio)

Mandibular tooth type

Evaluation scale used

Safety

63

53

Not reported

11 (12/8)

11 molars

Not reported

10 (7/13)

10 molars

50 (20/30)

1 first premolar, 3 second premolars, 23 first molars, 21 second molars, 2 third molars

33 6 10

Success

Heft-Parker VAS*

Not reported

8

9

Heft-Parker VAS*

Not reported

12

9

23

32 6 10

50 (16/34)

2 first premolars, 5 second premolars, 23 first molars, 19 second molars, 1 third molar

16

13

13

(continued on next page )

14

TABLE 1 - Continued

Zanjir et al.

Identification number

37

38

Author, year, country

Singh, 2010, India59

Singla, 2015, India60

Interventions as reported in studies

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0.9 mL 2% lidocaine/ 1:100,000/BI 1 1.8 mL 4% articaine/ 1:100,000/BI 1 800 mg ibuprofen and 1000 mg acetaminophen 3.6 mL 2% lidocaine/ 1:100,000/IANB 1 0.9 mL 2% lidocaine/ 1:100,000/BI 1 1.8 mL 4% articaine/ 1:100,000/BI 11.8 mL 2% lidocaine/ 1:100,000/IO injection 1 800 mg ibuprofen and 1000 mg acetaminophen 2% lidocaine/1:200,000/ IANB 1 placebo 2% lidocaine/1:200,000/ IANB 1 600 mg ibuprofen 2% lidocaine/1:200,000/ IANB 1 400 1 500 mg ibuprofen and acetaminophen 2% lidocaine/1:200,000/ IANB 1 10 mg ketorolac 1.8 mL 4% articaine/ 1:100,000/IANB 1.8 mL 4% articaine/ 1:100,000/IANB 1 1.8 mL 4% articaine/ 1:100,000/BI 1.8 mL 4% articaine/ 1:100,000/IANB 1 3.6 mL 4% articaine/ 1:100,000/BI 1.8 mL 4% articaine/ 1:100,000/IANB

Age in years (mean ± SD/range if available)

Sample size (male/ female ratio)

Mandibular tooth type

Evaluation scale used

Safety

Success

18

Not reported

—

—

7

Molar

Heft-Parker VAS*

Not reported

2

7

4

7

5

7

5

128

First or second molar

Heft-Parker VAS*

Not reported

52

38 6 5.2/24–51

38 (17/21)

23

32 6 4.4/21–43

39 (19/20)

21

106

36 (continued on next page )

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TABLE 1 - Continued

Identification number

39

Author, year, country

Sood, 2014, India61

Interventions as reported in studies 1.8 mL 4% articaine/ 1:100,000/IANB 1 1.8 mL 4% articaine/ 1:100,000/BI 1.8 mL 4% articaine/ 1:100,000/IANB 1 3.6 mL 4% articaine/ 1:100,000/BI 1.8 mL 2% lidocaine/ 1:80,000/IANB

1.8 mL 4% articaine/ 1:100,000/IANB

40

Efficacy and Safety of Pulpal Anesthesia Strategies

41

42

Stanley, 2012, United States62

Tortamano, 2009, Brazil63

Visconti, 2016, Brazil64

Age in years (mean ± SD/range if available)

Sample size (male/ female ratio)

Evaluation scale used

Safety

Success

31 6 5.2/20–48

35 (20/15)

22

37 6 53.8/24–44

35 (16/19)

26

28.9

50 (27/23)

26.46

50 (20/30)

3.6 mL 2% lidocaine/ 1:100,000/IANB 1 placebo

35 6 13

50 (23/27)

3.6 mL 2% lidocaine/ 1:100,000/IANB 1 nitrous oxide

33 6 11

50 (20/30)

3.6 mL 2% lidocaine/ 1:100,000/IANB

34.1

20 (6/14)

3.6 mL 4% articaine/ 1:100,000/IANB

29.9

20 (10/10)

1.8 mL or 3.6 mL 2% lidocaine/1:100,000/ IANB 1.8 mL or 3.6 mL 2% mepivacaine/ 1:100,000/IANB

Mandibular tooth type

28 6 11

21 (6/16)

26 6 10

21 (3/18)

1 first premolar, 3 second premolars, 26 first molars, 18 second molars, 2 third molars 1 first premolar, 1 second premolar, 16 first molars, 29 second molars, 3 third molars 1 first premolar, 8 second premolars, 23 first molars, 17 second molars, 1 third molar 2 first premolars, 7 second premolars, 30 first molars, 11 second molars 4 second premolars, 9 first molars, 5 second molars, 2 third molars 1 second premolar, 10 first molars, 8 second molars, 1 third molar 9 first molars, 9 second molars, 3 third molars 12 first molars, 6 second molars, 3 third molars

VAS†

Not reported

41

44

Heft-Parker VAS*

Not reported

14

25

VAS†

Not reported

9

13

VAS†

Not reported

14

18

(continued on next page )

15

16

TABLE 1 - Continued

Zanjir et al.

Identification number 43

44

Author, year, country Wali, 2012, Pakistan65

Yadav, 2015, India14

Interventions as reported in studies

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1.8 mL 2% lidocaine/ 1:200,000/IANB 1 placebo 1.8 mL 2% lidocaine/ 1:200,000/IANB 1 550 mg naproxen sodium 1.8 mL 2% lidocaine/ 1:200,000/IANB 1 50 mg diclofenac potassium 1.8 mL 2% lidocaine/ 1:200,000/IANB 1 20 mg piroxicam 1.8 mL 2% lidocaine/ 1:80,000/IANB 1 0.9 mL 2% lidocaine/ 1:80,000/BI 1 0.9 mL 2% lidocaine/ 1:80,000/LI 1.8 mL 2% lidocaine/ 1:80,000/IANB 1 0.9 mL 2% lidocaine/ 1:80,000/BI 1 0.9 mL 2% lidocaine/ 1:80,000/LI 1 10 mg oral ketorolac 1.8 mL 2% lidocaine/ 1:80,000/IANB 1 10 mg oral ketorolac 1.8 mL 4% articaine/ 1:100,000/IANB 1 10 mg oral ketorolac 1.8 mL 4% articaine/ 1:100,000/IANB 1 0.9 mL 4% articaine/ 1:100,000/BI 1 0.9 mL 4% articaine/ 1:100,000/LI 1 preoperative oral ketorolac

Age in years (mean ± SD/range if available) Not reported

Sample size (male/ female ratio) 80 (42/38)

Mandibular tooth type Molars

Evaluation scale used Heft-Parker VAS*

Safety Not reported

Success 2

7

15

18

30 6 7.6

25 (12/13)

10 first molars, 10 second molars

28 6 9

25 (12/13)

14 first molars, 11 second molars

14

31.6 6 9.5

25 (13/12)

13 first molars, 12 second molars

10

28.2 6 6.1

25 (13/12)

14 first molars, 11second molars

12

28.8 6 6.7

25 (14/11)

14 first molars, 11 second molars

19

Heft-Parker VAS*

Not reported

8

(continued on next page )

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TABLE 1 - Continued

Identification number

45

46

Author, year, country

Zain, 2016, Pakistan66

Zarei, 2012, Iran67

Interventions as reported in studies 1.8 mL 4% articaine/ 1:100,000/IANB 1 0.9 mL 4% articaine/ 1:100,000/BI 1 0.9 mL 4% articaine/ 1:100,000/LI 1.8 mL 2% lidocaine/ 1:100,000/IANB 1.8 mL 4% articaine/ 1:100,000/BI 1.8 mL 2% lidocaine/ 1:100,000/IANB 1.8 mL 2% lidocaine/ 1:100,000/IANB 1 1.8 mL 2% lidocaine/ 1:100,000/PDL 1.8 mL 2% lidocaine/ 1:100,000/IANB 1 1.8 mL 2% lidocaine/ 1:100,000/IO

Age in years (mean ± SD/range if available) 30 6 7.9

31.46 6 11/18–60

Sample size (male/ female ratio)

Mandibular tooth type

25 (14/11)

13 first molars, 12 second molars

78 (46/32)

First molar

Evaluation scale used

27.2/18–50

47 (18/22)

Second premolar or first or second molar

28.6/18–50

Efficacy and Safety of Pulpal Anesthesia Strategies

BI, buccal infiltration; IANB, inferior alveolar nerve block; IO, intraosseous; LI, lingual infiltration; NA, not available; PDL, periodontal ligament; VAS, visual analog scale. *Heft-Parker VAS of 170 mm: 0 mm 5 no pain, 0–54 mm 5 mild pain, 55–114 5 moderate pain, and 114–170 5 severe pain. † VAS: 0 5 no pain; 1 5 mild bearable pain; 2 5 moderate unbearable pain; and 3 5 severe, intense, and unbearable pain. ‡ Heft-Parker VAS of 100 mm: 11 measurement points for determining the intensity of pain where 0 mm 5 no pain and 100 mm 5 worst pain. § 10-cm VAS with end points: 0 cm 5 no pain and 10 cm 5 unbearable pain. ǁ VAS, no categories specified.

Success 16

Heft-Parker VAS*

78 (46/32) 18–50

Safety

VAS†

None of the patients reported side effects. Heart rate was monitored with an Oxypleth pulse oximeter (Novametrix, Wallingford, CT) 2 min before the supplemental injections up to 6 min after. The mean heart rate increased significantly after the X-Tip IO (Dentsply International Inc, Tulsa, OK) by 8–10 beats. In the PDL group, the heart rate did not change significantly with either the primary or the secondary supplemental injection.

49 60 7 14

20

17

FIGURE 1 – Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram.

probabilities were used to rank the interventions for the overall conclusions.

Sensitivity and Subgroup Analysis In 3 sensitivity analyses, we excluded studies 1. with results reported in aggregate for mandibular molars and premolars, 2. using anesthetic formulations uncommon in the United States, and 3. with high risk of bias domains. Subgroup analysis determined the effect of the increasing anesthetic volume (up to 1.8 mL vs .1.8 mL).

RESULTS Search Results From the initial search of 2062 records, 1388 duplicates were removed, and 541 records were excluded based on the title and abstract screening (Fig. 1). A total of 133 records were

18

Zanjir et al.

screened in full text; 87 were excluded (Supplemental Table S2 is available online at www.jendodon.com), and 46 RCTs met the inclusion criteria (Table 1). The included studies were mostly from India and the United States (15 and 11 studies, respectively).

