i

Pain Management During and Following Endodontic Treatment: Systematic Reviews and Network Meta-

analyses

by

Maryam Zanjir

A thesis submitted in conformity with the requirements for the degree of Master of Science in Dentistry

Faculty of Dentistry University of Toronto

© Copyright by Maryam Zanjir 2021

ii

Pain Management During and Following Endodontic Treatment:

Systematic Reviews and Network Meta-analyses

Maryam Zanjir

Master of Science in Dentistry

Faculty of Dentistry University of Toronto

2021

Abstract

Objectives: To identify effective interventions for 1) achieving successful pulpal anesthesia

during endodontic treatment; and 2) managing postoperative pain.

Methods: We searched major databases. Two review authors selected studies and extracted data.

Included studies were assessed by Cochrane risk of bias tool. Network meta-analyses (NMAs)

were undertaken using the Bayesian random-effects framework to rank and estimate the treatment

effects of the included interventions.

Results: Out of 37 interventions of 46 studies, we identified supplemental intraosseous injection

(IO) to be the most efficacious followed by supplemental buccal and lingual infiltrations using 4%

articaine+preoperative NSAIDS. In eight of 11 studies, NSAIDs+acetaminophen and NSAIDs

were the most effective for managing postoperative pain.

Conclusion/significance: Supplemental IO using 2% lidocaine with or without pre-operative

analgesic or 4% articaine were the most efficacious strategies to achieve pulpal anesthesia during

endodontic treatment. Postoperatively, NSAIDs or NSAIDs+acetaminophen were the most

effective.

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Acknowledgments

I praise and thank Allah for enabling me to complete this thesis and ask him to turn it into a tool

that guides every clinician when managing pain during and following endodontic treatment for

their patients.

First and foremost I offer my sincerest appreciation and gratitude to my supervisor and mentor,

Dr. Amir Azarpazhooh, for the continuous support, guidance, advice, supervision and exceptional

patience. Without his help and motivation, it would not be possible to complete my research project

and write this thesis while publishing two papers out of it and co-authoring many others. Thank

you Dr. Amir!

I would like to thank both, Dr. Joseph Beyene and Dr. Bruno daCosta, who taught me the principles

for conducting Network meta-analysis and supported me during the analysis phase of my project.

I would also like to thank Dr. Prakesh Shah who not only co-supervised my progress, but also

brought his methodological expertise to ensure a high-quality product. My thanks are extended to

Dr. Carilynne Yarascavitch who also supported my progress and guided me with her expertise

while designing my research project.

I would like to express gratitude to the Endodontics Department at the University of Toronto for

their support during my research project presentation at the American Association of Endodontists

meeting in Montreal in 2019. Special thanks to University of Toronto Pain Journal Club for their

informative sessions. In particular, Dr. Limor Avivi-Arber, who was not only my mentor, but also

a source of inspiration and motivation.

I was blessed by the invaluable assistance and encouragement I received from our research team:

Nima Laghapour Lighvan, Adam Sgro and Dr. Elaine Cardoso during the conduct of my research

project. Special thanks to Dr. Laura Macdonald and Dr. Jacqueline Lopez Gross for their

motivation and uplifting spirits. In addition, I would like to recognize Ms. Maria Zych from the

University of Toronto Libraries for her help in the search strategy of my research project, Ms. Nina

Munteanu and Dr. Boba Samuels from the Health Sciences Writing Centre for their support in

writing this thesis.

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Finally, I would like to express my sincere appreciation to my family. My mother, Nouran, and

father, Prof. Mohamad Rifat, for their unconditional love, continuous support and encouragement

to pursue my dreams. My brothers, Ahmad, Abdulrahman and Wayel who supported me and

continue to inspire me in every possible way. My husband, Abdulrahman, for his love, support,

and being by my side throughout my MSc journey. My bundle of joy, Omar, who brightens up my

world with his smile. This thesis is dedicated to my wonderful family.

v

Table of Contents

Acknowledgments.......................................................................................................................... iii

Table of Contents .............................................................................................................................v

List of Tables ................................................................................................................................ vii

List of Figures .............................................................................................................................. viii

List of Abbreviations ..................................................................................................................... ix

Chapter 1 ..........................................................................................................................................1

Introduction .................................................................................................................................1

1.1 Background ..........................................................................................................................1

1.2 Description of the condition.................................................................................................2

1.2.1 Pain origin and classification ...................................................................................2

1.2.2 Pain mechanism .......................................................................................................3

1.2.3 Pulpal pain ...............................................................................................................4

1.2.4 Irreversible pulpitis and endodontic treatment ........................................................5

1.2.5 Pain before and during endodontic treatment ..........................................................5

1.3 Definition of the problem...................................................................................................16

1.4 Introduction to the methods: systematic reviews and Network Meta-Analyses ................17

1.4.1 Background ............................................................................................................17

1.4.2 Systematic reviews.................................................................................................18

1.4.3 Definition and Advantages of Network meta-analysis ..........................................22

1.4.4 Guidelines of Network meta-analysis ....................................................................23

1.4.5 Statistical approach of Network meta-analysis ......................................................24

1.4.6 Quality of evidence evaluation ..............................................................................26

1.5 Objectives and specific aims ..............................................................................................28

1.6 Significance........................................................................................................................28

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Chapter 2 ........................................................................................................................................29

Efficacy and safety of pulpal anesthesia strategies during endodontic treatment: a systematic review and network meta-analysis ..........................................................................29

Chapter 3 ........................................................................................................................................70

Efficacy and safety of post-operative medications in reducing pain following nonsurgical endodontic treatment: a systematic review and network meta-analysis ...................................70

Chapter 4 ........................................................................................................................................91

Discussion .................................................................................................................................91

4.1 Summary of findings..........................................................................................................92

4.2 Agreements and disagreements with other systematic reviews and meta-analyses or network meta-analyses .......................................................................................................92

4.2.1 The efficacy and safety of pulpal anesthesia strategies during endodontic treatment ................................................................................................................92

4.2.2 The efficacy and safety of post-operative medications in reducing pain following nonsurgical endodontic treatment .........................................................94

4.3 Challenges ..........................................................................................................................95

4.3.1 Risk of bias ............................................................................................................95

4.3.2 Quality of evidence ................................................................................................96

4.4 Outcome measure...............................................................................................................97

4.5 Future clinical trials methodological and reporting quality ...............................................97

4.6 Strengths and limitations of our NMAs .............................................................................99

4.7 Implications for clinical practice .....................................................................................100

4.8 Implications for future research .......................................................................................100

Chapter 5 ......................................................................................................................................102

Conclusion ..............................................................................................................................102

References ....................................................................................................................................103

vii

List of Tables

Table 1. Pharmacodynamics data of commonly used amides in dentistry.

Table 2. Summary of data extracted in both our NMAs.

viii

List of Figures

Figure 1. Diagrammatic outline of the major neural structures relevant to pain.

Figure 2. Illustration of an indirect estimate that compares the effectiveness of treatment (B) and

treatment (C) through a common comparator, treatment (A)

ix

List of Abbreviations

BI: buccal infiltration

CI: confidence interval

CINeMA: confidence in network meta‐analysis

COX: cyclooxygenase

CrI: Credible interval

GRADE: Grading of recommendations assessment, development, and evaluation

IANB inferior alveolar nerve block

IO: Intraosseous

NMA: Network meta-analysis

NSAIDs: nonsteroidal anti-inflammatory drugs

OR: odd ratio

PABA: para-aminobenzoic acid

pH: potential of hydrogen

PICOS: population, interventions, comparators, outcomes

RCTs: randomized controlled trials

ROB: risk of bias

SD: standard deviation

SUCRA: surface under the cumulative ranking curve

x

MCMC: Markov chain Monte Carlo

MD: mean difference

1

Chapter 1

Introduction

It is well known that achieving successful pulpal anesthesia during endodontic treatment of

patients with symptomatic irreversible pulpitis can be challenging. The efficacy of various

injection techniques and local anesthetic solutions were investigated in multiple clinical trials.

Previous pairwise meta-analyses are limited as they can only compare the efficacy of two

interventions at a time and cannot compare nor rank all the available interventions with one

another.

To overcome such a limitation, we have utilized the application of network meta-analysis (NMA)

to compare and rank the efficacy of the interventions compared in clinical trials we identified

through a comprehensive search strategy (Chapter 2). NMA is an analytical approach used to

estimate the relative treatment effects of multiple sets of treatments for a particular condition and

to rank them according to their efficacy, regardless of whether or not these treatments were directly

compared in a clinical setting.

Likewise, we applied NMA to identify the most efficacious postoperative medications to manage

pain following endodontic treatment (Chapter 3), a complication that may follow endodontic

treatment in up to 40% of patients.

1.1 Background

Pain, an unpleasant sensory and emotional experience that burdens an individual and affects their

daily activities, is the typical reason for patients to seek treatment. Ideally, dental treatments should

be pain- free through the use of local anesthetics. However, pain may still arise while treating

inflammatory conditions such as symptomatic irreversible pulpitis, where pain originates from

inflamed pulpal tissues requiring endodontic treatment.

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1.2 Description of the condition

1.2.1 Pain origin and classification

From a neurobiological prospective, pain may be nociceptive, inflammatory or pathologic (1, 2).

Considered to be the most common type of pain, nociceptive pain is a high-threshold pain that is

provoked by noxious stimuli such as extreme temperatures or pressure that has the potential to

damage tissues (e.g., during sports injury, dental procedures, arthritis) and is detected by

specialized peripheral sensory neurons known as nociceptors. Nociceptors may be found in the

skin, muscles, joints or viscera. Once activated, they transduce these stimuli into long-ranging

electrical signals that are relayed to higher brain centers for pain perception (3). Nociceptive pain

acts as an early-warning physiological protective system to detect and minimize contact with

damaging or noxious stimuli, such as when touching something extremely hot, cold or sharp. It

immediately activates the withdrawal reflex and elicits the intrinsic unpleasantness sensation.

Inflammatory pain, a cardinal feature of inflammation, is the perception of a noxious stimulus

(e.g., tissue injury, infection) that occurs during an inflammatory or immune response when the

immune system is activated. It assists in the healing of the injured body part by creating a situation

that discourages physical contact and movement. Postoperatively or after a surgical wound, pain

hypersensitivity and tenderness reduce further risk of damage and promote recovery, though

normally innocuous stimuli now elicit pain. Acute inflammation produces overt pain through the

direct activation of sensory neurons that conduct the pain signal.

The last type is pathological pain, not protective but maladaptive in nature. It is considered a

disease state of the nervous system, and can occur after damage to, or malfunctioning of, the

peripheral or central nervous system such as in neuropathic pain, or in conditions in which there

is no damage or inflammation, such as in dysfunctional pain (2). Trigeminal neuralgia and post-

herpetic neuralgia are examples of neuropathic pain (4). Dysfunctional pain may be evoked by

several conditions, such as fibromyalgia, irritable bowel syndrome, tension type headaches,

temporomandibular joint disease, interstitial cystitis, and other syndromes in which there exists

substantial pain but no noxious stimulus and no, or minimal, peripheral inflammatory pathology

(2).

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1.2.2 Pain mechanism

There are four major processes involved in conducting pain-related information (Figure 1):

transduction, transmission, modulation, and perception (5). Transduction refers to the processes

by which tissue-damaging stimuli activate nerve endings. First, the stimulus events are converted

to chemical tissue events. Then, these events are changed into electrical events in neurons, which

get transduced as chemical events at the synapses. Next, transmission takes place, which refers to

transmitting the electrical events along the neuronal pathways to the brain regions underlying

perception, while neurotransmitters in the synaptic cleft transmit information from a post-synaptic

terminal of one cell to a pre-synaptic terminal of another. Modulation is a recently discovered

neural process that acts specifically to reduce activity in the transmission system. Perception is the

subjective awareness produced by sensory signals; it involves the integration of many sensory

messages into a coherent and meaningful whole. Perception is a complex function of several

processes, including attention, expectation, and interpretation. All these lead to one end result: the

pathway of pain has been initiated and completed, and we feel the painful sensation triggered by

the stimulus.

Figure 1. Diagrammatic outline of the major neural structures relevant to pain highlighting

the processes leading to pain perception, adapted from Osterweis and colleagues (5). It begins

4

with transduction (lower left), where a noxious stimulus generates nerve impulses in the primary

afferent nociceptor. Then, transmission occurs when the nerve impulses are conducted to the spinal

cord where the primary afferent nociceptors contact the central pain-transmission cells that relay

the message to the thalamus. This may happen directly via the spinothalamic tract, or indirectly

via the reticular formation and the reticulothalamic pathway. Next, the message is relayed from

the thalamus to the cerebral cortex. The pain-modulation system has inputs from the frontal cortex

and the hypothalamus (H). The outflow is through the midbrain and medulla to the dorsal horn of

the spinal cord (DRG: dorsal root ganglion), where it inhibits pain-transmission cells, thereby

reducing the intensity of perceived pain.

1.2.3 Pulpal pain

Both the central and peripheral nervous systems are involved in the pain mechanism. Following

tissue damage in the orofacial region, a noxious stimulus is detected by the peripheral nervous

system through terminal nerve fibers known as nociceptive primary afferent nerve fibers. These

fibers transmit nerve impulses from orofacial structures to the brain, and the central nervous system

modulates and interprets these impulses into what we feel as pain (6). Primarily the trigeminal

nerve detects and encodes noxious stimuli for the orofacial region. It has three divisions: the

ophthalmic nerve (V1), maxillary nerve (V2), and mandibular nerve (V3).

Two major classes of nociceptive fibers that detect noxious stimuli and encode pain can be found

in the oral mucosa and the dental pulp: the A-delta and C fibers. Early, shooting pain is mainly

transmitted by A-delta fibers while late, dull pain is transmitted by C fibers. Another type of

nociceptive fibers known as A-beta fibers is involved in detecting non-noxious stimuli such as

vibration and proprioception. It is found in the periodontal ligament, skin, and oral mucosa.

Pulpal pain is mediated by C nociceptive fibers which have a high pain threshold and transmit pain

in response to thermal, mechanical, or chemical stimuli. These fibers, which are believed to be

sensitized by inflammation, have slow conduction velocity, and are associated with dull, aching,

or burning sensation (6). Nociceptive pain reflects the perception of noxious stimuli. In the absence

of such potentially damaging stimuli there is no nociceptive pain. For example, under normal

circumstances with a normal pulp, having a cold drink will not initiate pain as long as this cold

sensation is below the c fibers threshold.

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1.2.4 Irreversible pulpitis and endodontic treatment

Irreversible pulpitis is a clinical diagnosis based on subjective and objective findings indicating

that the vital pulp is inflamed and incapable of healing (7). It may be caused by deep caries, caries

excavation or trauma. Irreversible pulpitis can be asymptomatic or symptomatic. Patients with

asymptomatic irreversible pulpitis are usually free of clinical symptoms, while those who are

symptomatic suffer from continuous radiating pain that may affect their sleep patterns resulting in

lower quality of life (8). Examination procedures required to reach an endodontic diagnosis are:

1- medical and dental history taking; 2- chief complaint; 3- clinical exam; 4- clinical testing

through pulp testing and periapical testing; and 5- Radiographic analysis. Characteristics of

symptomatic irreversible pulpitis include sharp pain upon thermal stimulus, lingering pain that

often lasts 30 seconds or longer upon stimulus removal, spontaneous unprovoked pain and referred

pain (6, 7). Pain is worsened by postural changes such as lying down or bending over and is not

relieved by analgesics.

Nonsurgical root canal treatment is indicated for patients with irreversible pulpitis in order to

eliminate and remove the infected or injured pulpal tissue from inside the crown and roots of a

tooth, debride and shape the root canal system, as well as to alleviate present and prevent future

adverse clinical signs or symptoms. It involves the use of biologically acceptable chemical and

mechanical treatment of the root canal system to promote healing and repair of the periradicular

tissues. Proper access to the pulp chamber and root canals is dictated by the size and shape of the

pulp chamber and its canal orifices, as well as by the tooth’s position in the arch. Enough roof of

the pulp chamber is removed to visualize the entire pulpal floor. Cleaning, shaping, disinfection

and obturation of all canals is achieved using an aseptic technique with dental dam isolation. Root

canal sealers are used in conjunction with a biologically acceptable semi-solid or solid obturating

material to establish an adequate seal of the root canal system.

1.2.5 Pain before and during endodontic treatment

1.2.5.1 Origin

In irreversible pulpitis, a condition where the dental pulp is injured and inflamed because of caries

or trauma, pain arises due to primary analgesia which originates from peripheral sensitization, or

secondary hyperalgesia which originates from central sensitization (1, 6, 9). In primary

hyperalgesia, nociceptive c fibers (responsible for heat pain) are exposed to inflammatory

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mediators and become sensitized; that lowers their threshold so they may fire under a less intense

stimulus that normally would not provoke pain. Prolonged activation of nociceptive inputs to

second‐order neurons facilitates augmentation of nociceptive impulses to higher brain centers

which may be manifested as referred pain or secondary hyperalgesia. In secondary hyperalgesia,

there is an increased pain response at the site of the injury to peripheral stimulation (percussion

pain); this is also known as dynamic tactile allodynia due to alterations and increased synaptic

function within the CNS that is transmitted by myelinated fibers (1, 6, 9).

1.2.5.2 Challenges in achieving pulpal anesthesia for patients with irreversible pulpitis

In order to complete nonsurgical root canal therapy for patients with irreversible pulpitis, profound

pulpal anesthesia is needed to manage pain during treatment. The pre-existing hyperalgesia in

patients makes it challenging to achieve successful pulpal anesthesia during treatment since they

can’t tolerate any noxious input. In addition, several reasons have been attributed to the difficulty

of achieving successful pulpal anesthesia in patients with irreversible pulpits including (6): 1) the

decreased level of PH in inflamed tissue reduces the amount of the base form of anesthetic that

penetrates the nerve membrane, thus less of the ionized form is available in the nerve to achieve

anesthesia; 2) altered resting potentials and decreased excitability thresholds in inflamed tissues;

3) the expression of tetrodotoxin-resistant voltage-gated sodium channels, which are resistant to

local anesthetic action, is increased in the primary sensory neurons due to the increase of

prostaglandin numbers; 4) the over expression of sodium channels; and 5) patients in pain are

often apprehensive, which lowers the pain threshold.

Moreover, achieving successful pulpal anesthesia in mandibular teeth is often more challenging

than in maxillary teeth for patients with irreversible pulpitis, more specifically in permanent

molars. Given the relative thick cortical bone overlying mandibular teeth when compared to the

trabecular porous bone in the maxilla, infiltration anesthesia has lower odds of success in the

mandible, and therefore nerve block anesthesia is the preferred choice to anesthetize mandibular

molars. The most common technique for anesthetizing mandibular molars is the IANB injection.

However, failure rates are high with a reported failure rate of 17% for maxillary molars (10), and

a range in failure rate from 46-86% for mandibular molars (11-14).

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Many causes of IANB failure have been reported. A common cause is accessory innervation to

mandibular teeth which may lead to failure of anesthesia. Occasionally, the buccal, lingual,

mylohyoid, auriculotemporal, and cervical cutaneous nerve C1 and C2 may innervate mandibular

molars, which makes the conventional method of IANB unsuccessful (15, 16). Variations in

mandibular foramen position, bifid alveolar nerve or bifid mandibular canal have also been

identified as reasons for IANB failure (15, 16). Furthermore, according to the central core theory,

nerve fibers toward the center of the nerve travel the furthest and are the last to be anesthetized. In

some situations, the anesthetic solution from IANB may not completely diffuse into the nerve

trunk to produce an adequate nerve block in all the mandibular molars (16).