Study Characteristics Population All studies included adults (18–68 years old). Two studies did not specify their population’s age59,65, and 1 study excluded patients under 18 years without identifying age distribution74 (Table 1). The majority of studies evaluated anesthetic efficacy in mandibular molars; 10 studies included mandibular molars or premolars5,34,37,45,54,58,61–63,67, and 1 included mandibular posterior teeth without specifying the tooth type38. All patients had the diagnosis of symptomatic irreversible pulpitis confirmed by a prolonged response to cold

tests3,5,14,33–35,37–39,42–46,48,51,52,54–59, 62,65,67,74–76 , a positive reading to electric pulp tests40, or both10,11,13,29–32,36,41,47,49, 53,60,61,63,64 . Three studies mentioned they confirmed the diagnosis by pulp tests without specifying the type of the test9,50,66. Most patients experienced moderate to severe preoperative pain confirmed by a verbal analog scale. Seven studies did not provide any information on the preoperative pain level of patients38,51,60,74,77.

Interventions A total of 37 primary or supplemental interventions were identified (Fig. 2). The most common primary injection technique was IANB followed by Gow-Gates11,34,51,57, VaziraniAkinosi11,34, buccal infiltration3,66, buccal infiltration with11,43 or without lingual infiltration3,66, and periodontal ligament injection50. The most common supplemental

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FIGURE 2 – The network geometry of the different interventions used to achieve pulpal anesthesia during the endodontic treatment of a mandibular molar with symptomatic irreversible pulpitis. injection was buccal infiltration followed by periodontal10,31,40,43,67, intraosseous (IO) injection37,40,45,56,58,67, and Gow-Gates51 injections. Various approaches were investigated including changing the local anesthetic solution5,9,32,35,43,53,57,61,63,64, premedication with nonsteroidal antiinflammatory drugs (NSAIDs)13,14,39,41,42, 44–46,48,49,52,55,59,65 , a combination of NSAIDs and acetaminophen38,39,42,58,59, opioids42, a combination of opioids and acetaminophen37, acetaminophen38,41, and nitrous oxide62 up to 1 hour before the treatment as well as changing the primary injection technique11,50,66 and using supplemental injection techniques3,10,29,31,33,34,36,40, 47,51,56,60,67 . The anesthetics compared in the included studies were 2% lidocaine with 1:100,00, 1:200,000, or 1:50,000 epinephrine3,5,9,13,14,29–43,45–49,51–59,61–67, 4% articaine with 1:100,000 epinephrine3,5, 9–11,14,29–37,40,43–45,50,54,56–58,61,63,77–79 , 2% mepivacaine with 1:100,000 epinephrine14,32,35,44,64,76, 0.5% bupivacaine 1:200,0009,53, and 3% prilocaine with 0.03 IU felypressin35.

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Outcome Assessment All patients underwent nonsurgical endodontic treatment. To verify successful pulpal anesthesia, a majority of studies checked for lip numbness within 5–25 minutes after the primary injection. Other methods used include the absence of pain during cold testing14,47,52,57 or negative reading of electric pulp testing when a maximum of 80 was used3,10,13,14,30,32–34, 37–40,42–46,49,51–56,58,61–63,66,67,80 . Access cavity preparation was terminated in these studies as soon as patients reported pain, and the level of pain was measured using different patient-reported approaches (Table 1). Patient reports of mild or no pain were the measure of success. Of the 46 included studies, 23 studies were graded as low risk, 20 as moderate risk, and 3 as high risk (Fig. 3). Overall, moderate and high risk of bias in the judgment was found in the random sequence generation, allocation concealment, and blinding of patients and operators domains. Thirty-seven interventions (with a total number of 5094 patients) were used in the

NMA (Fig. 2), of which 2632 patients had successful pulpal anesthesia during treatment. Figure 4 summarizes relative treatment effects for all possible comparisons, expressed by ORs with 95% CrIs. Compared with a commonly accepted practice of IANB injection using 2% lidocaine with 1:100,000 epinephrine, the following supplemental IO injections were deemed most effective at providing successful pulpal anesthesia when treating mandibular molars with symptomatic irreversible pulpitis (Tables 2 and 3): 1. Supplemental IO injection using 2% lidocaine and preoperative NSAIDs (in particular, ibuprofen) combined with acetaminophen (OR 5 74; 95% CrI, 15–470; SUCRA 5 97%; very low confidence) 2. Supplemental IO injection using 2% lidocaine and preoperative NSAIDs (OR 5 46; 95% CrI, 8–420; SUCRA 5 94%; very low confidence) 3. Supplemental IO injection using 2% lidocaine (OR 5 33; 95% CrI, 14–80; SUCRA 5 93%; moderate confidence)

Efficacy and Safety of Pulpal Anesthesia Strategies

19

FIGURE 3 – (A ) A summary of the risk of bias in the included studies and (B ) review authors’ judgments about each risk of bias domain presented as percentages across the included studies.

20

Zanjir et al.

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FIGURE 4 – Relative treatment effects for all possible comparisons expressed by ORs with 95% CrIs.

4. Supplemental IO injection using 2% lidocaine and preoperative opioids (oral hydrocodone) combined with acetaminophen (OR 5 20; 95% CrI, 4.4– 98; SUCRA 5 86%; very low confidence) 5. Supplemental IO using 4% articaine (OR 5 20; 95% CrI, 6.3–96; SUCRA 5 87%; very low confidence) The next efficacious intervention was supplemental buccal and lingual infiltrations using 4% articaine combined with preoperative NSAIDs (OR 5 18; 95% CrI, 6–56; SUCRA 5 86%; very low confidence). This was followed by IANB using 2% mepivacaine when combined with preoperative NSAIDs (OR 5 13; 95% CrI, 2.1–88; SUCRA 5 77%; very low confidence). The least effective intervention was IANB using 2% lidocaine with 1:100,000 epinephrine (SUCRA 5 6%). No significant inconsistency or heterogeneity was noted in the results.

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Sensitivity and Subgroup Analysis When excluding studies with a mix of molars and premolars, the most efficacious intervention was supplemental IO injection using 4% articaine with 1:100,000 epinephrine (OR 5 21; 95% CrI, 5.9–77; SUCRA 5 94%). The results of the other 2 sensitivity analyses as well as our subgroup analysis were similar to the primary analysis (Table 2).

Safety The majority of studies included in our analyses either reported no major concerns or did not report any information on safety (Table 1). For IO injection, a study in which the injection was combined with 1 hour of preoperative administration of oral hydrocodone/ acetaminophen reported euphoria, sleepiness, and nausea as side effects from opioid analgesia37. Another study reported a transient increased heart rate (8–10 beats) in patients

receiving IO injection in the first 4 minutes after injection67.

DISCUSSION This NMA identified very low– to moderatequality evidence that suggested that compared with IANB using 2% lidocaine, supplemental IO injections with 2% lidocaine or 4% articaine and supplemental buccal and lingual infiltrations using 4% articaine were the top-ranked interventions to achieve pulpal anesthesia during nonsurgical endodontic treatment for mandibular molars with symptomatic irreversible pulpitis. Premedication with NSAIDs, a combination of NSAIDs and acetaminophen, and opioids administered up to 1 hour preoperatively may increase the efficacy of these injections because they resulted in higher ORs and SUCRA values. No major safety concerns were reported in the included studies.

Efficacy and Safety of Pulpal Anesthesia Strategies

21

22

TABLE 2 - Relative Treatment Effects for All Interventions Compared with Inferior Alveolar Nerve Block (IANB) Using 2% Lidocaine Expressed by Odds Ratios with 95% Credible Intervals

Zanjir et al.

Primary analysis

Intervention

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Supplemental 2% lidocaine (IO) 1 NSAIDs and acetaminophen Supplemental 2% lidocaine (IO) 1 NSAIDs Supplemental 2% lidocaine (IO) Supplemental 4% articaine (IO) Supplemental 4% articaine (BI) 1 LI 1 NSAIDs Supplemental 2% lidocaine (IO) 1 opioids and acetaminophen 2% mepivacaine (IANB) 1 NSAIDs Supplemental 4% articaine (BI) 1 LI Supplemental 4% articaine (BI) 1 opioids and acetaminophen Supplemental 2% lidocaine (BI) 1 LI 1 NSAIDs Supplemental 4% articaine (BI) 1 NSAIDs and acetaminophen Supplemental 4% articaine (PDL) Supplemental 2% lidocaine (PDL) Supplemental 4% articaine (BI) 4% articaine (IANB) 1 NSAIDs

First sensitivity analysis

Second sensitivity analysis

Subgroup analysis

Third sensitivity analysis

Up to 1.8 mL

More than 1.8 mL

SUCRA (%)

Odds ratio (95% CrI)

SUCRA (%)

Odds ratio (95% CrI)

SUCRA (%)

Odds ratio (95% CrI)

SUCRA (%)

Odds ratio (95% CrI)

SUCRA (%)

Odds ratio (95% CrI)

SUCRA (%)

Odds ratio (95% CrI)

97.37

74 (15–470)

—

—

96.62

77 (12–600)

97.73

94 (22–520)

—

—

91.12

15 (1.3–190)

93.91

46 (8–420)

—

—

92.72

47 (6.5–520)

94.16

53 (11–430)

—

—

84.32

9.6 (0.66–150)

93.17

33 (14–80)

44.96

2.9 (0.61–16)

91.80

32 (12–96)

95.99

59 (25–150)

98.10

66 (18–310)

81.09

6.4 (1.0–38)

87.10

20 (6.3–69)

93.58

21 (5.9–77)

85.67

21 (5.0–98)

86.78

21 (8.2–61)

87.96

23 (6.4–94)

—

—

86.04

18 (6–56)

92.65

18 (5.7–59)

78.88

15 (2.1–110)

84.87

18 (7.1–50)

80.93

15 (3.7–61)

—

—

85.80

20 (4.4–98)

—

—

84.44

21 (3.6–140)

87.06

23 (6.2–100)

89.54

28 (5.8–170)

—

—

77.45

13 (2.1–88)

84.10

14 (2–99)

—

—

76.26

13 (2.7–73)

—

—

—

—

72.16

8.5 (3.8–19)

80.07

8.6 (3.7–20)

70.00

8.8 (2.1–39)

70.78

8.7 (4.3–18)

63.03

7.1 (2.2–23)

47.94

1.7 (0.14–21)

68.21

7.9 (2.2–29)

—

—

67.43

8.2 (1.7–43)

71.04

9.2 (3.1–29)

73.77

11 (2.8–51)

—

—

65.92

7.1 (2.5–20)

73.03

7 (2.3–21)

57.65

5.8 (0.87–40)

64.69

7.2 (2.9–18)

58.70

6.2 (1.3, 29)

—

—

63.69

6.7 (1.8–25)

—

—

63.32

7 (1.5–36)

68.55

8.4 (2.8–27)

—

—

41.50

1.4 (0.14–12)

62.14

6.2 (2.1–19)

70.72

6.7 (1.7–27)

63.08

6.7 (1.9–25)

58.29

6.3 (1.2–34)

64.35

7.4 (2.4–26)

—

—

59.68

5.7 (2.3–13)

54.93

4 (1.2–12)

37.04

2.8 (0.73–10)

77.06

12 (5.3–27)

75.15

11 (3.9–32)

10.29

0.33 (0.035–2.7)

57.84

5.2 (3.1–9.1)

69.51

5.8 (3.2–11)

60.58

5.7 (2.8–13)

57.61

5.5 (3.4–9.7)

62.87

6.8 (3.6–15)

30.64

0.97 (0.17–5.7)

55.40

5.1 (1.8–15)

62.55

5 (1.7–15)

48.36

4.1 (0.63–28)

53.83

5.2 (2.1–13)

49.05

4.5 (0.95–21)

—

—

(continued on next page )

TABLE 2 - Continued JOE  Volume -, Number -, - 2019

Primary analysis

Intervention

Efficacy and Safety of Pulpal Anesthesia Strategies

Supplemental 2% lidocaine (BI) 1 NSAIDs and acetaminophen 2% lidocaine (IANB) 1 opioids Supplemental 2% lidocaine (BI) 1 NSAIDs 2% lidocaine (IANB) 1 NSAIDs 4% articaine (Gow-Gates) Supplemental 2% lidocaine (BI) 1 opioids and acetaminophen Supplemental 4% articaine (BI) 1 NSAIDs Supplemental 2% lidocaine (Gow-Gates) 2% lidocaine (IANB) 1 NSAIDs and acetaminophen 2% mepivacaine (IANB) 2% lidocaine (IANB) 1 nitrous oxide Supplemental 2% lidocaine (BI) 4% articaine (Vazirani-Akinosi) Supplemental 2% lidocaine (BI) 1 LI 3% prilocaine (IANB)

First sensitivity analysis

Second sensitivity analysis

Subgroup analysis

Third sensitivity analysis

Up to 1.8 mL

More than 1.8 mL

SUCRA (%)

Odds ratio (95% CrI)

SUCRA (%)

Odds ratio (95% CrI)

SUCRA (%)

Odds ratio (95% CrI)

SUCRA (%)

Odds ratio (95% CrI)

SUCRA (%)

Odds ratio (95% CrI)

SUCRA (%)

Odds ratio (95% CrI)

55.28

5.1 (1.5–18)

—

—

55.64

5.2 (1.1–26)

60.70

6.4 (2.3–19)

—

—

33.26

1 (0.10–9)

51.70

4.6 (1–23)

58.89

4.6 (0.96– 23)

46.04

3.7 (0.63–24)

50.43

4.7 (1.2–19)

49.37

4.4 (0.88–23)

—

—

51.53

4.5 (1.6–14)

77.40

9.8 (1.5–72)

52.83

4.7 (1.2–19)

53.19

5 (2.0–13)

—

—

29.91

0.93 (0.11–7.3)

49.19

4.2 (2.6–6.8)

56.13

4.1 (2.4–6.8)

35.94

2.7 (0.86–8.7)

47.84

4.3 (2.9–6.4)

46.03

4.1 (2.4–6.9)

—

—

45.71

3.7 (0.90–16)

54.37

3.9 (0.86–18)

48.09

4 (0.74–22)

42.47

3.6 (1.0–13)

—

—

66.60

3.5 (0.43–31)

43.93

3.6 (1.1–13)

—

—

46.00

3.8 (0.82–19)

47.52

4.3 (1.5–13)

53.03

5.1 (1.4–22)

—

—

43.42

3.6 (0.95–14)

—

—

44.95

3.7 (0.73–19)

46.58

4.2 (1.4–13)

—

—

23.50

0.73 (0.065–6.6)

38.62

3 (0.81–12)

45.81

3 (0.75–12)

—

—

36.44

3.0 (1.0–8.9)

—

—

63.38

3.1 (0.55–17)

37.61

3 (1.3–7.1)

46.13

3.1 (1.2–8.2)

33.23

2.5 (0.83–7.7)

35.43

3.0 (1.5–6.3)

34.27

2.7 (0.94–7.7)

70.11

4.4 (0.47–48)

35.00 34.06

2.8 (1.1–7.3) 2.6 (0.70–10)

43.00 —

2.8 (1.1–7.7) —

— 36.23

— 2.6 (0.51–14)

32.40 32.10

2.7 (1.2–6.5) 2.6 (0.90–7.9)

— —

— —

62.20 59.08

2.8 (0.78–11) 2.6 (0.47–14)

33.86

2.8 (1.5–5.3)

40.25

2.6 (1.2–6.2)

36.49

2.8 (1.2–7.1)

35.99

3.1 (1.9–5.7)

41.81

16.50

0.62 (0.084–3.9)

32.26

2.4 (0.57–11)

40.25

2.5 (0.55–12)

35.59

2.6 (0.48–14)

28.94

2.3 (0.67–8.3)

—

—

54.35

2.3 (0.27–20)

31.54

2.6 (1–6.5)

38.26

2.5 (0.97–6.7)

29.13

2 (0.29–14)

30.49

2.6 (1.2–5.8)

29.64

2.3 (0.68–7.6)

—

—

30.20

2.2 (0.48–11) 2 (0.36–12) 0.84 (0.018–19)

37.00

2.3 (0.46–11)

—

—

27.32

2.2 (0.54–8.7)

—

—

55.71

2.4 (0.40–16)

34.90

2.1 (0.33–13)

31.54

2.1 (0.29–17)

24.86

1.9 (0.43–9.2)

27.94

1.9 (0.29–13)

—

—

22.17

0.84 (0.017–20)

19.89

0.83 (0.013–24)

15.55

0.78 (0.019–14)

—

—

—

—

4% articaine (PDL)

27.92

2% lidocaine (Gow-Gates)

18.32

3.5 (1.6–9)

23

(continued on next page )

9.87 6.09 2% lidocaine (IANB)

17.41 12.51

BI, buccal infiltration; CrI, credible interval; IANB, inferior alveolar nerve block; LI, lingual infiltration; NSAIDs, nonsteroidal anti-inflammatory drugs; PDL, periodontal ligament; SUCRA, surface under the cumulative ranking curve. Results from the primary network meta-analysis and other analyses are presented. For first sensitivity analysis, studies in which results were reported in aggregate for mandibular molars and premolars were excluded; 11 studies were excluded (5, 38–47). For second sensitivity analysis, studies using anesthetic formulations that are not commercially available in North America were excluded; 16 studies and interventions from another 3 studies were excluded for using 2% lidocaine with 1:80,000 or 1:200,000 epinephrine, 3% prilocaine with felypressin, and 2% mepivacaine with 1:100,000 epinephrine (9, 13, 14, 35, 36, 44, 50, 53, 56, 57, 61, 63–67, 69–72). For third sensitivity analysis, studies with high risk of bias domains were excluded; 3 studies were excluded (48, 63, 65). Subgroup analysis was conducted to determine if any effect of the anesthetic volume (up to 1.8 mL vs more than 1.8 mL) existed. For studies using up to 1.8 mL anesthetic volume, we excluded 2 studies that met the criteria (49, 57) because of an error message in R (Version 3.5.0; R Project for Statistical Computing, Vienna, Austria) using the gemtc version 0.8.2, indicating that these 2 studies include comparisons that cannot be expressed as a linear combination of the available parameters.

— 27.71 — 10.04 — 5.53 7.76 —

—

2.4 (0.39–16) 56.51 0.62 (0.12–2.9) 7.27 1.2 (0.50–2.9) 11.23 1.3 (0.35–4.9) 17.42 1.2 (0.41–3.6)

1.8 (0.69–5) 1.1 (0.13–10) 3.2 (0.37–31) 47.47 34.30 62.53 1.5 (0.74–3.3) 1.6 (0.76–3.8) 0.45 (0.043–3) 19.52 21.97 5.66 1.5 (1.0–2.4) 1.4 (0.74–2.6) 1.2 (0.39–3.6) 15.38 13.02 11.92 1.7 (0.93–3.3) 1.5 (0.67–3.6) 2.5 (0.36–19) 20.24 18.87 35.38 23.82 21.87 6.36

— 1.5 (0.76–3) 1.2 (0.35–4.1) 1.2 (0.43–3.4) — 16.91 15.33 13.13

4% articaine (IANB) 4% articaine (BI) 6 LI 2% lidocaine (IANB) 1 acetaminophen 0.5% bupivacaine (IANB)

Intervention Zanjir et al.

1.6 (0.90–3.2) 1.5 (0.74–3.2) 0.44 (0.046–2.9)

Odds ratio (95% CrI) SUCRA (%) SUCRA (%)

Odds ratio (95% CrI)

Odds ratio (95% CrI)

SUCRA (%)

Odds ratio (95% CrI)

SUCRA (%)

Odds ratio (95% CrI)

SUCRA (%)

Odds ratio (95% CrI)

SUCRA (%)

More than 1.8 mL

Subgroup analysis

Up to 1.8 mL

Third sensitivity analysis Second sensitivity analysis First sensitivity analysis Primary analysis

TABLE 2 - Continued 24

IO injections deliver anesthetic solution into the cancellous bone surrounding a specific tooth to anesthetize the nerves supplying the tooth pulp81, providing a quick onset and long duration of pulpal anesthesia82. The use of 4% articaine in IO injections has been widely investigated in clinical trials and is shown to be safe and effective78,83. Nevertheless, there have been concerns of paresthesia and great bone penetration84. For clinicians with these concerns, we suggest the use of 2% lidocaine when delivering IO injections, especially because 4% articaine had a lower rank in efficacy compared with 2% lidocaine in all our analyses, except the first sensitivity analysis. Concerning IO injection safety, few studies reported an initial increase in heart rate. This increase poses no concern to healthy individuals, returns to baseline within 4 minutes85,86, and can be avoided by slowing down the rate of anesthetic solution deposition78,86. For those with high blood pressure, cardiovascular diseases, or any condition in which epinephrine is contraindicated, alternative anesthetic solutions such as a plain solution of 2% mepivacaine can be considered85,87. Other potential side effects reported in the literature while implementing the IO technique include pain during perforation and solution deposition12,87–90, high occlusion for a few days89,91,92, and swelling with or without exudate that would resolve within a few days91,92. This underscores the importance of reporting side effects in RCTs so that cumulative information on adverse effects can be gained. Supplemental buccal and lingual infiltrations using 4% articaine with preoperative NSAIDs were ranked the secondbest intervention. Therefore, they may be used as an adjunct to IANB injection to increase its success93. NSAIDs have been shown to relieve pain associated with symptomatic irreversible pulpitis and improve IANB success24,94. NSAIDs block the cyclooxygenase enzymes, which are responsible for the synthesis of inflammation-promoting mediators, such as prostaglandins, that cause pain95. Pulikkotil et al25 identified NSAIDs through NMA as the second best in improving IANB success after dexamethasone (risk ratio 5 1.92 [95% confidence interval, 1.63–2.27], SUCRA 5 74%; risk ratio 5 2.92 [95% confidence interval, 1.74–4.91]; SUCRA 5 96%, respectively). In another meta-analysis, they also identified that premedication with .400 mg oral ibuprofen is effective in increasing the anesthetic success of IANBs94. In our results, we found that preoperative NSAIDs may improve the success rates of supplemental IO injection and supplemental buccal with lingual