1.2.5.3 Local anesthetics

The electrophysiological status of a peripheral nerve determines its ability for conduction (17). In

cases of inactivity, a negative resting potential of -50 to -70 mV occurs within the cell compared

to the exterior surface of the cell membrane due to the high number of potassium ions and low

number of sodium ions. In activity or excitation, the cell membrane permeability increases

allowing an influx of the positive sodium ions into the nerve cell. This accounts for depolarization,

in which the electrical potential becomes less negative until reaching the threshold potential. Then,

the potential within the cell is reversed into a positive charge to reach about 40mV. Thereafter,

repolarization occurs to restore the intracellular resting potential. As a result, a chain reaction

produces a sequential series of depolarization steps along the nerve fiber that generates an electrical

impulse.

Local anesthetics produce anesthesia by blocking the nerve conduction when propagation of action

potentials is prevented, such that sensation cannot be transmitted from the tooth to the brain. This

occurs by reversibly binding and inactivating the sodium channels, resulting in a decreased

permeability of the nerve membrane to the positively charged sodium ions- this entails a reduction

in the degree of depolarization phase (18).

Based on their structure, local anesthetics include a lipophilic group joined by an amide or ester

linkage to a carbon chain which, in turn, is joined to a hydrophilic group. Local anesthetics are

classified by these amide or ester linkages into (17): Amino-esters which contain an ester link

between the aromatic portion and the intermediate chain. The first amino-ester to be used was

procaine in 1905, and was the standard drug for more than 40 years. Amino-amides have an amide

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link between the aromatic end and the intermediate chain. The first amide to be used was lidocaine,

which was developed by the Swedish chemist Nils Löfgren and Bengt Lundquist between 1943

and 1946 (19). In 1957, Bo af Ekenstam developed mepivacaine and bupivacaine. In 1969,

prilocaine was synthesized by Nils Löfgren and Cläes Tegner. Also in 1969 articaine was

synthesized in Germany, where it entered clinical use in 1976.

Ester and amide compounds vary in terms of their stability in solution, metabolism, and allergic

potential (20). Amides are stable in solution, while esters are unstable. Amides undergo enzymatic

degradation in the liver and excretion in the urine whereas amino-esters are hydrolyzed in plasma

by the enzyme pseudocholinesterase. Allergic reactions may result from amino-esters because they

metabolize to para-aminobenzoic acid (PABA). The amino-amides are not metabolized to PABA

and therefore rarely would cause allergic reactions. All local anesthetics available in dental

cartridges are from the amide class, which include articaine, bupivacaine, lidocaine, mepivacaine

and prilocaine (18). Table 1 summarizes the pharmacodynamics data for these amides.

Drug Molecular

weight

pKa Onset Protein

binding

(%)

Half-life

(minutes)

FDA

category

Articaine 284 7.8 Fast 67 75 C

Lidocaine 220 7.9 Fast 64 90 B

Mepivacaine 234 7.6 Fast 77 120 C

Prilocaine 246 7.9 Fast 50 90 B

Bupivacaine 288 8.1 Slow 96 160 C

Table1. Pharmacodynamics data of commonly used amides in dentistry. Adopted from Seymour et al (21).

The onset of local anesthetics are influenced by five factors:

1. The pH of the tissue: in sites of infection where inflammation occurs, such in irreversible

pulpitis, the pH of the tissues may drop in sites of infection, which causes onset to be

delayed or even prevented;

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2. The dissociation constant (pKa) of the anesthetic: pKa represents the pH at which 50% of

the molecules exist in the lipid-soluble tertiary form and 50% in the quaternary, water-

soluble form. The closer the anesthetic pKa is to the pH at the site of its administration, the

greater is its fraction of free base molecules that can translocate across neuronal

membranes. No significant differences in pKa among the amides exist except for

bupivacaine, which has a slightly higher pKa and hence a slower onset of action;

3. The proximity of the deposition of local anesthetic to the nerve: this explains why

infiltration is associated with rapid onset whereas the Gow-Gates block is relatively slow;

4. The concentration of drug and lipid solubility of drug: higher concentration and greater

lipid solubility improve onset to a small degree; and

5. The morphology of the nerve: thin pain fibers are usually readily anesthetized (18).

The duration of action for each anesthetic depends on how long the anesthetic can stay in the nerve

to block the sodium channels. Since local anesthetics cause vasodilatation and diffuse rapidly away

from the site of action, they have a short duration action when administered plain. To overcome

this, vasoconstrictors are added to the local anesthetics. The most common vasoconstrictor is

epinephrine. Vasoconstrictors also decrease the peak plasma concentration of the local anesthetic

agent, increase the quality of anesthesia, reduce the minimum concentration of anesthetic needed

for nerve block, and decrease blood loss during surgical procedures (22).

Lidocaine, also called xylocaine or lignocaine, is the most common anesthetic type in dentistry. It

is also ranked the safest, along with prilocaine, by the Food and Drug Administration.

1.2.5.4 Injection techniques of local anesthesia in mandibular teeth

Mandibular teeth are mainly innervated by the mandibular nerve, the third division of the

trigeminal nerve, which is the fifth cranial nerve. It consists of general somatic efferent motor

fibers that supply the muscles of mastication, and general somatic sensory fibers that innervate

some regions in the face, oral cavity mucosa, and mandibular teeth pulps and gingiva. The inferior

alveolar nerve, a branch of the mandibular nerve, supplies the mandibular teeth from the molar

area to midline. Additional branches of the mandibular nerve are the buccal nerve which innervates

the gingiva of mandibular molars, and the lingual nerve which innervates the lingual gingiva. Both

10

the inferior alveolar nerve and the lingual nerve may be blocked by IANB injection, while the

buccal nerve requires another buccal injection.

To administer IANB injection, patients should be instructed to open their mouths widely in order

to provide a clear visualization of the anatomical features for the operator. Next, the coronoid notch

is palpated with the index finger. From there, sliding posteriorly, the internal oblique ridge is

palpated. At the level of the index figure and laterally to the pterygomandibular plicae, about 1

centimeter (cm) above the molars occlusal surfaces, the needle is inserted to a depth of about 2.5

cm from the opposite side with the syringe directed from the premolar region. Then, when the

needle touches the bone of the mandibular ramus, it should be withdrawn 1-2 mm and about 1.5

mm of the anesthetic deposited.

In conjunction with IANB, the lingual nerve may be blocked at a point 0.5 cm mesially and

ventrally from the lingual, after withdrawing the needle 1-2 mm after it touches the ramus. The

buccal nerve is anesthetized by infiltration, which is administered above the buccal fold near the

mandibular third molar with the needle directed distally. About 0.5 ml is needed for both buccal

and lingual nerves anesthesia. Other techniques to achieve mandibular anesthesia are Gow-Gates,

Vazirani Akinosi, intraligamentary, and intraosseous injections.

1.2.5.5 Managing pain during endodontic treatment: current evidence

The mission of every dental care provider is to eliminate and treat dental diseases with the least

pain and discomfort for patients. Obtaining successful anesthesia during endodontic treatment is

often difficult and challenging in patients with endodontic pain of pulpal origin (23); however, all

local anesthetics in dentistry are considered efficacious (18). Success rates of 13% to 54% were

reported for inferior alveolar nerve block (IANB) injection using 2% lidocaine and success rates

of 33% to 63% were reported for IANB injections using 4% articaine.

Many randomized controlled trials (RCTs) investigated various strategies to overcome the

difficulty of achieving pulpal anesthesia in patients with symptomatic irreversible pulpitis.

Examples include changing the local anesthetic solution type (24), premedication with oral

analgesics (25, 26), increasing the volume of anesthetics (27, 28), changing the injection technique

for mandibular anesthesia (29, 30) and supplemental injection techniques namely buccal, lingual,

intraosseous or intraligamentary injections (31-33)

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On the efficacy of the different anesthetic types, several meta‐analyses were conducted pooling

RCTs results to identify the best anesthetic type to achieve successful pulpal anesthesia. With

regards to articaine versus lidocaine, Corbella et al (34) concluded that no difference existed in

patients with symptomatic irreversible pulpitis when IANB is administered. Brandt et al (35) and

Tupyota et al (36) had the same conclusion for IANB and infiltration anesthesia. Kung et al (37),

however, found a significant difference, with articaine being superior in infiltration anesthesia

when administered as supplemental infiltration, but reported no difference between both anesthetic

solutions for IANB. On the contrary, Su et al (38) concluded that articaine achieved higher success

rates compared to lidocaine in both IANB and infiltration injections. Mepivacaine and lidocaine

were also found by Vieira et al to have no significant difference in efficacy when used for IANB

in patients with symptomatic irreversible pulpitis (39). Contradicting this finding, an NMA by

Nagendrababu et al (40) concluded that, compared to lidocaine, mepivacaine was superior for

IANB injection, but not significantly different from articaine, prilocaine or bupivacaine in terms

of efficacy. According to their NMA which investigated the efficacy of the different local

anesthetic solutions in achieving successful IANB during root canal therapy for patients with

irreversible pulpitis, lidocaine was ranked the least efficacious (SUCRA=13%), while the most

efficacious solution was mepivacaine (SUCRA=81%), followed by prilocaine (SUCRA = 62%),

articaine (SUCRA = 54%), and bupivacaine (SUCRA = 41%).

On the efficacy of different injection techniques, only supplemental buccal infiltration (BI) and

lingual infiltration (LI) were compared to IANB in two systematic reviews with meta-analyses.

Corbella et al (34) pooled two studies that used BI alone and combined with LI as a supplemental

injection and found no significant effect from the supplemental anesthetics on IANB success. In

the other meta-analysis, Tupyota et al (36) included two studies that compared IANB using 2%

lidocaine with 1:100,000 epinephrine to supplemental BI using 2% articaine with 1:200,000

epinephrine, supplemental BI using 4% articaine with 1:100,000 epinephrine, IANB using 2%

lidocaine with 1:100,000 epinephrine and BI using 30mg of ketorolac tromethamine, and IANB

using 2% lidocaine with 1:100,000 epinephrine and BI using 4 mg of dexamethasone. The authors

estimated the overall risk ratio to be 1.54 (1.13, 2.10). Although this indicates statistical

significance, the four supplemental interventions that were pooled together used different

medications and therefore it is not clear which specific medication using BI may increase the

12

efficacy of IANB. Other injection techniques (e.g., intraligamentary injection, intraosseous

injection, gow-gates, and vazirani-akinosi) were not compared in meta-analyses.

With regards to anesthetic volume, conflicting results exist. Corbella et al (34) reported no

significant increase in the anesthetic success rates, while Tupyota et al (36) found a significant

effect.

Premedication with NSAIDs was also investigated in meta-analyses. Both Corbella et al (34) and

Tupyota et al (36) concluded that premedication with NSAIDs significantly increases the success

of IANB success and pulpal anesthesia.

Hence, given the various techniques investigated in RCTs but not yet compared in meta-analysis,

and some conflicting findings from meta-analyses discussed above, it is a challenge for the dental

care provider to select the best approach for delivering pulpal anesthesia that yields the highest

success rate when performing endodontic treatment for patients with symptomatic irreversible

pulpitis.

1.2.5.6 Pain following endodontic treatment

1.2.5.6.1 Origin

Following root canal therapy, a procedure to extirpate the inflamed pulpal tissue, patients may still

complain of pain. In fact, postoperative pain has been reported in approximately 21%-40.2% of

patients, with moderate to severe pain in 7% to 16% of patients (41, 42). Patients may express

postoperative pain as hyperalgesia, an increased sensitivity for pain; or allodynia, pain response

from stimulants that normally do not provoke pain. Hyperalgesia and allodynia develop due to

central and peripheral sensitization, in which there is an increased response of central nociceptive

neurons and the primary afferent nociceptors to peripheral stimulation (6). The presence of

preoperative pain increases the incidence of postoperative pain (43); this may be explained by the

prolonged and intense input of C nociceptors resulting in central sensitization (6).

Postoperative pain may occur as a result of an inflammatory response to mechanical, chemical, or

microbial injury to the pulp or periradicular tissues (44). The latter is considered the most common

cause given that the frequency of inter-appointment pain has been reported to be significantly

higher in teeth with periradicular lesions as compared to teeth with vital pulps and normal

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periradicular tissues (45). Certain bacterial species have been associated with symptomatic

periradicular lesions, which include: Porphyromonas endodontalis, Porphyromonas gingivalis,

Prevotella species, Treponema denticola, Tannerella forsythia (formerly Bacteroides forsythus),

Filifactor alocis, Dialister pneumosintes, Peptostreptococcus micros, and Finegoldia (formerly

Peptostreptococcus) magna (44).

During endodontic treatment, some situations may actually facilitate microorganisms to cause

postoperative pain. These include: (a) apical extrusion of debris; (b) incomplete instrumentation

leading to changes in the endodontic microbiota or in environmental conditions; and (c) secondary

intraradicular infections (46).

1.2.5.6.2 Managing pain following root canal treatment

The efficacy of several oral pharmacological modalities for the treatment of post-endodontic pain

were investigated in RCTs (47, 48). These include analgesics such as nonsteroidal anti-

inflammatory drugs (NSAIDs), acetaminophen, opioids; and corticosteroids (49-52).

Nonsteroidal anti-inflammatory drugs

Following noxious stimuli, inflammatory mediators (e.g., bradykinin, serotonin, prostaglandins,

and cytokine) are released, stimulating nociceptor fibers, which play a direct role in postoperative

pain since they lower the tissue’s pain threshold (53). Indirectly, inflammatory mediators generally

exert potent vasodilation action that results in increased vascular permeability and an extravasation

of fluids and white blood cells, resulting in edema and elevation of tissue pressure that acts on the

sensory nerve receptors (54).

NSAIDs work by inhibiting the pro-inflammatory enzyme cyclooxygenase (COX) at the

peripheral nociceptors which inhibits the conversion of arachidonic acid to prostaglandins and

thromboxanes, the inhibition of cyclooxygenase synthesis exerts a clear anti-inflammatory effect,

thereby preventing the sensitization of pain receptors in response to injury (55). Centrally, NSAIDs

act in the spinal dorsal horn to inhibit prostaglandin E2 (PGE2) production via COX-2 and in the

brain by activating medullary and cortical regions involved in the descending inhibitory pain

cascade, resulting in central sensitization and a lower pain threshold in the surrounding uninjured

tissue (54).

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Although NSAIDs are considered safe when used as an adjunct to endodontic treatment to manage

pain, its chronic use is associated with a few side effects including gastrointestinal alterations

(nausea, dyspepsia, peptic or duodenal ulcers), increased risk of arterial hypertension in

hypertensive patients or patients with treated arterial hypertension, renal hypoperfusion, nephrotic

syndrome or interstitial nephritis in patients with diminished kidney perfusion (hypotension,

cirrhosis, congestive heart failure, diuretic use or blood loss) (56).

Acetaminophen

Acetaminophen, also known as paracetamol or Tylenol, is widely used for relieving pain and

reducing fever. However, the analgesic mechanism of acetaminophen still remains unclear. It has

been suggested that acetaminophen works by inhibiting cyclooxygenase in the central nervous

system, although interaction with multiple other neurotransmitter systems has been proposed to

explain its analgesic effects including the serotonergic system, opioidergic, noradrenergic,

cholinergic, and nitric acid synthase systems (57, 58). It has been shown that the synergic

interaction between NSAIDs and acetaminophen results in more analgesia (59).

Despite its reputation for safety, acetaminophen has been considered as the leading cause of liver

failure in Canada with approximately 4500 Canadians being hospitalized for acetaminophen

overdose annually; about 6% of these patients experience liver injury including acute liver failure

which may lead to death (60). Public Health Canada estimated that between 2011-2019, around

50% of acetaminophen- related poisonings were unintentional. These could have happened due to

patients’ lack of awareness of the importance of adhering to the maximum daily dosage, the belief

that over-the-counter drugs are absolutely safe, and taking more than one drug containing

acetaminophen at the same time (60).

Corticosteroids

Even though not currently classified under analgesics, corticosteroids have been used for managing

post-endodontic pain due to their anti-inflammatory effects. Also called “steroids”, they work by

decreasing inflammation and reducing the immune response in the body. More specifically, they

block the inflammatory pathway by inhibiting phospholipase A2 and the expression

cyclooxygenase enzyme (COX 2), and thus decreasing the production of leukotrienes and

prostaglandins (61). They also inhibit acute abscess metabolites, decrease transcription of

15

cytokines IL-1,2,3,4,5,6,11,12, TNFα which are responsible for multiple pro-inflammatory effects,

decrease COX2 transcription by monocytes and macrophages, and decrease neurogenic

inflammation by inhibiting tachykinins (62).

Steroids are commonly used to treat inflammatory conditions such as rheumatoid arthritis, lupus,

and asthma. Although shown to have no major side effect in clinical trials investigating its efficacy

in managing post-endodontic pain (63-65), multiple tissue specific side effects of steroids are seen

in high doses and prolonged use of corticosteroids therapy, such in the cardiovascular system

(hypertension, vasculitis, dyslipidemia), adrenal glands (adrenal atrophy, Cushing’s syndrome),

central nervous system (changes in behavior, mood and cognition), gastrointestinal tract

(gastrointestinal bleeding, pancreatitis, peptic ulcer), musculoskeletal system (bone necrosis,

muscular atrophy, osteoporosis), eyes (cataracts, glaucoma), kidneys (increased sodium retention

and potassium secretion), and reproductive system (delayed puberty, hypogonadism) (61).

Opioids

Opioids interact with three classical opioid receptors (mu, delta, kappa) in the CNS and GI tract as

agonists, antagonists or partial agonists to modulate synaptic transmission and elicit analgesia (66).

Dentists are among the highest prescribers of opioids in North America. In 2012, dentists

accounted for 6.4% of the total US opioid prescriptions, which is around 18.5 million (67). This

has led to widespread misuse and related overdoses among patients, accounting for more than 40%

of all US opioid overdose deaths in 2016 (68). Therefore, the American Dental Association

recommends that before prescribing opioids, dental care providers should conduct a medical and

dental history to determine current medications, potential drug interactions and history of

substance abuse, use their state’s prescription drug monitoring program, complete continuing

education, and, above all, use non-narcotics as the first-line therapy for acute dental pain (69).

Current evidence

Administered before or following endodontic treatment, only the efficacy of NSAIDs and

corticosteroids were evaluated in meta-analyses.

In a meta-analysis by Smith et al (70), both ibuprofen and ibuprofen+acetaminophen were found

effective. Likewise, in an overview of systematic reviews by Moore et al (71), NSAIDs were found

effective in reducing postoperative pain. Another meta-analysis conducted by Shirvani et al (72)

16

on the efficacy of non-narcotic analgesics concluded that NSAIDS and/or acetaminophen were

effective in relieving postoperative pain. Contradicting those findings, Nagendrababu and

colleagues (73) concluded that only preoperative corticosteroids offered a significant decrease in

postoperative pain following endodontic treatment, whereas NSAIDs were ranked as the least

effective class of drugs. Their NMA investigated the efficacy of preoperative medications to

manage post-endodontic pain, and they compared corticosteroids, NSAIDs, clooxygenase-2

inhibitors, and opioids.