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TABLE 3 - Confidence in the Top Intervention Effect Estimates When Compared with Inferior Alveolar Nerve Block (IANB) Using 2% Lidocaine Based on the GRADE Approach obtained from the CINeMA Web Application

Intervention

Number of studies

Supplemental 2% lidocaine (IO) 1 NSAIDs and acetaminophen Supplemental 2% lidocaine (IO) 1 NSAIDs Supplemental 2% lidocaine (IO) Supplemental 2% lidocaine (IO) 1 opioids and acetaminophen Supplemental 4% articaine (IO) Supplemental 4% articaine (BI) 1 (LI) 1 NSAIDs 2% mepivacaine (IANB) 1 NSAIDs

Withinstudy bias

Acrossstudies bias

Indirectness Imprecision Heterogeneity Incoherence

Confidence rating

0

Major Undetected No concerns No concerns No concerns concerns

Major concerns Very low

0

Major Undetected No concerns No concerns No concerns concerns

Major concerns Very low

2

Major Undetected No concerns No concerns No concerns concerns Major Undetected No concerns No concerns No concerns concerns

No concerns

0

0 0

0

Major Undetected No concerns No concerns No concerns concerns Major Undetected No concerns No concerns No concerns concerns Major Undetected No concerns No concerns No concerns concerns

Moderate

Major concerns Very low

Major concerns Very low Major concerns Very low

Major concerns Very low

BI, buccal infiltration; IANB, inferior alveolar nerve block; LI, lingual infiltration. Grading of Recommendations Assessment, Development, and Evaluation Working Group grades of evidence: high confidence, we are very confident that the true effect lies close to that of the estimate of the effect; moderate confidence, we are moderately confident in the effect estimate (the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different); low confidence, our confidence in the effect estimate is limited (the true effect may be substantially different from the estimate of the effect); and very low confidence, we have very little confidence in the effect estimate (the true effect is likely to be substantially different from the estimate of effect).

infiltration because it resulted in higher ORs but wide and overlapping CrIs when compared with those who did not receive NSAIDs (Table 2). Repeating IANB using 2% lidocaine with 1:100,000 epinephrine was the least effective intervention to achieve pulpal anesthesia for patients with symptomatic irreversible pulpits. This finding is in corroboration with the previous reports of the suboptimal success rates of 13%–54% for IANB using 2% lidocaine as a primary injection9,40,64,96 or success rates of 13% for repeating IANB as a supplemental injection40,96. Moreover, consistent with previous clinical trials21,47,97–99, the subgroup analysis showed that increasing the anesthetic volume to more than 1 carpule (1.8 mL) does not improve the success of IANB when treating mandibular molars with symptomatic irreversible pulpitis. Hence, the clinical trend to repeat IANB when it fails may need to be reconsidered. Our results also highlight the importance of increased training with IO injections in general and specialty dental training. A survey of 833 United States endodontists100 reported the significant underutilization of IO injection because practitioners may feel deterred by the perceived difficulty or extra time needed when using cortical bone perforating IO systems. We speculate with more robust,

JOE  Volume -, Number -, - 2019

didactic, and hands-on training with IO injection during dental training, future graduates of dental schools and specialty programs will feel confident performing the IO technique more frequently when indicated. Our study has the following strengths: we included 46 RCTs, we applied a comprehensive search strategy and strict inclusion criteria to meet the NMA assumption of similarity and to reduce selection bias, we identified no major threats from inconsistency and heterogeneity, and our sensitivity and subgroup analyses were informative from the standpoint of the potential impact of covariates that might have affected the outcome. However, our study has some limitations. Given the large number of interventions we had and the relatively small number of studies included, imprecision and uncertainty in our results are expected, which may be improved in future updates on this topic with the availability of new trials. Our findings on the safety of the interventions are also limited. Finally, although we assumed transitivity between interventions, we cannot rule out minor but important variations between interventions and baseline characteristics of the population included. Our study has some implications for future research. Given the wide CrIs in the estimates of IO efficacy (ie, imprecision),

additional large, well-designed RCTs are required to further assess the efficacy of IO interventions. Additionally, a potential of efficacy for IANB with 2% mepivacaine was identified only when it was combined with NSAIDs. This is an interesting finding because, in general, local anesthesia using mepivacaine has not been commonly considered a “rescue” for failed local anesthesia for teeth with symptomatic irreversible pulpitis. Further RCTs are needed to establish the efficacy and safety of IANB or IO with mepivacaine for these patients. Many RCTs about increasing the success of pulpal anesthesia during endodontic treatment of mandibular molars with symptomatic irreversible pulpitis are conducted annually, and they would need to be monitored and analyses would need to be updated as evidence changes.

CONCLUSION Very low to moderate quality of evidence suggests supplemental IO injections using 2% lidocaine with 1:100,000 epinephrine or 4% articaine with 1:100,000 epinephrine followed by supplemental buccal and lingual infiltrations using 4% articaine with 1:100,000 epinephrine are the most efficacious interventions to achieve successful pulpal anesthesia during

Efficacy and Safety of Pulpal Anesthesia Strategies

25

endodontic treatment of mandibular molars with symptomatic irreversible pulpitis according to the current literature.

ACKNOWLEDGMENTS We would like to thank Mrs. Maria Zych from the University of Toronto Libraries for her help in

conducting the search. The authors deny any conflicts of interest related to this study. There was no funding associated with this paper.

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34.

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35.

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36.

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37.

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38.

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40.

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41.

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Mahajan P, Singh G, Kaur R, et al. A comparative clinical study to evaluate the effect of premedication with ibuprofen, tramadol and combination of ibuprofen and acetaminophen on success of inferior alveolar nerve block in patients with asymptomatic irreversible pulpitis. Bangladesh J Med Sci 2017;16:370–4.

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44.

Noguera-Gonzalez D, Cerda-Cristerna BI, Chavarria-Bolanos D, et al. Efficacy of preoperative ibuprofen on the success of inferior alveolar nerve block in patients with symptomatic irreversible pulpitis: a randomized clinical trial. Int Endod J 2013;46:1056–62.

45.

Oleson M, Drum M, Reader A, et al. Effect of preoperative ibuprofen on the success of the inferior alveolar nerve block in patients with irreversible pulpitis. J Endod 2010;36:379–82.

46.

Parirokh M, Ashouri R, Rekabi AR, et al. The effect of premedication with ibuprofen and indomethacin on the success of inferior alveolar nerve block for teeth with irreversible pulpitis. J Endod 2010;36:1450–4.

47.

Parirokh M, Satvati SA, Sharifi R, et al. Efficacy of combining a buccal infiltration with an inferior alveolar nerve block for mandibular molars with irreversible pulpitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;109:468–73.

48.

Paul J, Ittyerah A, Kumar S. Effect of preoperative aceclofenac on the success of inferior alveolar nerve block in patients with irreversible pulpitis. Indian J Dent Sci 2011;3:1.

49.

Prasanna N, Subbarao CV, Gutmann JL. The efficacy of pre-operative oral medication of lornoxicam and diclofenac potassium on the success of inferior alveolar nerve block in patients with irreversible pulpitis: a double-blind, randomised controlled clinical trial. I Endod J 2011;44:330–6.

50.

Qiu W, Chi MX, Zhang TT. Comparative study in periodontal ligament anesthesia and inferior alveolar nerve block anesthesia in mandibular permanent molar. J Dalian Med Univ 2010;32:305–8.

51.

Saatchi M, Shafiee M, Khademi A, Memarzadeh B. Anesthetic efficacy of Gow-Gates nerve block, inferior alveolar nerve block, and their combination in mandibular molars with symptomatic irreversible pulpitis: a prospective, randomized clinical trial. J Endod 2018;44:384– 8.

52.

Saha SG, Jain S, Dubey S, et al. Effect of oral premedication on the efficacy of inferior alveolar nerve block in patients with symptomatic irreversible pulpitis: a prospective, double-blind, randomized controlled clinical trial. J Clin Diagn Res 2016;10:ZC25–9.

53.

Sampaio RM, Carnaval TG, Lanfredi CB, et al. Comparison of the anesthetic efficacy between bupivacaine and lidocaine in patients with irreversible pulpitis of mandibular molar. J Endod 2012;38:594–7.

54.

Schellenberg J, Drum M, Reader A, et al. Effect of buffered 4% lidocaine on the success of the inferior alveolar nerve block in patients with symptomatic irreversible pulpitis: a prospective, randomized, double-blind study. J Endod 2015;41:791–6.

55.

Shantiaee Y, Javaheri S, Movahhedian A, et al. Efficacy of preoperative ibuprofen and meloxicam on the success rate of inferior alveolar nerve block for teeth with irreversible pulpitis. Int Dent J 2017;67:85–90.

56.

Shapiro MR, Mcdonald NJ, Gardner RJ, et al. Efficacy of articaine versus lidocaine in supplemental infiltration for mandibular first versus second molars with irreversible pulpitis: a prospective, randomized, double-blind clinical trial. J Endod 2018;44:523–8.

57.

Sherman MG, Flax M, Namerow K, Murray PE. Anesthetic efficacy of the Gow-Gates injection and maxillary infiltration with articaine and lidocaine for irreversible pulpitis. J Endod 2008;34:656–9.

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58.

Simpson M, Drum M, Nusstein J, et al. Effect of combination of preoperative ibuprofen/ acetaminophen on the success of the inferior alveolar nerve block in patients with symptomatic irreversible pulpitis. J Endod 2011;37:593–7.

59.

Singh RD, Khatter R, Bal CS. The effect of preoperative ibuprofen, combination of ibuprofen and acetaminophen, ketorolac versus placebo on the efficacy of the inferior alveolar nerve block in patients with irreversible pulpitis. Indian J Dent Sci 2010;2:4–6.

60.