Two meta-analyses by Shamszadeh et al (64) and Nath et al (65) showed that corticosteroids were

effective in reducing post-endodontic pain. However, they pooled RCTs with various

administration times (e.g., preoperative and postoperative) and routes that are not commonly used

by the general dental practitioner (e.g., oral, intraligamentary, intracanal, intramuscular,

supraperiosteal). This resulted in the inclusion of a high number of studies that could have

overestimated the treatment effect of steroids, that wouldn’t be applicable to general dental

practice. Moreover, neither explored the effect of including studies judged to be of high risk of

outcome bias.

Therefore, given the various techniques investigated in RCTs and not compared in meta-analyses

or NMA especially that the NMA by Nagendrababu and colleagues (73) only considered

preoperative medications, and some conflicting findings, it is challenging for the dental care

provider to select the best medication, based on the highest level of evidence, to manage pain

following nonsurgical endodontic treatment.

1.3 Definition of the problem

Evidence-based medicine prioritizes evidence from clinical research rather than systemic clinical

experience, first used as a term by Guyatt in 1991 (74). Since then, it has evolved. According to

evidence-based dentistry, well-conducted meta-analyses of RCTs provide the highest level of

evidence on the relative benefit or harm of usually one or two treatments/interventions in a given

condition (75, 76). RCTs are considered the standard for evaluating the safety and efficacy of

therapeutic and preventive interventions as they have high internal validity, but the external

validity or applicability is limited, as the population in RCT is highly selected. To date, the

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available systematic reviews and meta-analyses on how best to manage pain during and following

endodontic treatment are inconclusive since these only compare two interventions at a time for a

given condition and do not compare all the approaches available due to their pairwise design (36-

38, 70, 77-80).

Network meta-analysis (NMA), an extension to pairwise meta-analysis, allows the comparison of

multiple sets of treatments for a particular condition. In other words, multiple treatments can be

compared using both direct comparisons of interventions within RCTs (i.e. estimates of treatment

comparisons that were directly compared in a clinical trial) and indirect comparisons across trials

based on a common comparator (i.e. estimates of treatment comparisons that have not been directly

compared in a clinical trial.) In this way, the "full picture" can be provided to clinicians.

No NMA has been conducted investigating the efficacy and safety of pulpal anesthesia strategies

during endodontic treatment of permanent mandibular molars with symptomatic irreversible

pulpitis, or on the efficacy and safety of postoperative medications in reducing pain following

nonsurgical endodontic treatment. Therefore, it is still a challenge for dentists to select the most

appropriate anesthetic while performing endodontic treatment; the best supplemental technique to

be used when the anesthetic fails; and the best interventions to manage (or prevent) the post-

endodontic pain.

1.4 Introduction to the methods: systematic reviews and Network Meta-Analyses

1.4.1 Background

With health care advances, new and different interventions are being introduced for the same

condition, and clinicians are always in search of the latest available evidence-based information

that can be utilized in the treatment of their patients, and whether a new intervention is more

effective. Since the introduction of Evidence- based Medicine, four types of epidemiological

studies have emerged: 1- descriptive studies; which include two major groups: a-those that deal

with individuals, such as case reports, case-series reports, cross-sectional studies, and surveillance;

b- those that relate to populations, such as ecological or correlational studies. 2- analytical studies;

cohort studies and case-control studies. 3- interventional studies; typically randomised control

trials. 4-research synthesis; informal or narrative review, b- formal and systemic reviews (81). Due

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to the high number of these studies being carried out every year in the different medical and dental

fields, RCTs are considered to be the gold standard in evaluating the efficacy of a specific

treatment. According to Sibbald et al. 1998 (82), RCTs are considered to be “the most rigorous

way of determining whether a cause-effect relation exists between treatment and outcome and for

assessing the cost effectiveness of a treatment”. Given the increased number of studies and RCTs

being published, it is difficult if not impossible for busy healthcare providers to keep up with the

literature and assess these studies in order to inform themselves about the most appropriate

decisions and have an evidence- based practice. Therefore, reviews were developed to summarize

the outcomes of individual trials and allow clinicians to acquire the highest level of evidence in an

efficient manner. In fact, the highest quality of evidence comes from reviewing trials, which

appeared in the form of systematic reviews and meta-analyses of RCTs in the 1970s and 1980s

(83).

1.4.2 Systematic reviews

Conducting systematic reviews is a way to provide up-to-date evidence by reviewing data and

results from literature of a particular question in a standardized systematic way. It uses systematic

and explicit methods to identify, select and critically appraise relevant research, and to collect and

analyze data from the included studies.

In 1993, the Cochrane collaboration was founded in response to the British epidemiologist Ian

Cochrane who emphasized in his book “Effectiveness and Efficiency: Random Reflections on

Health Services” (84) that clinical procedures should depend on the results of RCTs (85). Today,

Cochrane includes 53 review groups that are based at research institutions worldwide, with

approximately 30,000 volunteer experts. They developed a Handbook describing in detail the

process of preparing and maintaining Cochrane systematic reviews on the effects of healthcare

interventions. Although not all the systematic reviews are published through Cochrane, future

investigators could consult the Handbook for guidance on the standard methods used for

conducting a systematic review with/without MA/NMA (86). It includes steps involved in

planning a review, searching and selecting studies, data collection, risk of bias assessment,

statistical analysis, quality of evidence assessment and interpreting results, as well as more

specialised topics (non-randomized studies, adverse effects, complex interventions, equity,

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economics, patient-reported outcomes, individual patient data, prospective meta-analysis, and

qualitative research).

According to the Cochrane Handbook (86), systematic reviews start by formulating a clinical

question following the PICO format: Population– the target subjects or patients you are trying to

study; Intervention – the treatment or exposure to be studied; Comparison – the alternative to

compare to the intervention; and Outcome – what the study hopes to measure or achieve. Next, a

protocol specifying the methods to be used in the review needs to be developed to minimize bias.

It should include the following elements: Inclusion/exclusion and eligibility criteria, search

strategy, study selection, data extraction process, assessment of the included studies quality, data.

Synthesis methods, and assessing the quality of evidence are also included. Systematic reviews

need to be undertaken by a team in order to minimize the likelihood of errors. When defining

eligibility criteria for studies inclusion in systematic reviews, RCTs, which are the best study

design for evaluating the efficacy of interventions, are considered to be the most preferable study

design of trials to be included in systematic reviews because randomization is the only way to

prevent systematic differences between baseline characteristics of participants in different

intervention groups in terms of both known and unknown (or unmeasured) confounders (86). Then,

review authors need to undertake a thorough, objective and reproducible search of a range of

sources to identify as many eligible studies as possible (within resource limits). It is considered

mandatory by Cochrane to search the following bibliographic databases: CENTRAL, MEDLINE

and Embase (86). The index of the majority of abstracts relating to recent records can be searched

electronically. Additionally, it is highly desirable to search appropriate national, regional and

subject-specific bibliographic databases such as CINAHL, and to search for unpublished or

ongoing studies, as well as grey literature sources such as reports, dissertations, theses, databases

and databases of conference abstracts. In our search strategy, for both of our NMAs, we searched

five major electronic databases with the help of a librarian at the University of Toronto libraries:

MEDLINE, EMBASE, Cochrane CENTRAL, CINAHL, and SCOPUS through the University of

Toronto’s libraries. In an attempt to be as extensive as possible in order to reduce the risk of

publication bias and to identify as much relevant evidence as possible, we searched for completed

and ongoing trials through the WHO ICTRP and ClinicalTrials.gov trials registries. Unpublished

studies (or grey literature, such as technical reports or dissertations) through ProQuest, Google

Scholar™ (first 100 hits), and The Open Grey database were checked. Furthermore, we searched

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the reference lists within previous reviews in the same topic, and checked reference lists in

included studies and any relevant systematic reviews were identified.

Next, records identified through our search from different sources need to be merged using

reference management software, and duplicate records of the same report need to be removed. We

used both in our NMAs EndNoteTM. All the identified records details were downloaded into an

Excel sheet for screening against the eligibility criteria for potential inclusion, which is undertaken

in two stages: Title and Abstract screening, and full text screening. Two independent authors

usually examine studies independently in both stages, and then review their screening results. We

provided a table summarizing reasons for excluding studies at the full-text screening stage in both

of our NMAs. Discrepancies and disagreements are usually resolved by discussion or by

consulting a third author. We followed this approach in both our NMAs.

For data extraction, two review authors extracted the data needed from studies to confirm its

eligibility for inclusion, from “characteristics of the included studies” Table, assessed the risk of

bias and ran the NMA. In case of any missing information in the study design, methods, or outcome

reporting that would be essential to inform risk of bias assessment, and details of intervention and

outcome, we attempted to contact the authors. This was of great importance to make our review

more complete, enhance precision and reduce the impact of reporting biases (87). After that, data

needs to be extracted. We created a data extraction form using Microsoft Excel sheets. Table 1

summarizes data extracted in both our NMAs. We followed in both of our NMAs the Cochrane’s

risk of bias assessment tool (88) to appraise the methodological quality of the included studies.

Two review authors independently assessed the following seven domains for each study: random

sequence generalization, allocation concealment, blinding of participants and personnel, blinding

of outcome assessment, incomplete outcome data, selective reporting and other bias. Then,

conclusions regarding the risk of bias (high, low or unclear risk of bias) for each domain were

made based on the reported data in the studies. Finally, each study was judged to be of ‘low risk’

if all the domains were judged to be of low risk of bias; ‘moderate risk’ if any domain was judged

to be of unclear risk of bias; ‘high risk’ if any domain was judged to be of high risk of bias.

Disagreements in the judgment of any domain were resolved by consulting a third reviewer.

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Section Details

Study Source study ID, author name, year of publication, country,

citation and contact details

Study Eligibility To confirm eligibility of the study or record reasons

for exclusion

Study Information Objectives, study design, allocation, blinding,

Randomization and Masking Methods (in

randomization, intervention, outcome assessment),

other bias concerns, inclusion and exclusion criteria

Participant Characteristics number of participants in each intervention, age,

sex, setting, country, diagnosis, methods to confirm

diagnosis, preoperative pain level, teeth type

Outcomes Unit of analysis, Type of analysis, time points

reported, measurement tool

Intervention Information 1st NMA: total number of anesthetics used, types of

anesthetics used, volume of anesthesia administered

to patients, vasoconstrictor amount and type if given

with anesthesia, injection technique, methods to

confirm successful pulpal anesthesia.

2nd NMA: type of drugs and pharmacological class,

dosage, technique, time of delivery, instructions,

escape drug.

Miscellaneous Side effects/safety, whether correspondence is

needed to complete data extraction, conflict of

interest.

Table 2. Summary of data extracted in both our NMAs.

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Finally, the outcome data from the included studies is pooled in a meta-analysis or network meta-

analysis to give an overall result (89). Meta-analysis, first defined by Glass in 1976 as “the

statistical analysis of a large collection of analysis results from individual studies” (90), produces

a precise estimate of the effect of treatment or risk factor for disease, improves the effect sizes and

allows decisions based on the evidence. In addition, it answers questions that are not posed by the

individual studies and it settled controversies arising from apparently conflicting studies (89). Over

the years, meta-analysis has been used in comparative effectiveness research, which gets evidence

on the relative benefit or harm of one or two treatments/interventions in a given condition; that

limited its effectiveness, as several treatment options can be available. With the introduction of

Network meta-analysis, it was possible to compare multiple sets of treatments for a particular

condition.

1.4.3 Definition and Advantages of Network meta-analysis

Network meta-analysis, as defined by Li et al (91), is a meta-analysis in which multiple treatments

(3 or more) are being compared using both direct comparisons of interventions within RCTs and

indirect comparisons across trials based on a common comparator. For example, if two treatments:

(B) and (C) were compared to a common comparator, treatment (A), in two different sets of trials

(Figure 1), then the relative efficacy between treatments (B) and (C) can be estimated indirectly

via treatment (A) by conducting a meta-analysis for each direct comparison, and then subtracting

the two estimates to get the indirect treatment effect. This relationship can be written

mathematically as:

Effect of B versus C = (Effect of A versus C) – (Effect of A versus B).

23

Figure 2. Illustration of an indirect estimate that compares the effectiveness of treatment (B)

and treatment (C) through a common comparator, treatment (A)

Compared with a single direct or indirect estimate of the intervention, NMA yields more precise

estimates, and can provide information for comparisons between pairs of interventions that have

never been evaluated within RCTs by indirect comparisons. The simultaneous comparison of all

interventions of interest in the same analysis enables the estimation of their relative ranking for a

given outcome (92, 93). This is highly beneficial as data from current studies can be utilized to

draw conclusions on the best treatments possible. Network meta-analysis can be useful in studies

that report different treatment effects, or similar effects but different conclusions (89).

Since NMA combines results of multiple RCTs, the validity and accuracy of the NMA will depend

on how sufficient, similar and unbiased the treatment effects in those RCTs are. According to

Hoaglin et al (94), network meta-analysis suggests careful examination and testing of three

assumptions: 1- similarity or transitivity, in which the combining studies should only be considered

if they are clinically and methodologically similar. Thus, review authors need to ensure that

included trials do not differ with respect to effect modifiers; 2- homogeneity, in which the study

estimates must measure the same treatment effect; and 3- consistency, in which indirect evidence

must be consistent with direct evidence.

1.4.4 Guidelines of Network meta-analysis

Due to the complexity of NMA, a multidisciplinary review team including a skilled statistician

NMA and content area experts, is required to ensure that included studies are similar except for

the interventions being compared (95). Unlike a pairwise meta-analysis that can be conducted

using basic softwares (e.g. RevMan), NMA requires advanced statistical software packages such

as R, Stata, WinBUGS or OpenBUGS. In both our NMAs, we had a team of experts in

Endodontics, Dental Anesthesia, Clinical Epidemiology and Biostatistics ensuring proper design,

analysis and interpretation in our paper in order to use the highest degree of evidence available.

According to the International Society for Pharmacoeconomics and Outcomes Research (ISPOR)

(96), there are many guidelines and recommendations that can be used to carry out a Network

meta-analysis. We followed the PRISMA NMA extension guidelines to analyze and report our

data (97). Based on it, investigators need to first identify the clinical trials that may form the

24

network of comparisons by its search time frame and conduct, and search parameters through its

PICOS (population, interventions, comparators, outcomes). Second, to specify which databases

should be searched (e.g., MEDLINE, EMBASE, and the Cochrane (CENTRAL) databases form a

core specified by almost all the national guidelines). Third, to perform title/abstract screening and

full text screening to determine which study from the search results meets the eligibility criteria to

be included. Fourth, bias assessment for the included trials as treatments obtained from NMA may

be biased by heterogeneity between included studies and the adequacy of blinding. Fifth, to extract

the data and to conduct NMA by means of relative risk, relative risk difference, hazard ratio, odds

ratio, or a combination thereof. Finally, to interpret the results and make conclusions. The main

result of NMA would be a set of network estimates of the treatment effects for all possible

comparisons. Often we would identify one intervention as a reference (i.e. control or placebo), and

define the basic comparisons as the effect of each of the other interventions against this reference.

Grading of Recommendations Assessment, Development, and Evaluation (GRADE) assessment

tool may be applied to evaluate the quality of evidence generated.

1.4.5 Statistical approach of Network meta-analysis

Network meta-analysis can be performed either under a frequentist or a Bayesian framework.

Unlike Frequentist statistics, Bayesian statistics incorporate “subjective” prior knowledge into

statistical inference in the form of prior probability distribution into the final inferential estimates.

A Bayesian framework calculates probability distribution of all the model parameters by

incorporating observed data (likelihood) and prior beliefs (external information) about the values

of the parameters. It fully covers the uncertainty in the parameters of interest and thus can make

direct probability statements about these parameters (e.g., the probability that one intervention is

superior to another) (98). Results are usually presented as a point estimate (effect measures such

as odds ratio, risk ratio, mean difference) with a 95% credible interval (CrI) and are obtained by

Markov Chain Monte Carlo (MCMC) simulations, through which the model can be reproduced

several times until convergence of the model is achieved and deemed reliable. One advantage of

the Bayesian approach is that it has a straightforward way of making predictions, and it embraces

heterogeneity by including different sources of uncertainty through prior knowledge (usually

uninformed priors), with a more flexible statistical model (98).

25

In contrast, frequentist analyses calculate the probability that the observed data would have

occurred under their sampling distribution for hypothesized values of the parameters. The

frequentist method calculates the probability of significance (p-value is <0.05) or the 95%

confidence interval (CI) for rejecting or failing to reject the research hypothesis (98). Therefore,

the frequentist method is not related to external information, and the probability that the research

hypothesis is true within the present data (likelihood) is already specified, and it only determines

whether or not to accept or reject it based on the significance level. Results are presented as a point

estimate (effect measures such as odds ratio, risk ratio, mean difference) with a 95% confidence

interval (CI), similar to pairwise meta-analysis results (98).

The magnitude of the effect estimates may differ between frequentist and Bayesian approaches,

but the direction of treatments and treatment rankings are usually the same (99).

Similar to traditional pairwise meta-analysis, NMA can be undertaken with the fixed effect or the

random effect approach. Fixed effect approach assumes that all studies are trying to assume one

true effect size and any difference between estimates from different studies is attributable to

sampling error only (within study variation). A random effects approach assumes that in addition

to sampling error, observed differences in effect size considers the variation of true effect size

across studies (between study variation), otherwise called heterogeneity, can be attributed to

severity of disease, age of patients, dose of drugs, follow-up period, among others. Extending this

concept to NMA, it is expected that effect size estimates not only vary across studies but also

across comparisons (direct and indirect). Both models should be tested for each network (98). One

possible way is through the calculation of the mean residual deviance for both models; the model

that returns smaller deviance statistics would suggest having a better fit to the data.

Because we anticipated the presence of heterogeneity, we fitted a consistency model with a

Bayesian unified generalized linear model framework (GLM) in both NMAs. For our first NMA,

we adopted a binominal likelihood along with the logit link function, and in our second NMA we

adopted normal likelihood with identity function. Because we anticipated the presence of relative

treatment effect heterogeneity among studies, we adopted a random effects model assumption with

a common (single) heterogeneity parameter. Non-informative prior distributions were adopted for

all parameters in the model, as per the defaults in the software package used based on insufficient

information on the parameters, which is a common practice for network meta-analysis. Statistical

26

inference using the Bayesian approach relies on a computer-intensive Markov chain Monte Carlo

(MCMC) simulation strategy to generate posterior samples that form the posterior distributions

and get estimates for the treatment effects. It is essential that this MCMC simulation strategy does

its job correctly (i.e., converges) and there are controls we use to ensure this happens. For the

MCMC simulation, after specifying an adaption phase of 20000 samples, we allowed a burn-in of

100,000 samples before generating another 100,000 samples; after using a thinning interval of 10,

we therefore used 10000 samples for inference. To test if the posterior samples converged (i.e., if

estimates are trustworthy), we used 4 chains and the Gelman-Rubin-Brooks plot and diagnostic

test. Convergence was achieved, so the estimates returned from the model are reliable. We used

program R (version 3.5.0, R Project for Statistical Computing) 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 to run the network meta-

analysis fixed and random models. Pairwise I2 was used to detect heterogeneity. To evaluate

inconsistency, we compared the direct and indirect evidence within each loop of evidence and a

design by treatment test was used to detect it. The treatment effects were estimated in the first

NMA as odd ratios (OR) with 95% CrI, while in the second NMA as mean difference (MD) with

95% CrI. Posterior samples were used to calculate rank probabilities to make the overall

conclusions. Derived from posterior probabilities, the surface under the cumulative ranking curve

(SCURA) values were estimated for each treatment to summarize and rank its comparative

effectiveness, and identify the best treatment. SUCRA is a simple numerical summary that ranges

from 0 to 100%. A SUCRA value of 100 corresponds to a 100% probability of that treatment

ranking first in effectiveness for that outcome, and a value of 0 corresponds to a 100% probability

of that treatment ranking last in effectiveness (100).

1.4.6 Quality of evidence evaluation

Once the estimates are obtained through NMA, their certainty needs to be rated. A common

approach is through GRADE working group. We used the Confidence in Network Meta‐Analysis

(CINeMA) web application that was developed by Salanti et al (101) to evaluate confidence in

both our NMAs results. It considered six domains (102):

1) Within‐study bias, which includes limitations in the individual studies that may lead to a

biased estimated relative treatment effect. It is estimated through the per‐study contribution

27

matrix in conjunction with risk of bias assessments to evaluate each relative treatment

effect.

2) Reporting bias, which refers to biases that can occur due to publication bias, time‐lag bias,

selective non-reporting bias, or any other bias rendering the included studies a non-

representative sample of the studies undertaken

3) Indirectness, which evaluates how relevant are the included studies to the research

question. This was evaluated for each study by their PICO question.

4) Imprecision, which refers to the certainty in which each effect is estimated, and is judged

based on whether the confidence interval includes the line of no‐effect and the clinically

important values.

5) Heterogeneity, which refers to the variability in the results of studies contributing to each

comparison; it is evaluated by considering the agreement between confidence and

prediction intervals relative to the null effect and the clinically important effect. Prediction

intervals are intervals including range within which the true effect of a new study is likely

to lie; and

6) Incoherence, which measures the disagreement between direct estimates that were

estimated from studies directly comparing the particular comparison, and indirect estimates

that were estimated from an NMA including all but the direct studies. To assess

incoherence when both the direct and indirect evidence were available for a given

treatment, the side test p-value was used. If only the direct or indirect evidence was

available, the design-by-treatment interaction test was used.

Each of these domains were assessed for each result by two review authors independently: no

concerns, major or minor concerns. The latter downgraded the level of evidence. Finally, an overall

judgment across those domains was summarized into a single confidence rating of high, moderate,

low or very low. To reach consensus, a third author was consulted.

28

1.5 Objectives and specific aims

Our objective in this thesis was to perform a robust search that would identify RCTs through which

we can compare and rank all the interventions investigated for pain management during and

following endodontic treatment.

Our particular aim was to apply network meta-analysis to answer the following specific research

questions: 1) what is the most efficacious and safe local anesthetic agent and injection technique

that will achieve successful pulpal anesthesia in adults undergoing endodontic treatment of

mandibular molars with symptomatic irreversible pulpitis when compared to IANB using 2%

lidocaine? (Chapter 2); and 2) among adult patients who received nonsurgical endodontic

treatment, what is the most efficacious and safe postoperative medication to reduce postoperative

pain? (Chapter 3).

1.6 Significance

We aimed to resolve a long-debated topic in endodontics: “what are the best approaches to

achieving successful anesthesia and managing pain during and following endodontic treatment?”

Both NMAs introduced new valuable evidence-based knowledge which should have an impact on

not only endodontics, but dentistry as a whole as it will aid in the clinical decision-making of every

clinician to achieve more effective patient-centered care. Additionally, current guidelines may be

updated for practice and education according to the evidence generated. Our study is the first to

compare the efficacy and rank all the interventions used to achieve successful anesthesia and

manage pain in endodontics during endodontic treatment and following it through incorporating

the novel use of network-meta-analysis.

29

Chapter 2

Efficacy and safety of pulpal anesthesia strategies during endodontic treatment: a systematic review and network meta-analysis

REVIEW ARTICLE

Efficacy and Safety of PulpalAnesthesia Strategies duringEndodontic Treatment ofPermanent Mandibular Molarswith Symptomatic IrreversiblePulpitis: A Systematic Reviewand Network Meta-analysis

ABSTRACT

Introduction: Several strategies have been investigated for achieving successful pulpalanesthesia during endodontic treatment of mandibular molars with symptomatic irreversiblepulpitis. However, comprehensive evaluation and identification of the most efficacious andsafe intervention are lacking. We aimed to determine this using network meta-analysis.Methods: MEDLINE, Embase, Cochrane Central, CINAHL, and Scopus databases weresearched. Study selection and data extraction were performed in duplicate. Eligiblerandomized 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 ofresults. Results: Thirty-seven interventions from 46 studies were identified. Compared withthe common practice of an inferior alveolar nerve block with 2% lidocaine, a supplementalintraosseous injection was ranked the most efficacious with very low to moderate confidence(2% lidocaine 1 preoperative nonsteroidal anti-inflammatory drugs [NSAIDs] 1 acetamino-phen [OR5 74; 95%CrI, 15–470; SUCRA5 97%], 2% lidocaine1 preoperative NSAIDs [OR5 46; 95% CrI, 8–420; SUCRA5 94%], 2% lidocaine [OR5 33; 95% CrI, 14–80; SUCRA5

93%], 2% lidocaine 1 preoperative opioids 1 acetaminophen [OR 5 20; 95% CrI, 4.4–98;SUCRA5 86%], and 4% articaine [OR5 20; 95% CrI, 6.3–96; SUCRA5 87%]) followed bysupplemental buccal and lingual infiltrations using 4% articaine1 preoperative NSAIDs (OR5

18; 95% CrI, 6–56; SUCRA 5 86%; very low confidence). No major safety concerns werereported. Conclusions: Very low- to moderate-quality evidence suggests intraosseous in-jection using 2% lidocaine with 1:100,000 epinephrine or 4% articaine with 1:100,000epinephrine or buccal and lingual infiltrations of 4% articaine with 1:100,000 epinephrine aresuperior strategies to achieve pulpal anesthesia during endodontic treatment of mandibularmolars with symptomatic irreversible pulpitis. Preoperative NSAIDs or opioids with or withoutacetaminophen may increase the efficacy of these injections. (J Endod 2019;45:1435–1464.)

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 bereferred, unprovoked, or provoked by thermal stimulus, lingering often 30 seconds or longer afterstimulus removal and indicating the need for endodontic treatment1. Obtaining successful pulpal

SIGNIFICANCE

A supplemental intraosseousinjection using 2% lidocaine or4% articaine followed bysupplemental buccal andlingual infiltrations of 2%articaine is a superior injectiontechnique to achieve pulpalanesthesia during theendodontic treatment ofmandibular molars withsymptomatic irreversiblepulpitis.

From the *Faculty of Dentistry, Universityof Toronto, Toronto, Ontario, Canada;†Department of Dentistry, SunnybrookSciences Health Centre, University ofToronto, Toronto, Ontario, Canada;‡Department of Health ResearchMethods, Evidence, and Impact, Facultyof Health Sciences, McMaster University,Hamilton, Ontario, Canada; §Departmentof Pediatrics, Faculty of Medicine,University of Toronto, Toronto, Ontario,Canada; kDepartment of Pediatrics,Mount Sinai Hospital, Toronto, Ontario,Canada; ¶Clinical Epidemiology andHealth Care Research, Institute of HealthPolicy, 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 AmirAzarpazhooh, 455–124 Edward Street,Toronto, Ontario M5G 1G6, Canada.E-mail address: amir.azarpazhooh@dentistry.utoronto.ca0099-2399/$ - see front matter

Copyright © 2019 American Associationof Endodontists.https://doi.org/10.1016/j.joen.2019.09.002

Maryam Zanjir, DDS,*

Nima Laghapour Lighvan,HBSc,* Carilynne Yarascavitch,BSc, DDS, MSc, Dip. ADBA,*†

Joseph Beyene, BSc, MSc,PhD,‡ Prakesh S. Shah, MSc,

MBBS, MD, DCH, MRCP,FRCPC,§k¶ and

Amir Azarpazhooh, DDS, MSc,PhD, FRCD(C)*¶#

JOE � Volume 45, Number 12, December 2019 Efficacy and Safety of Pulpal Anesthesia Strategies 1435

anesthesia during endodontic treatment ofteeth with symptomatic irreversible pulpitis isimportant for patients’ pain and stressmanagement; however, this can be especiallychallenging for patients with symptomaticirreversible pulpitis in mandibular teethbecause of the failure of the inferior alveolarnerve block (IANB) to always provide profoundanesthesia2–5. Increased acidity in the inflamedpulp reduces the amount of basic anestheticthat penetrates the nerve’s membrane, thusdelaying or preventing pulpal anesthesia6.Additionally, increased expression oftetrodotoxin-resistant sodium channels occursbecause of the increase of prostaglandins andthe overexpression of sodium channels7,8.

Several randomized controlled trials(RCTs) have investigated interventions toovercome the difficulty of achieving pulpalanesthesia in mandibular teeth for patients withsymptomatic irreversible pulpits. Interventionssuch as changing the local anesthetic solutiontype9, supplemental injection techniques10–12,premedication with oral analgesics13,14, andincreasing the volume of anesthetics15,16 havebeen assessed; however, available systematicreviews and meta-analyses are inconclusiveregarding the most effective intervention.Although some sources concluded that 4%articaine was more successful than 2%lidocaine in patients with irreversiblepulpitis17–20, others concluded that the type ofanesthetic does not affect efficacy21,22. Thesepairwise meta-analyses compared theefficacies of only 2 interventions at a time ratherthan all the interventions available in RCTs,making it challenging to determinethe superiority of one intervention overanother17–23.

With the introduction of network meta-analysis (NMA), it is now possible to compareand rank multiple sets of treatments for aparticular condition regardless of whether ornot the treatments were directly compared inRCTs24. For instance, 1 NMA compared theeffect of oral premedication on the successrates of IANB as a primary injection25, but nonecompared the effect of all the primary andsupplemental injection techniques. Thus, theobjective of this review was to identify the mostefficacious and safe intervention to achievepulpal anesthesia in adult patients undergoingnonsurgical endodontic treatment formandibular molars with symptomaticirreversible pulpitis. Our research question wasas follows: What is the most efficacious andsafe local anesthetic agent and injectiontechnique to achieve successful pulpalanesthesia in adults undergoing endodontictreatment of mandibular molars withsymptomatic irreversible pulpitis whencompared with IANB using 2% lidocaine?

MATERIALS AND METHODS

The Preferred Reporting Items for SystematicReviews and Meta-Analyses extensionstatement for NMA was followed whenreporting results (Supplemental Table S1 isavailable online at www.jendodon.com)26.

Inclusion CriteriaRCTs of adults undergoing nonsurgicalendodontic treatment for permanentmandibular molars with the pulpal diagnosis ofsymptomatic irreversible pulpitis wereincluded. Interventions included any localanesthetic types and injection techniquescombined with any oral preoperativemedication to achieve anesthesia duringnonsurgical endodontic treatment. In order torender results applicable to routine dailypractice, studies using pharmacologic agentsthat require mixing/extra preparation or theiruse is restricted to those who meet specialqualifications were excluded.

OutcomesThe primary outcome was successful pulpalanesthesia during nonsurgical endodontictreatment measured by any form of verbal orvisual analog scales. The secondary outcomewas safety of the interventions. Any study notreporting the primary outcome was excluded.

Search MethodThe electronic databases MEDLINE, Embase,Cochrane Central, CINAHL, and Scopus weresearched from inception until February 23,2018, with no restriction on publicationlanguage (Supplemental Table S2 is availableonline at www.jendodon.com). Completedand ongoing trials were searched using theWorld Health Organization International ClinicalTrials Registry Platform and ClinicalTrials.govtrials registries. Unpublished and gray literaturewas searched through ProQuest, OpenGrey,and Google Scholar (first 100 hits). Abstractsfrom the annual meetings of the AmericanAssociation of Endodontists, the InternationalFederation of Endodontic Association, and theEuropean Society of Endodontology weresearched. Wemanually scanned reference listsfrom the identified research syntheses and 3major textbooks7,27,28. An attempt to contactthe authors was made in case of missinginformation from any of the studies.

Screening and Data ExtractionTwo review authors (M.Z. and N.L.L.)independently reviewed and selected trialsfrom searches. Disagreements were resolvedthrough discussion and consensus or byconsulting a third reviewer (A.A.). Any reasonfor exclusion was reported (Supplemental

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

Assessment of Risk of BiasTwo review authors (M.Z. and N.L.L.)independently used the Cochrane risk of biastool68 to evaluate the quality of included trialsacross 6 domains (random sequencegeneralization, allocation concealment,blinding of participants and personnel, blindingof outcome assessment, incomplete outcomedata, and selective reporting and other bias).The possible judgment for these domainscould be “high risk,” “low risk,” or “unclear risk”of bias. A final judgment for each study wasgiven based on the following: low risk if all thedomains were judged to be of low risk,moderate risk if any domain was to be ofunclear risk, and high risk if any domain wasjudged to be of high risk. Disagreements wereresolved through discussion and consensus orby consulting a third reviewer (P.S.).

Quality of EvidenceTwo review authors (M.Z. and N.L.L.) used theCINeMA Web application (University of Bern,Bern, Switzerland) to judge the confidence inthe NMA results considering 6 domains:within- and across-studies bias, indirectness,imprecision, heterogeneity, and incoherence.Each domain was judged as having noconcerns, major concerns, or minor concerns.The latter would downgrade the level ofevidence. An overall final judgment of eitherhigh, moderate, low, or very low confidencewas given to each result69. Consensus wasreached by consulting a third reviewer (P.S.).

Data Synthesis and AnalysisNMA was conducted using the program R(Version 3.5.0; R Project for StatisticalComputing, Vienna, Austria) with the gemtcversion 0.8.2 and rjags packages, whichinterface with Just Another Gibbs Samplersoftware (Version 4.0.0; developed by MartynPlummer) for Markov chain Monte Carlomodeling. A Bayesian NMA was preformedusing a hierarchical random effects frameworkand unified generalized linear model withbinominal likelihood along with the logit linkfunction to compare the interventions with oneanother70–72. The treatment effects wereestimated as odd ratios (ORs) with associated95% credible intervals (CrIs) and the surfaceunder the cumulative ranking curve (SUCRA).Heterogeneity was assessed using the I2

statistic. The node splitting method and itsBayesian P value were used to calculate theinconsistency of the model73. Posterior

1436 Zanjir et al. JOE � Volume 45, Number 12, December 2019

TABLE 1 - Characteristics of the Included Studies

Identificationnumber

Author, year,country

Interventionsas reported in studies

Age in years(mean ± SD/range

if available)Sample size (male/

female ratio)Mandibular tooth

typeEvaluation scale

used Safety Success

1 Aggarwal, 2009,India29

1.8 mL 2% lidocaine/1:200,000/IANB

28 6 9/24–37 24 (14/10) 15 first molars, 9second molars

Heft-Parker VAS* Not reported 8

1.8 mL 2% lidocaine/1:200,000/IANB 11.7 mL 4% articaine/1:100,000/BI 1 1.7mL 4% articaine/1:100,000/LI

29 6 8/26–37 30 (15/15) 19 first molars, 11second molars

20

1.8 mL 2% lidocaine/1:200,000/IANB 11.7 mL 2% lidocaine/1:100,000/BI 1 1.7mL 4% articaine/1:100,000/LI

30 6 6/23–36 30 (16/14) 20 first molars, 10second molars

14

2 Aggarwal, 2010,India11

1.8 mL 2% lidocaine/1:200,000/IANB

26 6 9/21–35 24 (14/10) 12 first molars, 12second molars

Heft-Parker VAS* Not reported 7

1.8 mL 2% lidocaine/1:200,000/IANB 1300 mg ibuprofen

30 6 8/23–38 22 (10/12) 10 first molar, 12second molars

6

1.8 mL 2% lidocaine/1:200,000/IANB 1 10mg ketorolac capsule

29 6 8/24–37 23 (12/11) 11 first molars, 12second molars

9

3 Aggarwal, 2010,India13

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

26 6 6/21–32 22 (12/10) 12 first molars, 10second molars

Heft-Parker VAS* Not reported 8

2.2 mL 4% articaine/1:100,000/Gow-Gates

27 6 5/22–32 25 (13/12) 14 first molars, 11second molars

13

2.2 mL 4% articaine/1:100,000/Vazirani-Akinosi

25 6 6/21–31 24 (12/12) 13 first molars, 11second molars

10

1.1 mL 4% articaine/1:100,000/BI 1 1.1mL 4% articaine/1:100,000/LI

26 6 5/21–31 26 (14/12) 13 first molars, 13second molars

7

4 Aggarwal, 2011,India30

1.8 mL 2%lidocaine/1:200,000/IANB

30 6 4/24–34 23 (12/11) 11 first molars, 12second molars

Heft-Parker VAS* Not reported 9

1.8 mL 2% lidocaine/1:200,000/IANB 11.8 mL 4% articaine/1:100,000/BI

31 6 5/26–35 24 (11/13) 14 first molars, 14second molars

13

5 Aggarwal, 2017,India9

1.8 mL 2% lidocaine/1:200,000/IANB

37 6 8.3/31–47 31 (22/9) 19 first molars, 12second molars

Heft-Parker VAS* Not reported 7

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TABLE 1 - Continued

Identificationnumber

Author, year,country

Interventionsas reported in studies

Age in years(mean ± SD/range

if available)Sample size (male/

female ratio)Mandibular tooth

typeEvaluation scale

used Safety Success

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

34 6 6.5/27–41 30 (16/14) 20 first molars, 10second molars

10

1.8 mL 0.5%bupivacaine/1:200,000/IANB

38 6 4.25/29–45 30 (19/11) 22 first molars, 8second molars

5

6 Aggarwal, 2018,India31

1.8 mL 2% lidocaine/1:80,000/IANB

NA 97 (40/38) Molars Heft-Parker VAS* There was a slightnonsignificantincrease in theheart rate after 30s to 1 min of PDLinjectionsmeasured byfinger pulseoximeter.