Singla M, Subbiya A, Aggarwal V, et al. Comparison of the anaesthetic efficacy of different volumes of 4% articaine (1.8 and 3.6 mL) as supplemental buccal infiltration after failed inferior alveolar nerve block. Int Endod J 2015;48:103–8.

61.

Sood R, Hans MK, Shetty S. Comparison of anesthetic efficacy of 4% articaine with 1:100,000 epinephrine and 2% lidocaine with 1:80,000 epinephrine for inferior alveolar nerve block in patients with irreversible pulpitis. J Clin Exp Dent 2014;6:e520–3.

62.

Stanley W, Drum M, Nusstein J, et al. Effect of nitrous oxide on the efficacy of the inferior alveolar nerve block in patients with symptomatic irreversible pulpitis. J Endod 2012;38:565–9.

63.

Tortamano IP, Siviero M, Costa CG, et al. A comparison of the anesthetic efficacy of articaine and lidocaine in patients with irreversible pulpitis. J Endod 2009;35:165–8.

64.

Visconti RP, Tortamano IP, Buscariolo IA. Comparison of the anesthetic efficacy of mepivacaine and lidocaine in patients with irreversible pulpitis: a double-blind randomized clinical trial. J Endod 2016;42:1314–9.

65.

Wali A, Siddiqui TM, Qamar N, et al. Effectiveness of premedication with analgesics vs placebo for success of inferior alveolar nerve block in irreversible pulpitis. Int J Prosthodont Restor Dent 2012;2:5–9.

66.

Zain M, Khattak SU, Sikandar H, et al. Comparison of anaesthetic efficacy of 4% articaine primary buccal infiltration versus 2% lidocaine inferior alveolar nerve block in symptomatic mandibular first molar teeth. J Coll Physicians Surg Pak 2016;26:4–8.

67.

Zarei M, Ghoddusi J, Sharifi E, et al. Comparison of the anaesthetic efficacy of and heart rate changes after periodontal ligament or intraosseous X-Tip injection in mandibular molars: a randomized controlled clinical trial. Int Endod J 2012;45:921–6.

68.

Higgins JP, Altman DG. Assessing risk of bias in included studies. In: Higgins JP, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions. London, UK: The Cochrane Collaboration; 2008. p. 187–241.

69.

Salanti G, Giovane CD, Chaimani A, et al. Evaluating the quality of evidence from a network meta-analysis. PLoS One 2014;9:e99682.

70.

Dias S, Sutton AJ, Ades AE, Welton NJ. Evidence synthesis for decision making 2: a generalized linear modeling framework for pairwise and network meta-analysis of randomized controlled trials. Med Decis Making 2012;33:607–17.

71.

Dias S, Ades AE, Welton NJ, et al. Network Meta-analysis for Decision-making. Hoboken, NJ: Wiley; 2018.

72.

Lu G, Ades AE. Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med 2004;23:3105–24.

73.

Dias S, Welton NJ, Caldwell DM, Ades AE. Checking consistency in mixed treatment comparison meta-analysis. Stat Med 2010;29:932–44.

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Thimmaiah PN, Hegde MT, Gundefined B, et al. Anesthetic efficacy of combination of two percent lidocaine with 1:80,000 epinephrine and 0.5 mol/l mannitol for inferior alveolar nerve blocks in patients with symptomatic irreversible pulpitis: an in vivo study. Int Res J Pharm 2013;4:161–3.

75.

Saatchi M, Khademi A, Baghaei B, Noormohammadi H. Effect of sodium bicarbonate-buffered lidocaine on the success of inferior alveolar nerve block for teeth with symptomatic irreversible pulpitis: a prospective, randomized double-blind study. J Endod 2015;41:33–5.

76.

Rodriguez-Wong L, Pozos-Guillen A, Silva-Herzog D, Chavarria-Bolanos D. Efficacy of mepivacaine-tramadol combination on the success of inferior alveolar nerve blocks in patients with symptomatic irreversible pulpitis: a randomized clinical trial. Int Endod J 2016;49:325–33.

77.

Aggarwal V, Singla M, Miglani S, Kohli S. Comparison of the anaesthetic efficacy of epinephrine concentrations (1: 80 000 and 1 : 200 000) in 2% lidocaine for inferior alveolar nerve block in patients with symptomatic irreversible pulpitis: a randomized, double-blind clinical trial. Int Endod J 2014;47:373–9.

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Pereira L, Groppo F, Bergamaschi CC, et al. Articaine (4%) with epinephrine (1: 100,000 or 1: 200,000) in intraosseous injections in symptomatic irreversible pulpitis of mandibular molars: anesthetic efficacy and cardiovascular effects. Oral Surg Oral Med Oral Pathol Oral Radiol 2013;116:e85–91.

79.

Abt E. Analgesic premedication may increase the success rate of local anesthetics for teeth with irreversible pulpitis. J Evid Based Dent Pract 2011;11:141–2.

80.

Kennedy S, Reader A, Nusstein J, et al. The significance of needle deflection in success of the inferior alveolar nerve block in patients with irreversible pulpitis. J Endod 2003;29:630–3.

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Nusstein J, Wood M, Reader A, et al. Comparison of the degree of pulpal anesthesia achieved with the intraosseous injection and infiltration injection using 2% lidocaine with 1: 100,000 epinephrine. Gen Dent 2005;53:50–3.

83.

Vongsavan K, Samdrup T, Kijsamanmith K, et al. The effect of intraosseous local anesthesia of 4% articaine with 1: 100,000 epinephrine on pulpal blood flow and pulpal anesthesia of mandibular molars and canines. Clin Oral Investig 2019;23:673–80.

84.

Johansen O. Comparison of articaine and lidocaine used as dental local anesthetics [thesis]. Oslo, Norway: University of Oslo; 2004.

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Replogle K, Reader A, Nist R, et al. Anesthetic efficacy of the intraosseous injection of 2% lidocaine (1: 100,000 epinephrine) and 3% mepivacaine in mandibular first molars. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83:30–7.

86.

Susi L, Reader A, Nusstein J, et al. Heart rate effects of intraosseous injections using slow and fast rates of anesthetic solution deposition. Anesth Prog 2008;55:9–15.

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Reisman D, Reader A, Nist R, et al. Anesthetic efficacy of the supplemental intraosseous injection of 3% mepivacaine in irreversible pulpitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84:676–82.

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Guglielmo A, Reader A, Nist R, et al. Anesthetic efficacy and heart rate effects of the supplemental intraosseous injection of 2% mepivacaine with 1:20,000 levonordefrin. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:284–93.

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Reitz J, Reader A, Nist R, et al. Anesthetic efficacy of a repeated intraosseous injection given 30 min following an inferior alveolar nerve block/intraosseous injection. Anesth Prog 1998;45:143–9.

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Dunbar D, Reader A, Nist R, et al. Anesthetic efficacy of the intraosseous injection after an inferior alveolar nerve block. J Endod 1996;22:481–6.

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Nagendrababu V, Pulikkotil SJ, Veettil SK, et al. Effect of nonsteroidal anti-inflammatory drug as an oral premedication on the anesthetic success of inferior alveolar nerve block in treatment of irreversible pulpitis: a systematic review with meta-analysis and trial sequential analysis. J Endod 2018;44:914–22.

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APPENDIX

SUPPLEMENTAL TABLE S1 - Preferred Reporting Items for Systematic Reviews and Meta-Analyses Network Meta-analysis Checklist of Items to Include When Reporting a Systematic Review Involving a Network Meta-analysis Section/topic

Item no.

Checklist item

Reported on page no.

Title Title

1

Identify the report as a systematic review incorporating a network meta-analysis (or related form of metaanalysis).

1

Abstract Structured summary

2

Provide a structured summary including, as applicable: Background: main objectives Methods: data sources; study eligibility criteria, participants, and interventions; study appraisal; and synthesis methods, such as network meta-analysis. Results: number of studies and participants identified; summary estimates with corresponding confidence/ credible intervals; treatment rankings may also be discussed. Authors may choose to summarize pairwise comparisons against a chosen treatment included in their analyses for brevity. Discussion/Conclusions: limitations; conclusions and implications of findings. Other: primary source of funding; systematic review registration number with registry name.

1-2

Introduction Rationale

3

Describe the rationale for the review in the context of what is already known, including mention of why a network meta-analysis has been conducted. Provide an explicit statement of questions being addressed, with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

3

Objectives

Methods Protocol and registration

4

5

Eligibility criteria

6

Information sources

7

Search

8

Study selection

9

Data collection process

10

Data items

11

Indicate whether a review protocol exists and if and where it can be accessed (eg, Web address) and, if available, provide registration information, including registration number. Specify study characteristics (eg, PICOS, length of followup) and report characteristics (eg, years considered, language, publication status) used as criteria for eligibility, giving rationale. Clearly describe eligible treatments included in the treatment network and note whether any have been clustered or merged into the same node (with justification). Describe all information sources (eg, databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. Present full electronic search strategy for at least 1 database, including any limits used, such that it could be repeated. State the process for selecting studies (ie, screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). Describe method of data extraction from reports (eg, piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. List and define all variables for which data were sought (eg, PICOS, funding sources) and any assumptions and simplifications made.

3-4

—

4-5

4

Table S2

5

5

Table 1

(continued on next page )

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SUPPLEMENTAL TABLE S1 - Continued Section/topic

Item no.

Checklist item

Reported on page no.

Geometry of the network

S1

5-6

Risk of bias within individual studies

12

Summary measures

13

Planned methods of analysis

14

Assessment of inconsistency

S2

Risk of bias across studies

15

Additional analyses

16

Describe methods used to explore the geometry of the treatment network under study and potential biases related to it. This should include how the evidence base has been graphically summarized for presentation and what characteristics were compiled and used to describe the evidence base to readers. Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level) and how this information is to be used in any data synthesis. State the principal summary measures (eg, risk ratio, difference in means). Also describe the use of additional summary measures assessed, such as treatment rankings and surface under the cumulative ranking curve (SUCRA) values, as well as modified approaches used to present summary findings from meta-analyses. Describe the methods of handling data and combining results of studies for each network meta-analysis. This should include, but not be limited to:  Handling of multi-arm trials;  Selection of variance structure;  Selection of prior distributions in Bayesian analyses; and  Assessment of model fit. Describe the statistical methods used to evaluate the agreement of direct and indirect evidence in the treatment network(s) studied. Describe efforts taken to address its presence when found. Specify any assessment of risk of bias that may affect the cumulative evidence (eg, publication bias, selective reporting within studies). Describe methods of additional analyses if done, indicating which were prespecified. This may include, but not be limited to, the following:  Sensitivity or subgroup analyses;  Meta-regression analyses;  Alternative formulations of the treatment network; and  Use of alternative prior distributions for Bayesian analyses (if applicable).