19

1.8 mL 2% lidocaine/1:80,000/IANB 1 0.4mL 2%lidocaine/1:80,000/PDL

29 6 7/19–38 39 (16/23) Molars 25

1.8 mL 2% lidocaine/1:80,000/IANB 1 1.2mL 2% lidocaine/1:80,000/PDL

30 6 9/21–43 39 (24/15) Molars 33

7 Allegretti, 2016,Brazil32

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

30.3/18–49 22 (9/13) 11 first molars, 11second molars

VAS† Not reported 12

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

28.7/18–47 22 (12/10) 10 first molars, 12second molars

14

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

33.9/19–50 22 (6/16) 13 first molars, 9second molars

16

8 Ashraf, 2013, Iran33 1.5 mL 2% lidocaine/1:100,000/IANB 10.3 mL 2% lidocaine/1:100,000/BI

32.5 6 8.7 51 (23/28) 25 first molars, 26second molars

Heft-Parker VAS* Not reported 9

1.5 mL 2% lidocaine/1:100,000/BI 1 0.3mL 2% lidocaine/1:100,000/BI 1 1.8mL 2% lidocaine/1:100,000/BI

17

1.5 mL 4% articaine/1:100,000/IANB 10.3 mL 4% articaine/1:100,000/BI

37.9 6 10.0 51 (24/27) 17 first molars, 43second molars

8

1.5 mL 4% articaine/1:100,000/IANB 10.3 mL 4% articaine/1:100,000/BI 1 1.8mL 4% articaine/1:100,000/BI

41

9 Claffey, 2004,United States5

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

31 6 8.0/20–48 35 (12/23) 3 second premolars,20 first molars, 12second molars

Heft-Parker VAS* Not reported 8

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TABLE 1 - Continued

Identificationnumber

Author, year,country

Interventionsas reported in studies

Age in years(mean ± SD/range

if available)Sample size (male/

female ratio)Mandibular tooth

typeEvaluation scale

used Safety Success

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

31 6 8.3/21–53 37 (13/24) 1 first premolar, 3second premolars,21 first molars, 12second molars

9

10 Click, 2015, UnitedStates34

3.6 mL 2% lidocaine/1:100,000/Gow-Gates 1 0.9 mL 2%lidocaine/1:100,000/BI

33/18–58 60 (17/43) 3 second premolars,37 first molars, 21second molars

Heft-Parker VAS* Not reported 21

3.6 mL 2% lidocaine/1:100,000/Gow-Gates 1 1.8 mL 4%articaine/1:100,000/BI

20

3.6 mL 2% lidocaine/1:100,000/Vazirani-Akinosi 1 0.9 mL 2%lidocaine/1:100,000/BI

34/20–64 38 (17/21) 22 first molars, 16second molars

6

3.6 mL 2% lidocaine/1:100,000/Vazirani-Akinosi 1 1.8 mL 4%articaine/1:100,000/BI

12

11 Cunha, 2011,Brazil35

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

19–57 60 (41/19) Molars Heft-Parker VAS* Not reported 3

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

7

3.6 mL 3% prilocaine/0.03 IU felypressin/IANB

7

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

8

12 Dou, 2013, China36 4 mL 2% lidocaine/1:100,000/IANB 10.9 mL 4% articaine/1:100,000/BI

38.0 6 10.3/20–59 40 (22/18) First or secondmolars

Heft-Parker VAS* Not reported 28

4 mL 2% lidocaine/1:100,000/IANB 10.9mL 4% articaine/1:100,000/BI 1 0.9mL 4% articaine/1:100,000/LI

40.8 6 8.9/21–55 40 (26/14) 32

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TABLE 1 - Continued

Identificationnumber

Author, year,country

Interventionsas reported in studies

Age in years(mean ± SD/range

if available)Sample size (male/

female ratio)Mandibular tooth

typeEvaluation scale

used Safety Success

13 Fan, 2009, China10 1.7 mL 4% articaine/1:100,000/IANB 10.4 mL 4% articaine/1:100,000/BI

32.93 6 5.67/23–43 27 (15/12) First molars Heft-Parker VAS* Not reported 22

1.7 mL 4% articaine/1:100,000/IANB 10.4 mL 4% articaine/1:100,000/PDL

34.93 6 7.62/18–46 30 (19/11) First molars 25

14 Fullmer, 2014, UnitedStates37

1.8 mL 2% lidocaine/1:100,000/IANB 10.9 mL 2% lidocaine/1:100,000/BI 1placebo

36 6 13/18–61 50 (27/23) 2 first premolars, 4second premolars,28 first molars, 14second molars, 2third molars

Heft-Parker VAS* In theacetaminophen/hydrocodonegroup, 76% of thepatients reportedside effects fromthe medication.The majorityreported euphoria;a few reportedsleepiness, and afew reportednausea.

14

1.8 mL 2% lidocaine/1:100,000/IANB 10.9 mL 2% lidocaine/1:100,000/BI 1 1.8mL 4% articaine/1:100,000/BI 1placebo

15

1.8 mL2% lidocaine/1:100,000/IANB 10.9 mL 2% lidocaine/1:100,000/BI 1 1.8mL 4% articaine/1:100,000/BI 1 1.8mL 2% lidocaine/1:100,000/IO injection1 placebo

16

2% lidocaine 1.81:100,000/IANB/2%lidocaine 1 0.9 mL2% lidocaine/1:100,000/BI 1 1000mg acetaminophen/10-mg hydrocodonecapsules

35 6 12/20–67 50 (19/31) 7 second premolars,26 first molars, 17second molars

16

1.8 mL 2% lidocaine/1:100,000/IANB 10.9 mL 2% lidocaine/1:100,000/BI 1 1.8

17

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Identificationnumber

Author, year,country

Interventionsas reported in studies

Age in years(mean ± SD/range

if available)Sample size (male/

female ratio)Mandibular tooth

typeEvaluation scale

used Safety Success

mL 4% articaine/1:100,000/BI 1 1000mg acetaminophen/10-mg hydrocodonecapsules

1.8 mL 2% lidocaine/1:100,000/IANB 10.9 mL 2% lidocaine/1:100,000/BI 1 1.8mL 4% articaine/1:100,000/BI 1 1.8mL 2% lidocaine/1:100,000/IO injection1 1000 mgacetaminophen/10-mg hydrocodonecapsules

12

15 Ianiro, 2007, UnitedStates38

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

33.7 13 (7/6) Mandibular posteriorteeth

10-cm VAS‡ Not reported 6

3.6 mL 2% lidocaine/1:100,000/IANB 1acetaminophen 1000mg

38.5 14 (5/9) 10

3.6 mL 2% lidocaine/1:100,000/IANB 11000 mgacetaminophen1 600mg ibuprofen

36.6 13 (4/9) 10

16 Jena, 2013, India39 1.8 mL 2% lidocaine/1:100,000/IANB 1sugar-coated pills(placebo)

34 6 12.49 20 (13/7) First or second molar Heft-Parker VAS* Not reported 8

1.8 mL 2% lidocaine/1:100,000/IANB 1600 mg ibuprofen

38.80 6 12.01 20 (14/6) 11

1.8 mL 2% lidocaine/1:100,000/IANB 1 10mg ketorolac

33 6 10.33 20 (11/9) 14

1.8 mL 2% lidocaine/1:100,000/IANB 1400 mg etodolac and500 mg paracetamol

37.45 6 13.61 20 (13/7) 10

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

39.55 6 11.37 20 (12/8) 11

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TABLE 1 - Continued

Identificationnumber

Author, year,country

Interventionsas reported in studies

Age in years(mean ± SD/range

if available)Sample size (male/

female ratio)Mandibular tooth

typeEvaluation scale

used Safety Success

100 mg aceclofenacand 500 mgparacetamol

17 Kanaa, 2012, UnitedKingdom40

2 mL 2% lidocaine/1:80,000/IANB

31.9 6 10/18–66 182 (133/49) 93 first molars, 62second molars, 7third molars

Patient reports; if painfree or not, withoutthe use of anyscale

Not reported 42

2 mL 2% lidocaine/1:80,000/IANB 1 2mL 2% lidocaine/1:80,000/IANB

6

2 mL 2% lidocaine/1:80,000/IANB 1 2mL 4% articaine/1:100,000/BI

11

2% lidocaine/1:80,000/IANB/2% lidocaine 10.36 mL 2% lidocaine/1:80,000/PDL

3

2 mL 2% lidocaine/1:80,000/IANB 1 1mL 2% lidocaine/1:80,000/IO

11

18 Madani, 2013, Iran41 1.8 mL 2% lidocaine/1:80,000/IANB 1 500mg glucose (placebo)

22.80 6 8.53 15 (8/7) Molars Heft-Parker VAS* Not reported 3

1.8 mL 2% lidocaine/1:80,000/IANB 1 400mg ibuprofen

28.80 6 10.91 15 (8/7) 7

1.8 mL 2% lidocaine/1:80,000/IANB 1 325mg acetaminophen

24.53 6 7.44 15 (9/6) 2

1.8 mL 2% lidocaine/1:80,000/IANB 1 400mg ibuprofen

26.47 6 10.58 15 (5/10) 10

19 Mahajan, 2017,India42

1.8 mL 2% lidocaine/1:100,000/IANB 1lactose powdercapsules (placebo)

18–25 15 (9/6) First or second molar Heft-Parker VAS* Not reported 5

1.8 mL 2% lidocaine/1:100,000/IANB 1600 mg ibuprofen

18–25 15 (8/7) 7

1.8 mL 2% lidocaine/1:100,000/IANB 1 50mg tramadol

18–25 15 (8/7) 9

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

18–25 15 (7/8) 8

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Identificationnumber

Author, year,country

Interventionsas reported in studies

Age in years(mean ± SD/range

if available)Sample size (male/

female ratio)Mandibular tooth

typeEvaluation scale

used Safety Success

acetaminophen 325mg 1 ibuprofen 400mg

20 Monteiro, 2015,Brazil43

1.8 mL 4% articaine/1:100,000/BI 1 0.6mL 4%articaine/1:100,000/LI

28 6 13.8 30 (5/25) 17 first molars, 13second molars

VAS/did not specifycategories

Not reported 12

1.8 mL 4% articaine/1:100,000/BI 1 0.6mL 4% articaine/1:100,000/LI 1 0.9mL 4%articaine/1:100k/PDL

21

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

33.5 6 16.5 30 (4/16) 13 first molars, 7second molars

2

1.8 mL 2% lidocaine/1:100,000/IANB 11.8mL 4% articaine/1:100,000/BI

16

21 Noguera-Gonzalez,2013, Mexico44

1.8 mL 2% mepivacaine/1:100,000/IANB 1gelatin (placebo)

34 25 (8/17) First or secondmolars

Heft-Parker VAS* Not reported 9

1.8 mL 2% mepivacaine/1:100,000/IANB 1600 mg ibuprofen

33 25 (10/15) 18

22 Oleson, 2010,United States45

3.6 mL 2% lidocaine/1:100,000/IANB 10.9 mL 2% lidocaine/1:100,000/BI 1placebo

33 6 12 51 (25/26) 4 first premolar, 9second premolars,17 first molars, 19second molars, 2third molars

Heft-Parker VAS* Not reported 18

3.6 mL 2% lidocaine/1:100,000/IANB 10.9 mL 2% lidocaine/1:100,000/BI 1 1.8mL 4%articaine/1:100,000/BI 1placebo

17

3.6 mL 2% lidocaine/1:100,000/IANB 10.9 mL 2% lidocaine/1:100,000/BI 1 1.8mL 4% articaine/1:100,000/BI 1 1.8

15

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Identificationnumber

Author, year,country

Interventionsas reported in studies

Age in years(mean ± SD/range

if available)Sample size (male/

female ratio)Mandibular tooth

typeEvaluation scale

used Safety Success

mL 2% lidocaine/1:100,000/IO injection1 placebo

3.6 mL 2% lidocaine/1:100,000/IANB 10.9 mL 2% lidocaine/1:100,000/BI 1 800mg ibuprofen

32 6 8 49 (20/29) 3 first premolars, 7second premolars,28 first molars, 8second molars, 3third molars

20

3.6 mL 2% lidocaine/1:100,000/IANB 10.9 mL 2% lidocaine/1:100,000/BI 1 1.8mL 4% articaine/1:100,000/BI 1ibuprofen 800 mg

12

3.6 mL 2% lidocaine/1:100,000/IANB 10.9 mL 2% lidocaine/1:100,000/BI 1 1.8mL 4% articaine/1:100,000/BI 1 1.8mL 2% lidocaine/1:100,000/IOinjection1 ibuprofen800 mg

15

23 Parirokh, 2010,Iran46

1.8 mL 2%lidocaine/1:80,000/IANB

25.9 6 6.0 50 (22/28) First or secondmolars

Heft-Parker VAS* None of the patientsreported any sideeffects for up to 48hours

16

1.8 mL 2% lidocaine/1:80,000/IANB 1 600mg ibuprofen

26.2 6 9.5 50 (26/24) 39

1.8 mL 2% lidocaine/1:80,000/IANB 1 75mg indomethacincapsule

26.2 6 5.7 50 (23/27) 31

24 Parirokh, 2010,Iran47

1.8 mL 2% lidocaine/1:80,000/IANB

26.0 6 6.9 27 (10/17) Molars Heft-Parker VAS* Not reported 4

3.6 mL 2% lidocaine/1:80,000/IANB

28.4 6 8.1 28 (8/20) 11

1.8 mL 2% lidocaine/1:80,000/IANB 1 1.8mL 2% lidocaine/1:100,000/BI

27.7 6 7.9 27 (7/20) 17

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Identificationnumber

Author, year,country

Interventionsas reported in studies

Age in years(mean ± SD/range

if available)Sample size (male/

female ratio)Mandibular tooth

typeEvaluation scale

used Safety Success

25 Paul, 2011, India48 3.6 mL 2% lidocaine/1:100,000/IANB 10.9 mL 2% lidocaine/1:100,000/BI 1placebo with sugar-coated pills

31.76 8.933 20 (11/9) 14 first molars, 6second molars

Heft-Parker VAS* Not reported 7

3.6 mL 2% lidocaine/1:100,000/IANB 10.9 mL 2% lidocaine/1:100,000/BI 1 100mg aceclofenac

30.4 6 9.832 20 (12/8) 12 first molars, 8second molars

13

26 Poorni, 2011, India3 1.8 mL 4% articaine/1:100,000/IANB

24.40 6 4.19 52 (28/24) Molars Heft-Parker VAS* Not reported 36

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

24.13 6 4.21 52 (32/20) 34

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

23.46 6 3.7 52 (30/22) 34

27 Prasanna, 2011,United States49

1.8 mL 2% lidocaine/1:200,000/IANB 1cellulose powder

28 6 7 38 (18/20) 20 first molars,18second molars

Heft-Parker VAS* Not reported 10

1.8 mL 2% lidocaine/1:200,000/IANB 1 8mg lornoxicamcapsule

26 6 9 38 (22/16) 19 first molars, 19second molars

28

1.8 mL 2% lidocaine/1:200,000/IANB 1 50mg diclofenac capsule

30 6 6 38 (15/23) 22 first molars, 16second molars

24

28 Qiu, 2010, China50 1.2 mL 4% articaine/1:100,000/IANB

18–55, 38 50 (01/49) Molars VAS§,ǁ Not reported 44

1.2 mL 4% articaine/1:100,000/PDL

50 45

29 Saatchi, 2018, Iran51 3.6 mL 2% lidocaine/1:80,000/IANB

18–64 50 (21/29) Molars Heft-Parker VAS* Not reported 22

3.6 mL 2%lidocaine/1:80,000/Gow-Gates

18–55 50 (16/34) 20

1.8 mL 2% lidocaine/1:80,000/IANB 1 1.8mL 2% lidocaine/1:80,000/Gow-Gates

18–56 50 (15/35) 35

30 Saha, 2016, India52 1.8 mL 2% lidocaine/1:200,000/IANB 1placebo

18–65 42 (22/20) 18 first molars, 24second molars

Heft-Parker VAS* Not reported 12

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Identificationnumber

Author, year,country

Interventionsas reported in studies

Age in years(mean ± SD/range

if available)Sample size (male/

female ratio)Mandibular tooth

typeEvaluation scale

used Safety Success

1.8 mL 2% lidocaine/1:200,000/IANB 1 10mg ketorolac

18–65 42 (23/19) 30 first molars, 12second molars

32

1.8 mL 2% lidocaine/1:200,000/IANB 150-mg diclofenaccapsule

18–65 42 (20/22) 19 first molars, 23second molars

23

31 Sampaio, 2012,Brazil53

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

32.3 35 (16/19) 17 first molars, 18second molars

VAS† Not reported 22

3.6 mL 0.5%bupivacaine/1:200,000/IANB

29.4 35 (16/19) 20 first molars, 15second molars

28

32 Schellenberg, 2015,United States54

2.8 mL 4% lidocaine/1:100,000/IANB 10.9 mL 2% lidocaine/1:100,000/BI

36/18–64 50 (21/32) 3 second premolars25 first molars, 21second molars, 1third molars

Heft-Parker VAS* Not reported 20

2.8 mL 4% lidocaine/1:100,000/IANB 10.9 mL 2% lidocaine/1:100,000/BI 1 1.8mL 4% articaine/1:100,000/BI

11

33 Shantiaee, 2017,Iran55

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

29.26 6 5.93 23 (11/12) First molar Heft-Parker VAS* Not reported 5

1.8 mL 2% lidocaine/1:100,000/IANB 17.5 mg meloxicam

32.78 6 9.55 23 (10/13) 16

1.8 mL 2% lidocaine/1:100,000/IANB 1600 mg ibuprofen

31.70 6 8.04 23 (10/13) 20

2% lidocaine 1.81:100,000/IANB 1placebo

32.22 6 8.87 23 (13/10) 8

34 Shapiro, 2018,United States56

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

39 6 15 199 (97/102) First and secondmolars

Heft-Parker VAS* None of the patientsreported any sideeffects.

50

1.7 mL 4% articaine/1:100,000/IANB 11.7 mL 4% articaine/1:100,000/BI

37 6 13 for firstmolars and41 6 16 for

second molars

76 (41/35) 47

1.7 mL 4% articaine/1:100,000/IANB 11.7 mL 2% lidocaine/1:100,000/BI

73 (23/41) 35

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Identificationnumber

Author, year,country

Interventionsas reported in studies

Age in years(mean ± SD/range

if available)Sample size (male/

female ratio)Mandibular tooth

typeEvaluation scale

used Safety Success

1.7 mL 4% articaine/1:100,000/IANB 11.7mL 2% lidocaine or4% articaine/1:100,000/BI 1 1.7mL 4% articaine/1:100,000/IO injection

63 53

35 Sherman, 2008,United States57

1.8 mL 2% lidocaine/1:100,000/Gow-Gates

Not reported 11 (12/8) 11 molars Heft-Parker VAS* Not reported 8

1.7 mL 4% articaine/1:100,000/Gow-Gates

Not reported 10 (7/13) 10 molars 9

36 Simpson, 2011,United States58

3.6 mL 2% lidocaine/1:100,000/IANB 10.9 mL 2% lidocaine/1:100,000/BI 1placebo

33 6 10 50 (20/30) 1 first premolar, 3second premolars,23 first molars, 21second molars, 2third molars

Heft-Parker VAS* Not reported 12

3.6 mL 2% lidocaine/1:100,000/IANB 10.9 mL 2% lidocaine/1:100,000/BI 1 1.8mL 4% articaine/1:100,000/BI 1placebo

9

3.6 mL 2% lidocaine/1:100,000/IANB 10.9 mL 2% lidocaine/1:100,000/BI 1 1.8mL 4% articaine/1:100,000/BI 1 1.8mL 2% lidocaine/1:100,000/IO injection1 placebo

23

3.6 mL 2% lidocaine/1:100,000/IANB 10.9 mL 2% lidocaine/1:100,000/BI 1 800mg ibuprofen and1000 mgacetaminophen

32 6 10 50 (16/34) 2 first premolars, 5second premolars,23 first molars, 19second molars, 1third molar

16

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

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TABLE 1 - Continued

Identificationnumber

Author, year,country

Interventionsas reported in studies

Age in years(mean ± SD/range

if available)Sample size (male/

female ratio)Mandibular tooth

typeEvaluation scale

used Safety Success

0.9 mL 2% lidocaine/1:100,000/BI 1 1.8mL 4% articaine/1:100,000/BI 1 800mg ibuprofen and1000 mgacetaminophen

3.6 mL 2% lidocaine/1:100,000/IANB 10.9 mL 2% lidocaine/1:100,000/BI 1 1.8mL 4% articaine/1:100,000/BI 11.8mL 2% lidocaine/1:100,000/IO injection1 800 mg ibuprofenand 1000 mgacetaminophen

18

37 Singh, 2010, India59 2% lidocaine/1:200,000/IANB 1 placebo

Not reported 7 Molar Heft-Parker VAS* Not reported 2

2% lidocaine/1:200,000/IANB 1 600 mgibuprofen

7 4

2% lidocaine/1:200,000/IANB 1 400 1 500mg ibuprofen andacetaminophen

7 5

2% lidocaine/1:200,000/IANB 1 10 mgketorolac

7 5

38 Singla, 2015, India60 1.8 mL 4% articaine/1:100,000/IANB

— 128 First or second molar Heft-Parker VAS* Not reported 52

1.8 mL 4% articaine/1:100,000/IANB 11.8 mL 4% articaine/1:100,000/BI

38 6 5.2/24–51 38 (17/21) 23

1.8 mL 4% articaine/1:100,000/IANB 13.6 mL 4% articaine/1:100,000/BI

32 6 4.4/21–43 39 (19/20) 21

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

— 106 36

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Identificationnumber

Author, year,country

Interventionsas reported in studies

Age in years(mean ± SD/range

if available)Sample size (male/

female ratio)Mandibular tooth

typeEvaluation scale

used Safety Success

1.8 mL 4% articaine/1:100,000/IANB 11.8 mL 4% articaine/1:100,000/BI

31 6 5.2/20–48 35 (20/15) 22

1.8 mL 4% articaine/1:100,000/IANB 13.6 mL 4% articaine/1:100,000/BI

37 6 53.8/24–44 35 (16/19) 26

39 Sood, 2014, India61 1.8 mL 2% lidocaine/1:80,000/IANB

28.9 50 (27/23) 1 first premolar, 3second premolars,26 first molars, 18second molars, 2third molars

VAS† Not reported 41

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

26.46 50 (20/30) 1 first premolar, 1second premolar,16 first molars, 29second molars, 3third molars

44

40 Stanley, 2012,United States62

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

35 6 13 50 (23/27) 1 first premolar, 8second premolars,23 first molars, 17second molars, 1third molar

Heft-Parker VAS* Not reported 14

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

33 6 11 50 (20/30) 2 first premolars, 7second premolars,30 first molars, 11second molars

25

41 Tortamano, 2009,Brazil63

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

34.1 20 (6/14) 4 second premolars,9 first molars, 5second molars, 2third molars

VAS† Not reported 9

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

29.9 20 (10/10) 1 second premolar,10 first molars, 8second molars, 1third molar

13

42 Visconti, 2016,Brazil64

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

28 6 11 21 (6/16) 9 first molars, 9second molars, 3third molars

VAS† Not reported 14

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

26 6 10 21 (3/18) 12 first molars, 6second molars, 3third molars

18

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TABLE 1 - Continued

Identificationnumber

Author, year,country

Interventionsas reported in studies

Age in years(mean ± SD/range

if available)Sample size (male/

female ratio)Mandibular tooth

typeEvaluation scale

used Safety Success

43 Wali, 2012,Pakistan65

1.8 mL 2% lidocaine/1:200,000/IANB 1placebo

Not reported 80 (42/38) Molars Heft-Parker VAS* Not reported 2

1.8 mL 2% lidocaine/1:200,000/IANB 1550 mg naproxensodium

7

1.8 mL 2% lidocaine/1:200,000/IANB 1 50mg diclofenacpotassium

15

1.8 mL 2% lidocaine/1:200,000/IANB 1 20mg piroxicam

18

44 Yadav, 2015, India14 1.8 mL 2% lidocaine/1:80,000/IANB 1 0.9mL 2% lidocaine/1:80,000/BI 1 0.9 mL2% lidocaine/1:80,000/LI

30 6 7.6 25 (12/13) 10 first molars, 10second molars

Heft-Parker VAS* Not reported 8

1.8 mL 2% lidocaine/1:80,000/IANB 1 0.9mL 2% lidocaine/1:80,000/BI 1 0.9 mL2% lidocaine/1:80,000/LI 1 10 mgoral ketorolac

28 6 9 25 (12/13) 14 first molars, 11second molars

14

1.8 mL 2% lidocaine/1:80,000/IANB 1 10mg oral ketorolac

31.6 6 9.5 25 (13/12) 13 first molars, 12second molars

10

1.8 mL 4% articaine/1:100,000/IANB 1 10mg oral ketorolac

28.2 6 6.1 25 (13/12) 14 first molars,11second molars

12

1.8 mL 4% articaine/1:100,000/IANB 10.9 mL 4% articaine/1:100,000/BI 1 0.9mL 4% articaine/1:100,000/LI 1preoperative oralketorolac

28.8 6 6.7 25 (14/11) 14 first molars, 11second molars

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Identificationnumber

Author, year,country

Interventionsas reported in studies

Age in years(mean ± SD/range

if available)Sample size (male/

female ratio)Mandibular tooth

typeEvaluation scale

used Safety Success

1.8 mL 4% articaine/1:100,000/IANB 10.9 mL 4% articaine/1:100,000/BI 1 0.9mL 4% articaine/1:100,000/LI

30 6 7.9 25 (14/11) 13 first molars, 12second molars

16

45 Zain, 2016,Pakistan66

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

31.46 6 11/18–60 78 (46/32) First molar Heft-Parker VAS* None of the patientsreported sideeffects.

49

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

78 (46/32) 60

46 Zarei, 2012, Iran67 1.8 mL 2% lidocaine/1:100,000/IANB

18–50 47 (18/22) Second premolar orfirst or secondmolar

VAS† Heart rate wasmonitored with anOxypleth pulseoximeter(Novametrix,Wallingford, CT) 2min before thesupplementalinjections up to 6min after. Themean heart rateincreasedsignificantly afterthe X-Tip IO(DentsplyInternational Inc,Tulsa, OK) by 8–10beats.

In the PDL group, theheart rate did notchangesignificantly witheither the primaryor the secondarysupplementalinjection.

7

1.8 mL 2% lidocaine/1:100,000/IANB 11.8 mL 2% lidocaine/1:100,000/PDL

27.2/18–50 14

1.8 mL 2% lidocaine/1:100,000/IANB 11.8 mL 2% lidocaine/1:100,000/IO

28.6/18–50 20

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.ǁVAS, no categories specified.

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probabilities were used to rank theinterventions for the overall conclusions.

Sensitivity and Subgroup AnalysisIn 3 sensitivity analyses, we excluded studies

1. with results reported in aggregate formandibular molars and premolars,

2. using anesthetic formulations uncommonin the United States, and

3. with high risk of bias domains. Subgroupanalysis determined the effect of theincreasing anesthetic volume (up to 1.8 mLvs .1.8 mL).

RESULTS

Search ResultsFrom the initial search of 2062 records, 1388duplicates were removed, and 541 recordswere excluded based on the title and abstractscreening (Fig. 1). A total of 133 records were

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

Study CharacteristicsPopulationAll studies included adults (18–68 years old).Two studies did not specify their population’sage59,65, and 1 study excluded patients under18 years without identifying age distribution74

(Table 1). The majority of studies evaluatedanesthetic efficacy in mandibular molars; 10studies included mandibular molars orpremolars5,34,37,45,54,58,61–63,67, and 1included mandibular posterior teeth withoutspecifying the tooth type38. All patients had thediagnosis of symptomatic irreversible pulpitisconfirmed 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 pulptests40, or both10,11,13,29–32,36,41,47,49,53,60,61,63,64. Three studies mentioned theyconfirmed the diagnosis by pulp tests withoutspecifying the type of the test9,50,66. Mostpatients experienced moderate to severepreoperative pain confirmed by a verbal analogscale. Seven studies did not provide anyinformation on the preoperative pain level ofpatients38,51,60,74,77.

InterventionsA total of 37 primary or supplementalinterventions were identified (Fig. 2). The mostcommon primary injection technique was IANBfollowed by Gow-Gates11,34,51,57, Vazirani-Akinosi11,34, buccal infiltration3,66, buccalinfiltration with11,43 or without lingualinfiltration3,66, and periodontal ligamentinjection50. The most common supplemental

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

1452 Zanjir et al. JOE � Volume 45, Number 12, December 2019

injection was buccal infiltration followed byperiodontal10,31,40,43,67, intraosseous (IO)injection37,40,45,56,58,67, and Gow-Gates51

injections. Various approaches wereinvestigated including changing the localanesthetic solution5,9,32,35,43,53,57,61,63,64,premedication with nonsteroidal anti-inflammatory drugs (NSAIDs)13,14,39,41,42,44–46,48,49,52,55,59,65, a combination of NSAIDsand acetaminophen38,39,42,58,59, opioids42, acombination of opioids and acetaminophen37,acetaminophen38,41, and nitrous oxide62 up to1 hour before the treatment as well aschanging the primary injectiontechnique11,50,66 and using supplementalinjection techniques3,10,29,31,33,34,36,40,47,51,56,60,67. The anesthetics compared in theincluded studies were 2% lidocaine with1:100,00, 1:200,000, or 1:50,000epinephrine3,5,9,13,14,29–43,45–49,51–59,61–67, 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 1:100,000epinephrine14,32,35,44,64,76, 0.5% bupivacaine1:200,0009,53, and 3% prilocaine with 0.03 IUfelypressin35.

Outcome AssessmentAll patients underwent nonsurgicalendodontic treatment. To verify successfulpulpal anesthesia, a majority of studieschecked for lip numbness within 5–25minutes after the primary injection. Othermethods used include the absence of painduring cold testing14,47,52,57 or negativereading of electric pulp testing when amaximum of 80 was used3,10,13,14,30,32–34,37–40,42–46,49,51–56,58,61–63,66,67,80. Accesscavity preparation was terminated in thesestudies as soon as patients reported pain,and the level of pain was measured usingdifferent patient-reported approaches(Table 1). Patient reports of mild or no painwere the measure of success.

Of the 46 included studies, 23 studieswere graded as low risk, 20 as moderate risk,and 3 as high risk (Fig. 3). Overall, moderateand high risk of bias in the judgment was foundin the random sequence generation, allocationconcealment, and blinding of patients andoperators domains.

Thirty-seven interventions (with a totalnumber of 5094 patients) were used in the

NMA (Fig. 2), of which 2632 patients hadsuccessful pulpal anesthesia duringtreatment. Figure 4 summarizes relativetreatment effects for all possiblecomparisons, expressed by ORs with 95%CrIs. Compared with a commonly acceptedpractice of IANB injection using 2% lidocainewith 1:100,000 epinephrine, the followingsupplemental IO injections were deemedmost effective at providing successful pulpalanesthesia when treating mandibular molarswith symptomatic irreversible pulpitis(Tables 2 and 3):

1. Supplemental IO injection using 2% lidocaineand preoperative NSAIDs (in particular,ibuprofen) combined with acetaminophen(OR574;95%CrI, 15–470;SUCRA597%;very low confidence)

2. Supplemental IO injection using 2%lidocaine and preoperative NSAIDs(OR 5 46; 95% CrI, 8–420; SUCRA5 94%; very low confidence)

3. Supplemental IO injection using 2%lidocaine (OR 5 33; 95% CrI, 14–80;SUCRA 5 93%; moderate confidence)

FIGURE 2 – The network geometry of the different interventions used to achieve pulpal anesthesia during the endodontic treatment of a mandibular molar with symptomaticirreversible pulpitis.

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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 includedstudies.

1454 Zanjir et al. JOE � Volume 45, Number 12, December 2019

4. Supplemental IO injection using 2%lidocaine and preoperative opioids (oralhydrocodone) combined withacetaminophen (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%; verylow confidence)

The next efficacious intervention wassupplemental buccal and lingual infiltrationsusing 4% articaine combined with preoperativeNSAIDs (OR 5 18; 95% CrI, 6–56; SUCRA 5

86%; very low confidence). This was followedby IANB using 2% mepivacaine whencombined with preoperative NSAIDs (OR 5

13; 95% CrI, 2.1–88; SUCRA5 77%; very lowconfidence). The least effective interventionwas IANB using 2% lidocaine with 1:100,000epinephrine (SUCRA 5 6%). No significantinconsistency or heterogeneity was noted inthe results.

Sensitivity and Subgroup AnalysisWhen excluding studies with a mix of molarsand premolars, the most efficaciousintervention was supplemental IO injectionusing 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 aswell as our subgroup analysis were similar tothe primary analysis (Table 2).

SafetyThe majority of studies included in our analyseseither reported no major concerns or did notreport any information on safety (Table 1). ForIO injection, a study in which the injection wascombined with 1 hour of preoperativeadministration of oral hydrocodone/acetaminophen reported euphoria, sleepiness,and nausea as side effects from opioidanalgesia37. Another study reported a transientincreased heart rate (8–10 beats) in patients

receiving IO injection in the first 4 minutes afterinjection67.

DISCUSSION

This NMA identified very low– to moderate-quality evidence that suggested thatcompared with IANB using 2% lidocaine,supplemental IO injections with 2% lidocaine or4% articaine and supplemental buccal andlingual infiltrations using 4% articaine were thetop-ranked interventions to achieve pulpalanesthesia during nonsurgical endodontictreatment for mandibular molars withsymptomatic irreversible pulpitis.Premedication with NSAIDs, a combination ofNSAIDs and acetaminophen, and opioidsadministered up to 1 hour preoperatively mayincrease the efficacy of these injectionsbecause they resulted in higher ORs andSUCRA values. No major safety concernswere reported in the included studies.

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

JOE � Volume 45, Number 12, December 2019 Efficacy and Safety of Pulpal Anesthesia Strategies 1455

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

Intervention

Primary analysis First sensitivity analysisSecond sensitivity

analysisThird sensitivity

analysis

Subgroup 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)

Supplemental 2%lidocaine (IO) 1NSAIDs andacetaminophen

97.37 74 (15–470) — — 96.62 77 (12–600) 97.73 94 (22–520) — — 91.12 15 (1.3–190)

Supplemental 2%lidocaine (IO) 1NSAIDs

93.91 46 (8–420) — — 92.72 47 (6.5–520) 94.16 53 (11–430) — — 84.32 9.6 (0.66–150)

Supplemental 2%lidocaine (IO)

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)

Supplemental 4%articaine (IO)

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) — —

Supplemental 4%articaine (BI) 1LI 1 NSAIDs

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) — —

Supplemental 2%lidocaine (IO) 1opioids andacetaminophen

85.80 20 (4.4–98) — — 84.44 21 (3.6–140) 87.06 23 (6.2–100) 89.54 28 (5.8–170) — —

2% mepivacaine(IANB) 1 NSAIDs

77.45 13 (2.1–88) 84.10 14 (2–99) — — 76.26 13 (2.7–73) — — — —

Supplemental 4%articaine (BI) 1 LI

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)

Supplemental 4%articaine (BI) 1opioids andacetaminophen

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) — —

Supplemental 2%lidocaine (BI) 1LI 1 NSAIDs

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) — —

Supplemental 4%articaine (BI) 1NSAIDs andacetaminophen

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)

Supplemental 4%articaine (PDL)

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) — —

Supplemental 2%lidocaine (PDL)

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)

Supplemental 4%articaine (BI)

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)

4% articaine (IANB) 1NSAIDs

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 )

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TABLE 2 - Continued

Intervention

Primary analysis First sensitivity analysisSecond sensitivity

analysisThird sensitivity

analysis

Subgroup 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)

Supplemental 2%lidocaine (BI) 1NSAIDs andacetaminophen

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)

2% lidocaine (IANB) 1opioids

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) — —

Supplemental 2%lidocaine (BI) 1NSAIDs

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)

2% lidocaine (IANB) 1NSAIDs

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) — —

4% articaine(Gow-Gates)

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)

Supplemental 2%lidocaine (BI) 1opioids andacetaminophen

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) — —

Supplemental 4%articaine (BI) 1NSAIDs

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)

Supplemental 2%lidocaine(Gow-Gates)

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)

2% lidocaine (IANB) 1NSAIDs andacetaminophen

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)

2% mepivacaine (IANB) 35.00 2.8 (1.1–7.3) 43.00 2.8 (1.1–7.7) — — 32.40 2.7 (1.2–6.5) — — 62.20 2.8 (0.78–11)2% lidocaine (IANB) 1nitrous oxide

34.06 2.6 (0.70–10) — — 36.23 2.6 (0.51–14) 32.10 2.6 (0.90–7.9) — — 59.08 2.6 (0.47–14)

Supplemental 2%lidocaine (BI)

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 3.5 (1.6–9) 16.50 0.62 (0.084–3.9)

4% articaine(Vazirani-Akinosi)

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)

Supplemental 2%lidocaine (BI) 1 LI

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) — —

3% prilocaine (IANB) 30.20 2.2(0.48–11)

37.00 2.3 (0.46–11) — — 27.32 2.2 (0.54–8.7) — — 55.71 2.4 (0.40–16)

4% articaine (PDL) 27.92 2(0.36–12)

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) — —

2% lidocaine(Gow-Gates)

18.32 0.84(0.018–19)

22.17 0.84 (0.017–20) 19.89 0.83 (0.013–24) 15.55 0.78 (0.019–14) — — — —

4% articaine (IANB) 16.91 — 23.82 1.6 (0.90–3.2) 20.24 1.7 (0.93–3.3) 15.38 1.5 (1.0–2.4) 19.52 1.5 (0.74–3.3) 47.47 1.8 (0.69–5)

(continued on next page )

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Strategies

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IO injections deliver anesthetic solution intothe cancellous bone surrounding a specifictooth to anesthetize the nerves supplying thetooth pulp81, providing a quick onset andlong duration of pulpal anesthesia82. The useof 4% articaine in IO injections has beenwidely investigated in clinical trials and isshown to be safe and effective78,83.Nevertheless, there have been concerns ofparesthesia and great bone penetration84.For clinicians with these concerns, wesuggest the use of 2% lidocaine whendelivering IO injections, especially because4% articaine had a lower rank inefficacy compared with 2% lidocaine in allour analyses, except the first sensitivityanalysis.

Concerning IO injection safety, fewstudies reported an initial increase in heart rate.This increase poses no concern to healthyindividuals, returns to baseline within 4minutes85,86, and can be avoided by slowingdown the rate of anesthetic solutiondeposition78,86. For those with high bloodpressure, cardiovascular diseases, or anycondition in which epinephrine iscontraindicated, alternative anestheticsolutions such as a plain solution of 2%mepivacaine can be considered85,87. Otherpotential side effects reported in the literaturewhile implementing the IO technique includepain during perforation and solutiondeposition12,87–90, high occlusion for a fewdays89,91,92, and swelling with or withoutexudate that would resolve within a fewdays91,92. This underscores the importance ofreporting side effects in RCTs so thatcumulative information on adverse effects canbe gained. Supplemental buccal and lingualinfiltrations using 4% articaine withpreoperative NSAIDs were ranked the second-best intervention. Therefore, they may be usedas an adjunct to IANB injection to increase itssuccess93.