Results* Study selection

17

Presentation of network structure

S3

Summary of network geometry

S4

Study characteristics

18

Risk of bias within studies

19

Results of individual studies

20

Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. Provide a network graph of the included studies to enable visualization of the geometry of the treatment network. Provide a brief overview of characteristics of the treatment network. This may include commentary on the abundance of trials and randomized patients for the different interventions and pairwise comparisons in the network, gaps of evidence in the treatment network, and potential biases reflected by the network structure. For each study, present characteristics for which data were extracted (eg, study size, PICOS, follow-up period) and provide the citations. Present data on risk of bias of each study and, if available, any outcome level assessment. For all outcomes considered (benefits or harms), present, for each study (1) simple summary data for each intervention group and (2) effect estimates and confidence intervals. Modified approaches may be needed to deal with information from larger networks.

5

5-6

5-6

6

5

6

6, Figure 1

Figure 2 6-7

Table 1

8, Figure 3A,B Table 1

(continued on next page )

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SUPPLEMENTAL TABLE S1 - Continued Section/topic

Item no.

Checklist item

Reported on page no.

Synthesis of results

21

8, Table 2

Exploration for inconsistency

S5

Risk of bias across studies

22

Results of additional analyses

23

Present results of each meta-analysis done, including confidence/credible intervals. In larger networks, authors may focus on comparisons versus a particular comparator (eg. placebo or standard care), with full findings presented in an appendix. League tables and forest plots may be considered to summarize pairwise comparisons. If additional summary measures were explored (such as treatment rankings), these should also be presented. Describe results from investigations of inconsistency. This may include such information as measures of model fit to compare consistency and inconsistency models, P values from statistical tests, or summary of inconsistency estimates from different parts of the treatment network. Present results of any assessment of risk of bias across studies for the evidence base being studied. Give results of additional analyses, if done (eg, sensitivity or subgroup analyses, meta-regression analyses, alternative network geometries studied, alternative choice of prior distributions for Bayesian analyses, and so forth). Summarize the main findings, including the strength of evidence for each main outcome; consider their relevance to key groups (eg, health care providers, users, and policy makers). Discuss limitations at study and outcome level (eg, risk of bias), and at review level (eg, incomplete retrieval of identified research, reporting bias). Comment on the validity of the assumptions, such as transitivity and consistency. Comment on any concerns regarding network geometry (eg, avoidance of certain comparisons). Provide a general interpretation of the results in the context of other evidence and implications for future research.

9-10

Describe sources of funding for the systematic review and other support (eg, supply of data) and role of funders for the systematic review. This should also include information regarding whether funding has been received from manufacturers of treatments in the network and/or whether some of the authors are content experts with professional conflicts of interest that could affect use of treatments in the network.

12

Discussion Summary of evidence

24

Limitations

25

Conclusions

26

Funding Funding

27

8

8 9

11

12

PICOS, population, intervention, comparators, outcomes, study design. Text in italics indicates wording specific to reporting of network meta-analyses that has been added to guidance from the PRISMA statement. *Authors may wish to plan for the use of appendices to present all relevant information in full detail for items in this section.

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SUPPLEMENTAL TABLE S2 - Search Strategy of the Online Databases from Their Inception until February 23, 2018 Database Ovid MEDLINE: Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE

Embase Classic 1 Embase

Cochrane

CINAHL

SCOPUS

WHO ICTRP

Search strategy 1. endodontic*.mp. (n518122); 2. pulpitis.mp. (n53082); 3. "irreversible pulpitis".mp. (n5459); 4. "symptomatic irreversible pulpitis".mp. (n595); 5. (inflammation adj3 pulp).mp (n5323); 6. dental pulp diseases/ or pulpitis/ (n55145); 7. exp "Root Canal Therapy"/ (n519536); 8. "root canal treatment*".mp. (n52379); 9. "root canal therap*".mp. (n512927); 10. pulpectomy.mp. (n51519); 11. Pulpectomy/ (n51106);12. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 (n534154); 13. articaine.mp. (n5442); 14. bupivacaine.mp. or exp BUPIVACAINE/ (n515318); 15. lidocaine.mp. or exp LIDOCAINE/ (n530295); 16. mepivacaine.mp. or exp MEPIVACAINE/ (n52549); 17. prilocaine.mp. or exp PRILOCAINE/ (n52496); 18. Anesthetics, Local/ (n531567); 19. efficacy.mp. (n5675909); 20. "oral ana?lgesics".mp. (n5551); 21. exp Analgesics/ (n5489685); 22. 13 or 14 or 15 or 16 or 17 or 18 or 20 or 21 (n5540408) ; 23. 12 and 22 (n5712); 24. 19 and 23 (n5137); 25. effectiveness.mp. (n5376254); 26. 19 or 25 (n51007860); 7. 23 and 26 (n5177) 1. endodontic*.mp. (n533763); 2. pulpitis.mp. (n53140); 3. "irreversible pulpitis".mp. (n5364); 4. "symptomatic irreversible pulpitis".mp (n560); 5. (inflammation adj3 pulp).mp. (n5333); 6. "root canal treatment*".mp. (n52128); 7. "root canal therap*".mp. (n51404); 8. pulpectomy.mp. (n5439); 9. articaine.mp. (n51059); 10. bupivacaine.mp. or exp BUPIVACAINE/ (n535308); 11. lidocaine.mp. or exp LIDOCAINE/ (n573782); 12. mepivacaine.mp. or exp MEPIVACAINE/ (n56539); 13. prilocaine.mp. or exp PRILOCAINE/ (n55002); 14. efficacy.mp. (n51472377); 15. "oral ana?lgesics".mp. (n5849); 16. exp tooth pulp disease/ (n57571); 17. exp pulpitis/ (n52847); 18. ‘Root Canal Therapy.mp. (n51394); 9. exp endodontic procedure/ (n51747); 20. exp articaine/ (n51024); 21. exp local anesthetic agent/ (n5234530); 22. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 16 or 17 or 18 or 19 (n539658); 23. exp analgesic agent/ (n5844707); 24. 9 or 10 or 11 or 12 or 13 or 15 or 20 or 21 or 23 (n51012416); 25. 14 and 22 and 24 (n5231); 26. effectiveness.mp. (n5671956); 27. 14 or 26 (n51992356); 28. 22 and 24 and 27 (n5284) 1. endodontic* (n52318); 2. pulpitis (n5325); 3. "irreversible pulpitis" (n5175); 4. "symptomatic irreversible pulpitis" (n539); 5. inflammation near/3 pulp (n519); 6. MeSH descriptor: [Dental Pulp Diseases] explode all trees (n5550); 7. MeSH descriptor: [Pulpitis] explode all trees (n5181); 8. MeSH descriptor: [Root Canal Therapy] explode all trees (n51064); 9. "root canal treatment*" (n5206); 10. "root canal therap*" (n5516); 11. pulpectomy (n5167); 12. MeSH descriptor: [Pulpectomy] explode all trees (n572); 13. #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 (n52835); 14. articaine (n5243); 15. bupivacaine (n59183); 16. lidocaine (n59229); 17. mepivacaine (n5857); 18. prilocaine (n51092); 19. MeSH descriptor: [Bupivacaine] explode all trees (n53936); 20. MeSH descriptor: [Lidocaine] explode all trees (n54355); 21. MeSH descriptor: [Mepivacaine] explode all trees (n5393); 22. MeSH descriptor: [Prilocaine] explode all trees (n5660); 23. MeSH descriptor: [Anesthetics, Local] explode all trees (n57312); 24. "oral analgesics" (n5696); 25. MeSH descriptor: [Analgesics] explode all trees (n518714); 26. #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 (n535588); 27. efficacy (n5225890); 28. effectiveness (n5116425); 29. #27 or #28 (n5306524); 30. #13 and #26 and #29 (n5192) 1. TX endodontic* (n52224); 2. TX pulpitis (n592); 3. TX "irreversible pulpitis" (n553); 4. TX "symptomatic irreversible pulpitis" (n512); 5. TX inflammation pulp* (n50); 6. MH dental pulp (n5426); 7. MH root canal therapy (n51046); 8. TX "root canal therap*" (n51073); 9. TX "root canal treatment*" (n5169); 10. TX pulpectomy (n544); 11. MH Pulpectomy (n539); 12. S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 (n53033); 13. TX articaine (n581); 14. TX bupivacaine (n51819); 15. TX lidocaine (n53269); 16. TX mepivacaine (n5106); 17. TX prilocaine (n5269); 18. MH BUPIVACAINE (n51493); 19. MH lidocaine (n52521); 20. MH Anesthetics, Local (n53808); 21. TX "oral analgesics" (n5146); 22. MH Analgesics (n56518); 23. S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 (n513462); 24. TX efficacy (n590154); 25. S12 AND S23 AND S24 (n536); 26. TX effectiveness (n582776); 27. S24 OR S26 (n5163895); 28. S12 AND S23 AND S27 (n542) ( ( TITLE-ABS-KEY ( endodontic* ) OR TITLE-ABS-KEY ( pulpitis ) OR TITLE-ABS-KEY ( "irreversible pulpitis" ) OR TITLE-ABS-KEY ( "symptomatic irreversible pulpitis" ) OR TITLE-ABS KEY ( pulp AND inflammation ) OR TITLE-ABS-KEY ( "root canal treatment*" ) OR TITLE-ABS-KEY ( "root canal therap*" ) OR TITLE-ABS-KEY ( pulpectom* ) ) ) AND ( ( TITLE-ABS-KEY ( articaine ) OR TITLE-ABSKEY ( bupivacaine ) OR TITLE-ABS-KEY ( lidocaine ) OR TITLE-ABS-KEY ( mepivacaine ) OR TITLEABS-KEY ( prilocaine ) OR TITLE-ABS-KEY ( "local anaesthetic*" ) OR TITLE-ABS-KEY ( "local anesthetic*" ) OR TITLE-ABS-KEY ( "analgesi*" ) ) ) AND ( TITLE-ABS-KEY ( efficacy ) OR TITLE-ABS ( effective* ) ) - CANAL THERAPIES, ROOT, CANAL THERAPY, ROOT, ROOT CANAL, ROOT CANAL (TREATMENT), ROOT CANAL NOS, ROOT CANAL PROCEDURE, ROOT CANAL SURGERY, ROOT CANAL THER, ROOT CANAL THERAPIES, ROOT CANAL, NOT OTHERWISE SPECIFIED, THER ROOT CANAL, THERAPIES, ROOT CANAL, THERAPY, ROOT CANAL, root canal therapy plupectomy - DISORDERS OF TEETH AND JAW, ENDODONTIC INFLAMMATION, ENDODONTIC INFLAMMATIONS, INFLAMMATION, ENDODONTIC, INFLAMMATIONS, ENDODONTIC, (continued on next page )

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PROQUEST

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Search strategy PULPITIDES, pulpitis - PIPERIDINE, mepivacaine - 1-BUTYL-N-(2,6-DIMETHYLPHENYL)-2PIPERIDINECARBOXAMIDE, bupivacaine - AGENTS, ANESTHETIC, ANAESTHESIA, ANAESTHETIC, ANAESTHETICS, ANESTHESIOL, ANESTHESIOLOGY, ANESTHESIOLOGY (FIELD), ANESTHETIC, ANESTHETIC (PRODUCT), ANESTHETIC (SUBSTANCE), ANESTHETIC AGENT, ANESTHETIC AGENTS, ANESTHETIC DRUGS, ANESTHETIC, NOS, DRUGS CAUSING LOSS OF SENSATION, DRUGS, ANESTHETIC, anesthetics - PROPITOCAINE, prilocaine - 2(DIETHYLAMINO)-N-(2,6-DIMETHYLPHENYL) ACETAMIDE, 2-2ETN-2MEPHACN, INSULIN NPH, LIGNOCAINE, lidocaine - ARTICAIN, CARTICAIN, articaine 25 records for 24 trials found! pulpitis AND (efficacy OR effectiveness) AND (Anesthetics OR Lidocaine OR articling OR Prilocaine OR mepivacaine OR mupivacaine); 147 results.