NSAIDs have been shown to relieve painassociated with symptomatic irreversiblepulpitis and improve IANB success24,94.NSAIDs block the cyclooxygenase enzymes,which are responsible for the synthesis ofinflammation-promoting mediators, such asprostaglandins, that cause pain95. Pulikkotilet al25 identified NSAIDs through NMA as thesecond best in improving IANB success afterdexamethasone (risk ratio 5 1.92 [95%confidence interval, 1.63–2.27], SUCRA 5

74%; risk ratio 5 2.92 [95% confidenceinterval, 1.74–4.91]; SUCRA 5 96%,respectively). In another meta-analysis, theyalso identified that premedication with .400mg oral ibuprofen is effective in increasing theanesthetic success of IANBs94. In our results,we found that preoperative NSAIDs mayTA

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1458 Zanjir et al. JOE � Volume 45, Number 12, December 2019

improve the success rates of supplemental IOinjection and supplemental buccal with lingualinfiltration because it resulted in higher ORs butwide and overlapping CrIs when comparedwith those who did not receive NSAIDs(Table 2).

Repeating IANB using 2% lidocainewith 1:100,000 epinephrine was the leasteffective intervention to achieve pulpalanesthesia for patients with symptomaticirreversible pulpits. This finding is incorroboration with the previous reports ofthe suboptimal success rates of 13%–54%for IANB using 2% lidocaine as a primaryinjection9,40,64,96 or success rates of 13%for repeating IANB as a supplementalinjection40,96. Moreover, consistent withprevious clinical trials21,47,97–99, thesubgroup analysis showed that increasingthe anesthetic volume to more than 1carpule (1.8 mL) does not improve thesuccess of IANB when treating mandibularmolars with symptomatic irreversiblepulpitis. Hence, the clinical trend to repeatIANB when it fails may need to bereconsidered. Our results also highlight theimportance of increased training with IOinjections in general and specialty dentaltraining. A survey of 833 United Statesendodontists100 reported the significantunderutilization of IO injection becausepractitioners may feel deterred by the

perceived difficulty or extra time neededwhen using cortical bone perforating IOsystems. We speculate with more robust,didactic, and hands-on training with IOinjection during dental training, futuregraduates of dental schools and specialtyprograms will feel confident performing theIO technique more frequently whenindicated.

Our study has the followingstrengths: we included 46 RCTs, weapplied a comprehensive search strategyand strict inclusion criteria to meet theNMA assumption of similarity and to reduceselection bias, we identified no majorthreats from inconsistency andheterogeneity, and our sensitivity andsubgroup analyses were informative fromthe standpoint of the potential impact ofcovariates that might have affected theoutcome. However, our study has somelimitations. Given the large number ofinterventions we had and the relativelysmall number of studies included,imprecision and uncertainty in our resultsare expected, which may be improved infuture updates on this topic with theavailability of new trials. Our findings on thesafety of the interventions are also limited.Finally, although we assumed transitivitybetween interventions, we cannot rule outminor but important variations between

interventions and baseline characteristics ofthe population included.

Our study has some implications forfuture research. Given the wide CrIs in theestimates of IO efficacy (ie, imprecision),additional large, well-designed RCTs arerequired to further assess the efficacy of IOinterventions. Additionally, a potential ofefficacy for IANB with 2% mepivacaine wasidentified only when it was combined withNSAIDs. This is an interesting finding because,in general, local anesthesia using mepivacainehas not been commonly considered a “rescue”for failed local anesthesia for teeth withsymptomatic irreversible pulpitis. Further RCTsare needed to establish the efficacy and safetyof IANB or IO with mepivacaine for thesepatients.

Many RCTs about increasing thesuccess of pulpal anesthesia duringendodontic treatment of mandibular molarswith symptomatic irreversible pulpitis areconducted annually, and they would needto be monitored and analyses would needto be updated as evidence changes.

CONCLUSION

Very low to moderate quality of evidencesuggests supplemental IO injections using 2%lidocaine with 1:100,000 epinephrine or 4%articaine with 1:100,000 epinephrine followed

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 obtainedfrom the CINeMA Web Application

Intervention

Numberof

studies

Within-studybias

Across-studiesbias Indirectness Imprecision Heterogeneity Incoherence

Confidencerating

Supplemental 2%lidocaine (IO) 1NSAIDs and acetaminophen

0 Majorconcerns

Undetected No concerns No concerns No concerns Major concerns Very low

Supplemental 2%lidocaine (IO) 1NSAIDs

0 Majorconcerns

Undetected No concerns No concerns No concerns Major concerns Very low

Supplemental 2%lidocaine (IO)

2 Majorconcerns

Undetected No concerns No concerns No concerns No concerns Moderate

Supplemental 2%lidocaine (IO) 1opioids and acetaminophen

0 Majorconcerns

Undetected No concerns No concerns No concerns Major concerns Very low

Supplemental 4%articaine (IO)

0 Majorconcerns

Undetected No concerns No concerns No concerns Major concerns Very low

Supplemental 4%articaine (BI) 1(LI) 1 NSAIDs

0 Majorconcerns

Undetected No concerns No concerns No concerns Major concerns Very low

2% mepivacaine(IANB) 1 NSAIDs

0 Majorconcerns

Undetected No concerns No concerns No concerns Major concerns Very low

BI, buccal infiltration; IANB, inferior alveolar nerve block; LI, lingual infiltration.Grading of Recommendations Assessment, Development, and EvaluationWorkingGroup grades of evidence: high confidence, we are very confident that the true effect lies close to that ofthe 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 possibilitythat 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 lowconfidence, we have very little confidence in the effect estimate (the true effect is likely to be substantially different from the estimate of effect).

JOE � Volume 45, Number 12, December 2019 Efficacy and Safety of Pulpal Anesthesia Strategies 1459

by supplemental buccal and lingual infiltrationsusing 4% articaine with 1:100,000 epinephrineare the most efficacious interventions toachieve successful pulpal anesthesia duringendodontic treatment of mandibular molarswith symptomatic irreversible pulpitisaccording to the current literature.

ACKNOWLEDGMENTS

Wewould like to thankMrs.Maria Zych from theUniversity of Toronto Libraries for her help inconducting the search. The authors deny anyconflicts of interest related to this study. Therewas no funding associated with this paper.

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9. Aggarwal V, Singla M, Miglani S. Comparative evaluation of anesthetic efficacy of 2% lidocaine,4% articaine, and 0.5% bupivacaine on inferior alveolar nerve block in patients withsymptomatic irreversible pulpitis: a prospective, randomized, double-blind clinical trial. J OralFacial Pain Headache 2017;31:124–8.

10. Fan S, Chen W-L, Pan C-B, et al. Anesthetic efficacy of inferior alveolar nerve block plus buccalinfiltration or periodontal ligament injectionswith articaine in patients with irreversible pulpitis in themandibular first molar. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:e89–93.

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12. Nusstein J, Kennedy S, Reader A, et al. Anesthetic efficacy of the supplemental X-tipintraosseous injection in patients with irreversible pulpitis. J Endod 2003;29:724–8.

13. Aggarwal V, Singla M, Kabi D. Comparative evaluation of effect of preoperative oral medicationof ibuprofen and ketorolac on anesthetic efficacy of inferior alveolar nerve block with lidocaine inpatients with irreversible pulpitis: a prospective, double-blind, randomized clinical trial. J Endod2010;36:375–8.

14. Yadav M, Grewal MS, Grewal S, Deshwal P. Comparison of preoperative oral ketorolac onanesthetic efficacy of inferior alveolar nerve block and buccal and lingual infiltration with articaineand lidocaine in patients with irreversible pulpitis: a prospective, randomized, controlled,double-blind study. J Endod 2015;41:1773–7.

15. 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 irreversiblepulpitis: a prospective, randomized single-blind study. J Endod 2012;38:753–6.

16. Abazarpoor R, Parirokh M, Nakhaee N, Abbott PV. A comparison of different volumes ofarticaine for inferior alveolar nerve block for molar teeth with symptomatic irreversible pulpitis. JEndod 2015;41:1408–11.

17. Brandt RG, Anderson PF, Mcdonald NJ, et al. The pulpal anesthetic efficacy of articaine versuslidocaine in dentistry. J Am Dent Assoc 2011;142:493–504.

SUPPLEMENTARY MATERIAL

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1460 Zanjir et al. JOE � Volume 45, Number 12, December 2019

18. Balto K. Administration of articaine anesthesia may lead to superior profound pulpal anesthesiacompared with lidocaine in adult patients. J Evid Based Dent Pract 2011;11:183–4.

19. Kung J, Mcdonagh M, Sedgley CM. Does articaine provide an advantage over lidocaine inpatients with symptomatic irreversible pulpitis? A systematic review andmeta-analysis. J Endod2015;41:1784–94.

20. Su N, Li C, Wang H, et al. Efficacy and safety of articaine versus lidocaine for irreversible pulpitistreatment: a systematic review and meta-analysis of randomised controlled trials. Aust Endod J2016;42:4–15.

21. Corbella S, Taschieri S, Mannocci F, et al. Inferior alveolar nerve block for the treatment of teethpresenting with irreversible pulpitis: a systematic review of the literature and meta-analysis.Quintessence Int 2017;48:69–82.

22. Xiao JL, Li YL, Ma B, et al. Anesthetic efficacy of articaine versus lidocaine for irreversible pulpitis:a meta-analysis. Chin J Evid Based Med 2010;10:1058–62.

23. Tupyota P, Chailertvanitkul P, Laopaiboon M, et al. Supplementary techniques for pain controlduring root canal treatment of lower posterior teeth with irreversible pulpitis: a systematic reviewand meta-analysis. Aust Endod J 2018;44:14–25.

24. Li T, Puhan MA, Vedula SS, et al. Network meta-analysis-highly attractive but moremethodological research is needed. BMC Med 2011;9:79.

25. Pulikkotil SJ, Nagendrababu V, Veettil SK, et al. Effect of oral premedication on the anaestheticefficacy of inferior alveolar nerve block in patients with irreversible pulpitis - a systematic reviewand network meta-analysis of randomized controlled trials. Int Endod J 2018;51:989–1004.

26. Hutton BM, Salanti GH, Caldwell DP, et al. The PRISMA extension statement for reporting ofsystematic reviews incorporating network meta-analyses of health care interventions: checklistand explanations. Ann Intern Med 2015;162:777–84.

27. Malamed SF. Handbook of Local Anesthesia. Edinburg, UK: Elsevier Health Sciences; 2014.

28. Reader A, Nusstein J, Drum M. Successful Local Anesthesia for Restorative Dentistry andEndodontics. Hanover Park, IL: Quintessence Publishing Co Inc; 2017.

29. Aggarwal V, Jain A, Kabi D. Anesthetic efficacy of supplemental buccal and lingual infiltrations ofarticaine and lidocaine after an inferior alveolar nerve block in patients with irreversible pulpitis. JEndod 2009;35:925–9.

30. Aggarwal V, Singla M, Rizvi A, Miglani S. Comparative evaluation of local infiltration of articaine,articaine plus ketorolac, and dexamethasone on anesthetic efficacy of inferior alveolar nerveblock with lidocaine in patients with irreversible pulpitis. J Endod 2011;37:445–9.

31. Aggarwal V, Singla M, Miglani S, et al. Does the volume of supplemental intraligamentaryinjections affect the anaesthetic success rate after a failed primary inferior alveolar nerve block? Arandomized-double blind clinical trial. Int Endod J 2018;51:5–11.

32. Allegretti CE, Sampaio RM, Horliana AC, et al. Anesthetic efficacy in irreversible pulpitis: arandomized clinical trial. Braz Dent J 2016;27:381–6.

33. Ashraf H, Kazem M, Dianat O, Noghrehkar F. Efficacy of articaine versus lidocaine in block andinfiltration anesthesia administered in teeth with irreversible pulpitis: a prospective, randomized,double-blind study. J Endod 2013;39:6–10.

34. Click V, Drum M, Reader A, et al. Evaluation of the Gow-Gates and Vazirani-Akinosi techniquesin patients with symptomatic irreversible pulpitis: a prospective randomized study. J Endod2015;41:16–21.

35. Cunha RS, Nevares G, Pinheiro SL, et al. Comparison of the success rates of four anestheticsolutions for inferior alveolar nerve block in patients with irreversible pulpitis. A prospective,randomized, double-blind study. Dent Press Endod 2011;1:22–6.

36. Dou L, Luo J, Yang D. Anaesthetic efficacy of supplemental lingual infiltration of mandibularmolars after inferior alveolar nerve block plus buccal infiltration in patients with irreversiblepulpitis. Int Endod J 2013;46:660–5.

37. Fullmer S, Drum M, Reader A, et al. Effect of preoperative acetaminophen/hydrocodone on theefficacy of the inferior alveolar nerve block in patients with symptomatic irreversible pulpitis: aprospective, randomized, double-blind, placebo-controlled study. J Endod 2014;40:1–5.

38. Ianiro S, Jeansonne B, McNeal S, Eleazer P. The effect of preoperative acetaminophen or acombination of acetaminophen and ibuprofen on the success of inferior alveolar nerve block forteeth with irreversible pulpitis. J Endod 2007;33:11–4.

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39. Jena A, Shashirekha G. Effect of preoperative medications on the efficacy of inferior alveolarnerve block in patients with irreversible pulpitis: a placebo-controlled clinical study. J ConservDent 2013;16:171.

40. Kanaa MD, Whitworth JM, Meechan JG. A prospective randomized trial of differentsupplementary local anesthetic techniques after failure of inferior alveolar nerve block in patientswith irreversible pulpitis in mandibular teeth. J Endod 2012;38:421–5.

41. Madani ZS, Haddadi A, Moghadamnia A, et al. The efficacy of premedication with ibuprofen,gelofen and acetaminophen in the depth of anesthesia in mandibular molars with irreversiblepulpitis. Afr J Pharm Pharmacol 2013;6:1841–6.

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

43. Monteiro MR, Groppo FC, Haiter-Neto F, et al. 4% articaine buccal infiltration versus 2%lidocaine inferior alveolar nerve block for emergency root canal treatment in mandibular molarswith irreversible pulpits: a randomized clinical study. Int Endod J 2015;48:145–52.

44. Noguera-Gonzalez D, Cerda-Cristerna BI, Chavarria-Bolanos D, et al. Efficacy ofpreoperative ibuprofen on the success of inferior alveolar nerve block in patients withsymptomatic irreversible pulpitis: a randomized clinical trial. Int Endod J2013;46:1056–62.

45. Oleson M, Drum M, Reader A, et al. Effect of preoperative ibuprofen on the success of theinferior 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 andindomethacin on the success of inferior alveolar nerve block for teeth with irreversible pulpitis. JEndod 2010;36:1450–4.

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

48. Paul J, Ittyerah A, Kumar S. Effect of preoperative aceclofenac on the success of inferior alveolarnerve 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 oflornoxicam and diclofenac potassium on the success of inferior alveolar nerve block in patientswith irreversible pulpitis: a double-blind, randomised controlled clinical trial. I Endod J2011;44:330–6.

50. Qiu W, Chi MX, Zhang TT. Comparative study in periodontal ligament anesthesia and inferioralveolar nerve block anesthesia in mandibular permanent molar. J Dalian Med Univ2010;32:305–8.

51. SaatchiM, ShafieeM,Khademi A,MemarzadehB.Anesthetic efficacy ofGow-Gates nerve block,inferior alveolar nerve block, and their combination in mandibular molars with symptomaticirreversible 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 alveolarnerve 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 betweenbupivacaine and lidocaine in patients with irreversible pulpitis of mandibular molar. J Endod2012;38:594–7.

54. Schellenberg J, Drum M, Reader A, et al. Effect of buffered 4% lidocaine on the success of theinferior 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 andmeloxicam 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 insupplemental infiltration for mandibular first versus second molars with irreversible pulpitis: aprospective, 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 injectionand maxillary infiltration with articaine and lidocaine for irreversible pulpitis. J Endod2008;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 symptomaticirreversible pulpitis. J Endod 2011;37:593–7.

59. Singh RD, Khatter R, Bal CS. The effect of preoperative ibuprofen, combination of ibuprofen andacetaminophen, ketorolac versus placebo on the efficacy of the inferior alveolar nerve block inpatients 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 differentvolumes of 4% articaine (1.8 and 3.6 mL) as supplemental buccal infiltration after failed inferioralveolar nerve block. Int Endod J 2015;48:103–8.

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

62. Stanley W, DrumM, Nusstein J, et al. Effect of nitrous oxide on the efficacy of the inferior alveolarnerve 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 articaineand 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 mepivacaineand lidocaine in patients with irreversible pulpitis: a double-blind randomized clinical trial. JEndod 2016;42:1314–9.

65. Wali A, Siddiqui TM, Qamar N, et al. Effectiveness of premedication with analgesics vs placebofor success of inferior alveolar nerve block in irreversible pulpitis. Int J Prosthodont Restor Dent2012;2:5–9.

66. Zain M, Khattak SU, Sikandar H, et al. Comparison of anaesthetic efficacy of 4% articaineprimary buccal infiltration versus 2% lidocaine inferior alveolar nerve block in symptomaticmandibular 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 ratechanges after periodontal ligament or intraosseous X-Tip injection in mandibular molars: arandomized 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: TheCochrane Collaboration; 2008. p. 187–241.

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

70. Dias S, Sutton AJ, Ades AE,Welton NJ. Evidence synthesis for decision making 2: a generalizedlinear modeling framework for pairwise and network meta-analysis of randomized controlledtrials. 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 treatmentcomparison meta-analysis. Stat Med 2010;29:932–44.

74. Thimmaiah PN, Hegde MT, Gundefined B, et al. Anesthetic efficacy of combination of twopercent lidocaine with 1:80,000 epinephrine and 0.5 mol/l mannitol for inferior alveolar nerveblocks in patients with symptomatic irreversible pulpitis: an in vivo study. Int Res J Pharm2013;4:161–3.

75. Saatchi M, Khademi A, Baghaei B, Noormohammadi H. Effect of sodium bicarbonate-bufferedlidocaine on the success of inferior alveolar nerve block for teeth with symptomatic irreversiblepulpitis: 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 ofmepivacaine-tramadol combination on the success of inferior alveolar nerve blocks in patientswith 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 epinephrineconcentrations (1: 80 000 and 1 : 200 000) in 2% lidocaine for inferior alveolar nerve block inpatients with symptomatic irreversible pulpitis: a randomized, double-blind clinical trial. IntEndod J 2014;47:373–9.

78. 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 Radiol2013;116:e85–91.

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79. Abt E. Analgesic premedication may increase the success rate of local anesthetics for teeth withirreversible 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 theinferior alveolar nerve block in patients with irreversible pulpitis. J Endod 2003;29:630–3.

81. Nusstein JM, Reader A, Drum M. Local anesthesia strategies for the patient with a “hot” tooth.Dent Clin North Am 2010;54:237–47.

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

83. Vongsavan K, Samdrup T, Kijsamanmith K, et al. The effect of intraosseous local anesthesia of4% articaine with 1: 100,000 epinephrine on pulpal blood flow and pulpal anesthesia ofmandibular 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.

85. 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 SurgOral 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 andfast rates of anesthetic solution deposition. Anesth Prog 2008;55:9–15.

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

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

89. Reitz J, Reader A, Nist R, et al. Anesthetic efficacy of a repeated intraosseous injection given 30min following an inferior alveolar nerveblock/intraosseous injection. AnesthProg1998;45:143–9.