Efficacy and Safety of Pulpal Anesthesia Strategies

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SUPPLEMENTARY TABLE S3 - Excluded Studies at the Full-text Screening Stage with Reasons Reasons for exclusion Commentaries

Completed trials but could not retrieve full text, attempted to contact authors but no response

No enough data to perform NMA

No endodontic treatment was performed

References 1. Abt E. Analgesic premedication may increase the success rate of local anesthetics for teeth with irreversible pulpitis. J Evid Based Dent Pract 2011;11:141–142. 2. Nusstein JM. Preoperative oral use of ibuprofen or dexamethasone may improve the anesthetic efficacy of an inferior alveolar nerve block in patients diagnosed with irreversible pulpitis. J Evid Based Dent Pract 2013;13:102–103. 3. Parirokh M. Buffered lidocaine with sodium bicarbonate did not increase inferior alveolar nerve block success rate in patients having symptomatic irreversible pulpitis. J Evid Based Dent Pract 2016;16:59–61. 1. Anesthetic Efficacy of Gow-Gates Versus Conventional Inferior Alveolar Nerve Block Techniques (ClinicalTrials.gov Identifier: NCT01329874) 2. Effect of Sufentanil on the Rate of Anesthesia (ClinicalTrials.gov Identifier: NCT01572116) 3. Nermeen Awad Allah Abbas Ibrahim, Pre-operative Aceclofenac on the Anesthetic Efficacy of IANB in Symptomatic Irreversible Pulpitis (ClinicalTrials.gov Identifier: NCT03146481) 4. Amatallah Hussein Nasser Al-Rawhani, Effect of Preoperative Diclofenac Potassium on Articaine Buccal Infitration Success (ClinicalTrials.gov Identifier: NCT03174860) 1. Kanaa MD, Whitworth JM, Meechan JG. A comparison of the efficacy of 4% articaine with 1:100,000 epinephrine and 2% lidocaine with 1:80,000 epinephrine in achieving pulpal anesthesia in maxillary teeth with irreversible pulpitis. J Endod 2012;38:279–282. 2. Maniglia-Ferreira C, Almeida-Gomes F, Carvalho-Sousa B, et al. Clinical evaluation of the use of three anesthetics in endodontics. Acta Odontol Latinoam 2009;22:21–26. 3. Ramalho KM, de Souza LMP, Tortamano IP, Adde CA, Rocha RG, de Paula Eduardo C. A randomized placebo-blind study of the effect of low power laser on pain caused by irreversible pulpitis. Lasers Med Sci 2016;31:1899–1905. 4. Mellor AC, Dorman ML, Girdler NM. The use of an intra-oral injection of ketorolac in the treatment of irreversible pulpitis. Int Endod J 2005;38:789–794. 1. Axelsson S, Isacsson G. The efficacy of ropivacaine as a dental local anaesthetic. Swed Dent J 2004;28:85–91. 2. Batista da Silva C, Berto LA, Volpato MC, et al. Anesthetic efficacy of articaine and lidocaine for incisive/mental nerve block. J Endod 2010;36:438–441. 3. Goodman A, Reader A, Nusstein J, et al. Anesthetic efficacy of lidocaine/meperidine for inferior alveolar nerve blocks. Anesth Prog 2006;53:131–139. 4. Haas DA, Harper DG, Saso Ma, Young ER. Comparison of articaine and prilocaine anesthesia by infiltration in maxillary and mandibular arches. Anesth Prog 1990;37:230–237. 5. Haas DA, Harper DG, Saso MA, Young ER. Lack of differential effect by Ultracaine (articaine) and Citanest (prilocaine) in infiltration anaesthesia. J Can Dent Assoc 1991;57:217–223. 6. Replogle K, Reader A, Nist R, et al. Anesthetic efficacy of the intraosseous injection of 2% lidocaine (1:100,000 epinephrine) and 3% mepivacaine in mandibular first molars. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83:30–37. 7. McCartney M, Reader A, Beck M. Injection pain of the inferior alveolar nerve block in patients with irreversible pulpitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104:571–575. 8. Mikesell P, Nusstein J, Reader A, Beck M, Weaver J. A comparison of articaine and lidocaine for inferior alveolar nerve blocks. J Endod 2005;31:265–270. 9. Nagle D, Reader A, Beck M, Weaver J. Effect of systemic penicillin on pain in untreated irreversible pulpitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90:636–640. (continued on next page )

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Not randomized controlled trials

References 10. Ridenour S, Reader A, Beck M, Weaver J. Anesthetic efficacy of a combination of hyaluronidase and lidocaine with epinephrine. Anesth Prog 2001;48:9–15. 11. Saraf SP, Saraf PA, Kamatagi L, et al. A comparative evaluation of anesthetic efficacy of articaine 4% and lidocaine 2% with anterior middle superior alveolar nerve block and infraorbital nerve block: An in vivo study, Journal of conservative dentistry. J Conserv Dent 2016;19:527–531. 12. Satish SV, Shetty KP, Kilaru K, Bhargavi P, Reddy ES, Bellutgi A. Comparative evaluation of the efficacy of 2% lidocaine containing 1:200,000 epinephrine with and without hyaluronidase (75 IU) in patients with irreversible pulpitis. J Endod 2013;39:1116–1168. 13. Stabile P, Reader A, Gallatin E, Beck M, Weaver J. Anesthetic efficacy and heart rate effects of the intraosseous injection of 1.5% etidocaine (1:200,000 epinephrine) after an inferior alveolar nerve block. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89:407–411. 14. Volpato MC, Ranali J, Ramacciato J C, et al. Anesthetic efficacy of bupivacaine solutions in inferior alveolar nerve block. Anesth Prog 2005;52:132–135. 1. Ahmad ZH, Ravikumar H, Karale R, Preethanath RS, Sukumaran A. Study of the anesthetic efficacy of inferior alveolar nerve block using articaine in irreversible pulpitis. J Contemp Dent Pract 2014;15:71– 74.
n H. Anesthetic 2. Argueta-Figueroa L, Arzate-Sosa G, Mendieta Zero efficacy of articaine for inferior alveolar nerve blocks in patients with symptomatic versus asymptomatic irreversible pulpitis. Gen Dent 2012;60:e39–e43. 3. Bhuyan AC, Latha SS, Jain S, Kataki R. Anesthetic efficacy of the supplemental X-tip intraosseous injection using 4% articaine with 1:100,000 adrenaline in patients with irreversible pulpitis: an in vivo study. J Conserv Dent 2014;17:522–525. 4. Bigby J, Reader A, Nusstein J, et al. Articaine for supplemental intraosseous anesthesia in patients with irreversible pulpitis. J Endod 2006;32:1044–1047. 5. Sakkir N, Naik KG, Jayaram NK, Idris M. Intraosseous injection as an adjunct to conventional local anesthetic techniques: a clinical study. J Conserv Dent 2014;17:432–435. 6. Lin S, Wigler R, Huber R, Kaufman AY. Anaesthetic efficacy of intraligamentary injection techniques on mandibular molars diagnosed with asymptomatic irreversible pulpitis: a retrospective study. Aust Endod J 2017;43:34–37. 7. Matthews R, Drum M, Reader A, Nusstein J, Beck M. Articaine for supplemental buccal mandibular infiltration anesthesia in patients with irreversible pulpitis when the inferior alveolar nerve block fails. J Endod 2009;35:343–346. 8. Nusstein J, Claffey E, Reader A, Beck M, Weaver J. Anesthetic effectiveness of the supplemental intraligamentary injection, administered with a computer-controlled local anesthetic delivery system, in patients with irreversible pulpitis. J Endod 2005;31:354– 358. 9. Nusstein J, Kennedy S, Reader A, et al. Anesthetic efficacy of the supplemental X-tip intraosseous injection in patients with irreversible pulpitis. J Endod 2003;29:724–728. 10. Nusstein J, Reader A, Nist R, et al. Anesthetic efficacy of the supplemental intraosseous injection of 2% lidocaine with 1:100,000 epinephrine in irreversible pulpitis. J Endod 1998;24:487–491. 11. Parente SA, Anderson RW, Herman WW, et al. Anesthetic efficacy of the supplemental intraosseous injection for teeth with irreversible pulpitis. J Endod 1998;24:826–828. 12. Walton R, Reisman D, Nist R, et al. Anesthetic efficacy of the supplemental intraosseous injection of 3 % mepivacaine in (continued on next page )

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SUPPLEMENTARY TABLE S3 - Continued Reasons for exclusion

References

13.

14.

15.

16.

17.

Retrospective studies

1.

2.

Ongoing trials from clinicaltrials.gov and WHO ICTRP

1.

2.

3. 4.

5.

6.

7.

8.

9. 10. 11. 12. 13. 14.

irreversible pulpitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84:676–682. Subbiya A, Pradeepkumar AR, Vivekanandhan P, Karthick A. Comparative efficacy evaluation of articaine as buccal infiltration and lignocaine as IANB in the mandibular first molar with irreversible pulpitis. Indian J Multidiscip Dent 2011;2:370–373. Talati A, Bidar M, Sadeghi G, Nezami H. A comparative study of lidocaine and lidocaine-mannitol in anesthetizing human teeth with inflamed pulps. Int Endod J 2006;1:19–23. Vangheluwe J, Walton R. Intrapulpal injection: factors related to effectiveness. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83:38–40. Verma PK, Srivastava R, Kumar MR. Anesthetic efficacy of X-tip intraosseous injection using 2% lidocaine with 1:80,000 epinephrine in patients with irreversible pulpitis after inferior alveolar nerve block: a clinical study. J Conserv Dent 2013;16:162–166. Webster S Jr, Drum M, Reader A, et al. How effective is supplemental intraseptal anesthesia in patients with symptomatic irreversible pulpitis? J Endod 2016;42:1453–1457. Fowler S, Drum M, Reader A, Beck M. Anesthetic success of an inferior alveolar nerve block and supplemental articaine buccal infiltration for molars and premolars in patients with symptomatic irreversible pulpitis. J Endod 2016;42:390–392. Fowler S, Reader A. Is a volume of 3.6 ml better than 1.8 ml for inferior alveolar nerve blocks in patients with symptomatic irreversible pulpitis? J Endod 2013;39:970–972. Anesthetic Efficacy of 1,8mL and 3,6mL of Articaine in Inferior Alveolar Nerve Block in Irreversible Pulpitis (ClinicalTrials.gov Identifier: NCT02422823) Comparison of Anesthetic Efficacy of Dexmedetomidine and Epinephrine With Lidocaine in Irreversible Pulpitis (ClinicalTrials.gov Identifier: NCT03415724) Diclofenac Potassium on IANB Efficacy in Symptomatic Irreversible Pulpitis (ClinicalTrials.gov Identifier: NCT03163420) Effect of Lidocaine With Magnesium Sulfate on the Success of the Inferior Alveolar Nerve Block (ClinicalTrials.gov Identifier: NCT03262857) Efficacy of Block Injection of an Anti-Inflammatory Medicine in Patients With Mandibular Dental Pain (ClinicalTrials.gov Identifier: NCT03410212) Efficacy of Two Injection Techniques on Success Rate of Inferior Alveolar Nerve Anesthesia (ClinicalTrials.gov Identifier: NCT02543619) Ketorolac Premedication for Anesthetic Efficiency of IANB & Postendodontic Pain in Teeth With Irreversible Pulpitis (ClinicalTrials. gov Identifier: NCT02940405) Success of Inferior Alveolar Nerve Block in Women Taking Selective Serotonin Reuptake Inhibitors (ClinicalTrials.gov Identifier: NCT02884596) Comparison of two anesthestic agents in irreversible pulpitis cases of upper first molar (WHO ICTRP main ID CTRI/2016/12/007610); Painless Anesthesia for mandibular teeth (WHO ICTRP main ID CTRI/2016/12/007546) Effect of Dexamethasone on the efficacy of anesthesia in painful teeth (WHO ICTRP main ID CTRI/2017/05/008544) 4% Articaine and 2% Lidocaine by Intraligamentary Technique in Irreversible Pulpitis (ClinicalTrials.gov Identifier: NCT02807298) Evaluation of Anesthetic efficacy of injection technique in single visit root canal therapy (WHO ICTRP main ID CTRI/2017/05/008632) A clinical trial to study the effects of adding magnesium sulfate with local anesthetic injection on evaluating shooting tooth pain during (continued on next page )

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References

15.

16.

17.

18. 19.

20.

Results not binary

1.

2.

Results reported in another study

1.

Single-arm studies

1.

2.

3.

4.

5. 6.

7.

8.

and after the treatment (WHO ICTRP main ID IRCT2015011020238N2) Comparison of anesthetic efficacy of articaine in different anesthetic administration methods in the lower jaw molars (trial id: IRCT2014120820238N1) Comparison of anesthetic efficacy of articaine in different anesthetic administration methods and volumes in maxillary first molars (WHO ICTRP main ID IRCT2015011020238N) Comparison of the anesthetic efficacy of Articaine 4% in two supplemental anesthetic injections (WHO ICTRP main ID IRCT2015072023253N1) The efficacy of three different anesthetic technique in mandibular molars (WHO ICTRP main ID IRCT2015073023412N1) Comparison of Articaine and Lidocaine as an anesthetic supplemental injection (WHO ICTRP main ID IRCT2015100523253N2) Anesthetic efficacy of Articaine/Clonidine for inferior alveolar nerve block in patients with irreversible pulpitis (WHO ICTRP main ID IRCT201706022541N6) Shetkar P, Jadhav GR, Mittal P, et al. Comparative evaluation of effect of preoperative alprazolam and diclofenac potassium on the success of inferior alveolar, Vazirani-Akinosi, and Gow-Gates techniques for teeth with irreversible pulpitis: Randomized controlled trial. J Conserv Dent 2016;19:390–395. Sooraparaju SG, Abarajithan M, Sathish ES, et al. Anaesthetic efficacy of topical benzocaine gel combined with hyaluronidase for supplemental intrapulpal injection in teeth with irreversible pulpitis- a double blinded clinical trial. J Clin Diagn Res 2015;9:ZC95–ZC7. Rogers BS, Botero TM, Mcdonald NJ, et al. Efficacy of articaine versus lidocaine as a supplemental buccal infiltration in mandibular molars with irreversible pulpitis: a prospective, randomized, doubleblind study. J Endod 2014;40:753–758. Abazarpoor R, Parirokh M, Nakhaee N, Abbott PV. A comparison of different volumes of articaine for inferior alveolar nerve block for molar teeth with symptomatic irreversible pulpitis. J Endod 2015;41:1408–1411. Aggarwal V, Singla M, Miglani S, Kohli S. Comparison of the anaesthetic efficacy of epinephrine concentrations (1 : 80,000 and 1 : 200,000) in 2% lidocaine for inferior alveolar nerve block in patients with symptomatic irreversible pulpitis: a randomized, double-blind clinical trial. Int Endod J 2014;47:373–379. Aggarwal V, Singla M, Miglani S, et al. A prospective, randomized single-blind evaluation of effect of injection speed on anesthetic efficacy of inferior alveolar nerve block in patients with symptomatic irreversible pulpitis. J Endod 2012;38:1578–1580. Aggarwal V, Singla M, Miglani S, et al. Comparative evaluation of 1.8 mL and 3.6 mL of 2% lidocaine with 1:200,000 epinephrine for inferior alveolar nerve block in patients with irreversible pulpitis: a prospective, randomized single-blind study. J Endod 2012;38:753–756. Aggarwal V, Singla M, Subbiya A, et al. Effect of preoperative pain on inferior alveolar nerve block. Anesth Prog 2015;62:135–139. Kennedy S, Reader A, Nusstein J, et al. The significance of needle deflection in success of the inferior alveolar nerve block in patients with irreversible pulpitis. J Endod. 2003;29(10):630–3. Pereira LAP, Groppo FC, Bergamaschi Cde C, et al. Articaine (4%) with epinephrine (1:100,000 or 1:200,000) in intraosseous injections in symptomatic irreversible pulpitis of mandibular molars: anesthetic efficacy and cardiovascular effects. Oral Surg Oral Med Oral Pathol Oral Radiol 2013;116:85–91. Shadmehr E, Aminozarbian MG, Akhavan A, et al. Anaesthetic efficacy of lidocaine/clonidine for inferior alveolar nerve block in patients with irreversible pulpitis. Int Endod J 2017;50:531–539. (continued on next page )

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SUPPLEMENTARY TABLE S3 - Continued Reasons for exclusion Using pharmacologic agents that require mixing/extra preparation or its use is restricted to those who meet special qualifications

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References 1. Akhlaghi NM, Hormozi B, Abbott PV, Khalilak Z. Efficacy of ketorolac buccal infiltrations and inferior alveolar nerve blocks in patients with irreversible pulpitis: a prospective, double-blind, randomized clinical trial. J Endod 2016;42:691–695. 2. Bigby J, Reader A, Nusstein J, Beck M. Anesthetic efficacy of lidocaine/meperidine for inferior alveolar nerve blocks in patients with irreversible pulpitis. J Endod 2007;33:7–10. 3. Jalali S, Majd NM, Torabi S, et al. The effect of acupuncture on the success of inferior alveolar nerve block for teeth with symptomatic irreversible pulpitis: a triple-blind randomized clinical trial. J Endod 2015;41:1397–1402. 4. Khademi AA, Saatchi M, Minaiyan M, et al. Effect of preoperative alprazolam on the success of inferior alveolar nerve block for teeth with irreversible pulpitis. J Endod 2012;38:1337–1339. 5. Kreimer T, Kiser Ii R, Reader A, et al. Anesthetic efficacy of combinations of 0.5 mol/L mannitol and lidocaine with epinephrine for inferior alveolar nerve blocks in patients with symptomatic irreversible pulpitis. J Endod 2012;38:598–603. 6. Lindemann M, Reader A, Nusstein J, et al. Effect of sublingual triazolam on the success of inferior alveolar nerve block in patients with irreversible pulpitis. J Endod 2008;34:1167–1170. 7. Rodriguez-Wong L, Pozos-Guillen A, Silva-Herzog D, ChavarriaBolanos D. Efficacy of mepivacaine-tramadol combination on the success of inferior alveolar nerve blocks in patients with symptomatic irreversible pulpitis: a randomized clinical trial. Int Endod J 2016;49:325–333. 8. Saatchi M, Khademi A, Baghaei B, Noormohammadi H. Effect of sodium bicarbonate-buffered lidocaine on the success of inferior alveolar nerve block for teeth with symptomatic irreversible pulpitis: a prospective, randomized double-blind study. J Endod 2015;41:33– 35. 9. Sakhaeimanesh V, Khazaei S, Kaviani N, et al. Anesthetic efficacy of articaine and ketamine for inferior alveolar nerve block in symptomatic irreversible pulpitis: a prospective randomized doubleblind study. Iran Endod J 2017;12:449–453. 10. Schellenberg J, Drum M, Reader A, et al. Effect of buffered 4% lidocaine on the success of the inferior alveolar nerve block in patients with symptomatic irreversible pulpitis: a prospective, randomized, double-blind study. J Endod 2015;41:791–796. 11. Thimmaiah P, Hegde MN, Bhat GT, et al. Anesthetic efficacy of combination of two percent lidocaine with 1: 80,000 epinephrine and 0.5 mol/l mannitol for inferior alveolar nerve blocks in patients with symptomatic irreversible pulpitis: an in vivo study. Int Res J Pharm 2013;4:161–163. 12. Shetty KP, Satish SV, Kilaru KR, et al. Comparison of anesthetic efficacy between lidocaine with and without magnesium sulfate USP 50% for inferior alveolar nerve blocks in patients with symptomatic irreversible pulpitis. J Endod 2015;41:431–433.

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