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

91. Gallatin J, Reader A, Nusstein J, et al. A comparison of two intraosseous anesthetic techniquesin mandibular posterior teeth. J Am Dent Assoc 2003;134:1476–84.

92. Coggins R, Reader A, Nist R, et al. Anesthetic efficacy of the intraosseous injection in maxillaryand mandibular teeth. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81:634–41.

93. Kanaa MD, Whitworth JM, Corbett IP, Meechan JG. Articaine buccal infiltration enhances theeffectiveness of lidocaine inferior alveolar nerve block. Int Endod J 2009;42:238–46.

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

95. Haas DA. An update on analgesics for the management of acute postoperative dental pain. JCan Dent Assoc 2002;68:476–82.

96. Reader A. Taking the pain out of restorative dentistry and endodontics: current thoughts andtreatment options to help patients achieve profound anesthesia. Endodontics: Colleagues forExcellence. Winter; Chicago, IL: American Association of Endodontists; 2009. p. 1–8.

97. Pfeil L, Drum M, Reader A, et al. Anesthetic efficacy of 1.8 milliliters and 3.6 milliliters of 2%lidocaine with 1: 100,000 epinephrine for posterior superior alveolar nerve blocks. J Endod2010;36:598–601.

98. Nusstein J, Reader A, Beck FM. Anesthetic efficacy of different volumes of lidocaine withepinephrine for inferior alveolar nerve blocks. Gen Dent 2002;50:372–7.

99. Vreeland DL, Reader A, Beck M, et al. An evaluation of volumes and concentrations of lidocainein human inferior alveolar nerve block. J Endod 1989;15:6–12.

100. Bangerter C, Mines P, Sweet M. The use of intraosseous anesthesia among endodontists:results of a questionnaire. J Endod 2009;35:15–8.

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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 aSystematic Review Involving a Network Meta-analysis

Section/topic Item no. Checklist item Reported on page no.

TitleTitle 1 Identify the report as a systematic review incorporating a

network meta-analysis (or related form of meta-analysis).

1

AbstractStructured summary 2 Provide a structured summary including, as applicable:

Background: main objectivesMethods: data sources; study eligibility criteria,

participants, and interventions; study appraisal; andsynthesis methods, such as network meta-analysis.

Results: number of studies and participants identified;summary estimates with corresponding confidence/credible intervals; treatment rankings may also bediscussed. Authors may choose to summarize pairwisecomparisons against a chosen treatment included intheir analyses for brevity.

Discussion/Conclusions: limitations; conclusions andimplications of findings.

Other: primary source of funding; systematic reviewregistration number with registry name.

1-2

IntroductionRationale 3 Describe the rationale for the review in the context of what

is already known, including mention of why a networkmeta-analysis has been conducted.

3

Objectives 4 Provide an explicit statement of questions beingaddressed, with reference to participants, interventions,comparisons, outcomes, and study design (PICOS).

3-4

MethodsProtocol and registration 5 Indicate whether a review protocol exists and if and where

it can be accessed (eg, Web address) and, if available,provide registration information, including registrationnumber.

—

Eligibility criteria 6 Specify study characteristics (eg, PICOS, length of follow-up) and report characteristics (eg, years considered,language, publication status) used as criteria foreligibility, giving rationale. Clearly describe eligibletreatments included in the treatment network and notewhether any have been clustered or merged into thesame node (with justification).

4-5

Information sources 7 Describe all information sources (eg, databases withdates of coverage, contact with study authors toidentify additional studies) in the search and date lastsearched.

4

Search 8 Present full electronic search strategy for at least 1database, including any limits used, such that it couldbe repeated.

Table S2

Study selection 9 State the process for selecting studies (ie, screening,eligibility, included in systematic review, and, ifapplicable, included in the meta-analysis).

5

Data collection process 10 Describe method of data extraction from reports (eg,piloted forms, independently, in duplicate) and anyprocesses for obtaining and confirming data frominvestigators.

5

Data items 11 List and define all variables for which data were sought(eg, PICOS, funding sources) and any assumptions andsimplifications made.

Table 1

(continued on next page )

JOE � Volume 45, Number 12, December 2019 Efficacy and Safety of Pulpal Anesthesia Strategies 1464.e1

SUPPLEMENTAL TABLE S1 - Continued

Section/topic Item no. Checklist item Reported on page no.

Geometry of the network S1 Describe methods used to explore the geometry of thetreatment network under study and potential biasesrelated to it. This should include how the evidence basehas been graphically summarized for presentation andwhat characteristics were compiled and used todescribe the evidence base to readers.

5-6

Risk of bias within individual studies 12 Describe methods used for assessing risk of bias ofindividual studies (including specification of whether thiswas done at the study or outcome level) and how thisinformation is to be used in any data synthesis.

5

Summary measures 13 State the principal summary measures (eg, risk ratio,difference in means). Also describe the use of additionalsummary measures assessed, such as treatmentrankings and surface under the cumulative rankingcurve (SUCRA) values, as well as modified approachesused to present summary findings from meta-analyses.

5-6

Planned methods of analysis 14 Describe the methods of handling data and combiningresults of studies for each network meta-analysis. Thisshould 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.

5-6

Assessment of inconsistency S2 Describe the statistical methods used to evaluate theagreement of direct and indirect evidence in thetreatment network(s) studied. Describe efforts taken toaddress its presence when found.

6

Risk of bias across studies 15 Specify any assessment of risk of bias that may affect thecumulative evidence (eg, publication bias, selectivereporting within studies).

5

Additional analyses 16 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 Bayesiananalyses (if applicable).

6

Results*Study selection 17 Give numbers of studies screened, assessed for eligibility,

and included in the review, with reasons for exclusionsat each stage, ideally with a flow diagram.

6, Figure 1

Presentation of network structure S3 Provide a network graph of the included studies to enablevisualization of the geometry of the treatment network.

Figure 2

Summary of network geometry S4 Provide a brief overview of characteristics of the treatmentnetwork. This may include commentary on theabundance of trials and randomized patients for thedifferent interventions and pairwise comparisons in thenetwork, gaps of evidence in the treatment network,and potential biases reflected by the network structure.

6-7

Study characteristics 18 For each study, present characteristics for which datawere extracted (eg, study size, PICOS, follow-upperiod) and provide the citations.

Table 1

Risk of bias within studies 19 Present data on risk of bias of each study and, if available,any outcome level assessment.

8, Figure 3A,B

Results of individual studies 20 For all outcomes considered (benefits or harms), present,for each study (1) simple summary data for eachintervention group and (2) effect estimates andconfidence intervals. Modified approaches may beneeded to deal with information from larger networks.

Table 1

(continued on next page )

1464.e2 Zanjir et al. JOE � Volume 45, Number 12, December 2019

SUPPLEMENTAL TABLE S1 - Continued

Section/topic Item no. Checklist item Reported on page no.

Synthesis of results 21 Present results of each meta-analysis done, includingconfidence/credible intervals. In larger networks,authors may focus on comparisons versus a particularcomparator (eg. placebo or standard care), with fullfindings presented in an appendix. League tables andforest plots may be considered to summarize pairwisecomparisons. If additional summary measures wereexplored (such as treatment rankings), these shouldalso be presented.

8, Table 2

Exploration for inconsistency S5 Describe results from investigations of inconsistency. Thismay include such information as measures of model fitto compare consistency and inconsistency models, Pvalues from statistical tests, or summary ofinconsistency estimates from different parts of thetreatment network.

8

Risk of bias across studies 22 Present results of any assessment of risk of bias acrossstudies for the evidence base being studied.

8

Results of additional analyses 23 Give results of additional analyses, if done (eg, sensitivityor subgroup analyses, meta-regression analyses,alternative network geometries studied, alternativechoice of prior distributions for Bayesian analyses, andso forth).

9

DiscussionSummary of evidence 24 Summarize the main findings, including the strength of

evidence for each main outcome; consider theirrelevance to key groups (eg, health care providers,users, and policy makers).

9-10

Limitations 25 Discuss limitations at study and outcome level (eg, risk ofbias), and at review level (eg, incomplete retrieval ofidentified research, reporting bias). Comment on thevalidity of the assumptions, such as transitivity andconsistency. Comment on any concerns regardingnetwork geometry (eg, avoidance of certaincomparisons).

11

Conclusions 26 Provide a general interpretation of the results in thecontext of other evidence and implications for futureresearch.

12

FundingFunding 27 Describe sources of funding for the systematic review and

other support (eg, supply of data) and role of funders forthe systematic review. This should also includeinformation regarding whether funding has beenreceived from manufacturers of treatments in thenetwork and/or whether some of the authors arecontent experts with professional conflicts of interestthat could affect use of treatments in the network.

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.

JOE � Volume 45, Number 12, December 2019 Efficacy and Safety of Pulpal Anesthesia Strategies 1464.e3

SUPPLEMENTAL TABLE S2 - Search Strategy of the Online Databases from Their Inception until February 23, 2018

Database Search strategy

Ovid MEDLINE: Epub Ahead ofPrint, In-Process &Other Non-Indexed Citations, OvidMEDLINE Daily and Ovid MEDLINE

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. dentalpulp diseases/ or pulpitis/ (n55145); 7. exp "Root Canal Therapy"/ (n519536); 8. "root canaltreatment*".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 or15 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)

Embase Classic 1 Embase 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. "rootcanal 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 or17 or 18 or 19 (n539658); 23. exp analgesic agent/ (n5844707); 24. 9 or 10 or 11 or 12 or 13 or 15or 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)

Cochrane 1. endodontic* (n52318); 2. pulpitis (n5325); 3. "irreversible pulpitis" (n5175); 4. "symptomaticirreversible pulpitis" (n539); 5. inflammation near/3 pulp (n519); 6. MeSH descriptor: [Dental PulpDiseases] 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 #10or #11 or #12 (n52835); 14. articaine (n5243); 15. bupivacaine (n59183); 16. lidocaine (n59229);17. mepivacaine (n5857); 18. prilocaine (n51092); 19. MeSH descriptor: [Bupivacaine] explode alltrees (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. "oralanalgesics" (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)

CINAHL 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 canaltreatment*" (n5169); 10. TX pulpectomy (n544); 11. MH Pulpectomy (n539); 12. S1 OR S2OR S3OR 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. TXprilocaine (n5269); 18. MH BUPIVACAINE (n51493); 19. MH lidocaine (n52521); 20. MHAnesthetics, Local (n53808); 21. TX "oral analgesics" (n5146); 22. MH Analgesics (n56518); 23.S13ORS14ORS15ORS16ORS17ORS18ORS19ORS20ORS21ORS22 (n513462); 24. TXefficacy (n590154); 25. S12 AND S23 AND S24 (n536); 26. TX effectiveness (n582776); 27. S24OR S26 (n5163895); 28. S12 AND S23 AND S27 (n542)

SCOPUS ( ( TITLE-ABS-KEY ( endodontic* ) OR TITLE-ABS-KEY ( pulpitis ) OR TITLE-ABS-KEY ( "irreversiblepulpitis" ) OR TITLE-ABS-KEY ( "symptomatic irreversible pulpitis" ) OR TITLE-ABS KEY ( pulp ANDinflammation ) OR TITLE-ABS-KEY ( "root canal treatment*" ) OR TITLE-ABS-KEY ( "root canaltherap*" ) OR TITLE-ABS-KEY ( pulpectom* ) ) ) AND ( ( TITLE-ABS-KEY ( articaine ) OR TITLE-ABS-KEY ( bupivacaine ) OR TITLE-ABS-KEY ( lidocaine ) OR TITLE-ABS-KEY ( mepivacaine ) OR TITLE-ABS-KEY ( prilocaine ) OR TITLE-ABS-KEY ( "local anaesthetic*" ) OR TITLE-ABS-KEY ( "localanesthetic*" ) OR TITLE-ABS-KEY ( "analgesi*" ) ) ) AND ( TITLE-ABS-KEY ( efficacy ) OR TITLE-ABS( effective* ) )

WHO ICTRP - 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 - DISORDERSOF TEETH AND JAW, ENDODONTIC INFLAMMATION, ENDODONTICINFLAMMATIONS, INFLAMMATION, ENDODONTIC, INFLAMMATIONS, ENDODONTIC,

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SUPPLEMENTAL TABLE S2 - Continued

Database Search strategy

PULPITIDES, pulpitis - PIPERIDINE, mepivacaine - 1-BUTYL-N-(2,6-DIMETHYLPHENYL)-2-PIPERIDINECARBOXAMIDE, bupivacaine - AGENTS, ANESTHETIC, ANAESTHESIA,ANAESTHETIC, ANAESTHETICS, ANESTHESIOL, ANESTHESIOLOGY, ANESTHESIOLOGY(FIELD), ANESTHETIC, ANESTHETIC (PRODUCT), ANESTHETIC (SUBSTANCE), ANESTHETICAGENT, ANESTHETIC AGENTS, ANESTHETIC DRUGS, ANESTHETIC, NOS, DRUGS CAUSINGLOSS OF SENSATION, DRUGS, ANESTHETIC, anesthetics - PROPITOCAINE, prilocaine - 2-(DIETHYLAMINO)-N-(2,6-DIMETHYLPHENYL) ACETAMIDE, 2-2ETN-2MEPHACN, INSULINNPH,LIGNOCAINE, lidocaine - ARTICAIN, CARTICAIN, articaine 25 records for 24 trials found!

PROQUEST pulpitis AND (efficacy OR effectiveness) AND (Anesthetics OR Lidocaine OR articling OR PrilocaineOR mepivacaine OR mupivacaine); 147 results.

JOE � Volume 45, Number 12, December 2019 Efficacy and Safety of Pulpal Anesthesia Strategies 1464.e5

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

Reasons for exclusion References

Commentaries 1. Abt E. Analgesic premedicationmay increase the success rate of localanesthetics for teeth with irreversible pulpitis. J Evid Based Dent Pract2011;11:141–142.

2. Nusstein JM. Preoperative oral use of ibuprofen or dexamethasonemay improve the anesthetic efficacy of an inferior alveolar nerve blockin patients diagnosed with irreversible pulpitis. J Evid Based DentPract 2013;13:102–103.

3. Parirokh M. Buffered lidocaine with sodium bicarbonate did notincrease inferior alveolar nerve block success rate in patients havingsymptomatic irreversible pulpitis. J Evid Based Dent Pract2016;16:59–61.

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

1. Anesthetic Efficacy of Gow-Gates Versus Conventional InferiorAlveolar Nerve Block Techniques (ClinicalTrials.gov Identifier:NCT01329874)

2. Effect of Sufentanil on the Rate of Anesthesia (ClinicalTrials.govIdentifier: NCT01572116)

3. Nermeen Awad Allah Abbas Ibrahim, Pre-operative Aceclofenac onthe Anesthetic Efficacy of IANB in Symptomatic Irreversible Pulpitis(ClinicalTrials.gov Identifier: NCT03146481)

4. Amatallah Hussein Nasser Al-Rawhani, Effect of PreoperativeDiclofenac Potassium on Articaine Buccal Infitration Success(ClinicalTrials.gov Identifier: NCT03174860)

No enough data to perform NMA 1. KanaaMD,Whitworth JM, Meechan JG. A comparison of the efficacyof 4% articaine with 1:100,000 epinephrine and 2% lidocaine with1:80,000 epinephrine in achieving pulpal anesthesia in maxillary teethwith 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. ActaOdontol Latinoam 2009;22:21–26.

3. Ramalho KM, de Souza LMP, Tortamano IP, AddeCA, Rocha RG, dePaula Eduardo C. A randomized placebo-blind study of the effect oflow power laser on pain caused by irreversible pulpitis. Lasers MedSci 2016;31:1899–1905.

4. Mellor AC, Dorman ML, Girdler NM. The use of an intra-oral injectionof ketorolac in the treatment of irreversible pulpitis. Int Endod J2005;38:789–794.

No endodontic treatment was performed 1. Axelsson S, Isacsson G. The efficacy of ropivacaine as a dental localanaesthetic. Swed Dent J 2004;28:85–91.

2. Batista da Silva C, Berto LA, Volpato MC, et al. Anesthetic efficacy ofarticaine and lidocaine for incisive/mental nerve block. J Endod2010;36:438–441.

3. Goodman A, Reader A, Nusstein J, et al. Anesthetic efficacy oflidocaine/meperidine for inferior alveolar nerve blocks. Anesth Prog2006;53:131–139.

4. Haas DA, Harper DG, Saso Ma, Young ER. Comparison of articaineand prilocaine anesthesia by infiltration in maxillary and mandibulararches. Anesth Prog 1990;37:230–237.

5. Haas DA, Harper DG, Saso MA, Young ER. Lack of differential effectby Ultracaine (articaine) and Citanest (prilocaine) in infiltrationanaesthesia. J Can Dent Assoc 1991;57:217–223.

6. Replogle K, Reader A, Nist R, et al. Anesthetic efficacy of theintraosseous injection of 2% lidocaine (1:100,000 epinephrine) and3% mepivacaine in mandibular first molars. Oral Surg Oral Med OralPathol Oral Radiol Endod 1997;83:30–37.

7. McCartney M, Reader A, Beck M. Injection pain of the inferior alveolarnerve block in patients with irreversible pulpitis. Oral Surg Oral MedOral Pathol Oral Radiol Endod 2007;104:571–575.

8. Mikesell P, Nusstein J, Reader A, BeckM,Weaver J. A comparison ofarticaine and lidocaine for inferior alveolar nerve blocks. J Endod2005;31:265–270.

9. Nagle D, Reader A, Beck M, Weaver J. Effect of systemic penicillin onpain in untreated irreversible pulpitis. Oral Surg Oral Med Oral PatholOral Radiol Endod 2000;90:636–640.

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Reasons for exclusion References

10. Ridenour S, Reader A, Beck M, Weaver J. Anesthetic efficacy of acombination of hyaluronidase and lidocaine with epinephrine.Anesth Prog 2001;48:9–15.

11. Saraf SP, Saraf PA, Kamatagi L, et al. A comparative evaluation ofanesthetic efficacy of articaine 4% and lidocaine 2% with anteriormiddle superior alveolar nerve block and infraorbital nerve block: Anin vivo study, Journal of conservative dentistry. J Conserv Dent2016;19:527–531.

12. Satish SV, Shetty KP, Kilaru K, Bhargavi P, Reddy ES, Bellutgi A.Comparative evaluation of the efficacy of 2% lidocaine containing1:200,000 epinephrine with and without hyaluronidase (75 IU) inpatients with irreversible pulpitis. J Endod 2013;39:1116–1168.

13. Stabile P, Reader A, Gallatin E, Beck M, Weaver J. Anestheticefficacy and heart rate effects of the intraosseous injection of 1.5%etidocaine (1:200,000 epinephrine) after an inferior alveolar nerveblock. Oral Surg Oral Med Oral Pathol Oral Radiol Endod2000;89:407–411.

14. Volpato MC, Ranali J, Ramacciato J C, et al. Anesthetic efficacy ofbupivacaine solutions in inferior alveolar nerve block. Anesth Prog2005;52:132–135.

Not randomized controlled trials 1. Ahmad ZH, Ravikumar H, Karale R, Preethanath RS, Sukumaran A.Study of the anesthetic efficacy of inferior alveolar nerve block usingarticaine in irreversible pulpitis. J Contemp Dent Pract 2014;15:71–74.

2. Argueta-Figueroa L, Arzate-Sosa G, Mendieta Zer�on H. Anestheticefficacy of articaine for inferior alveolar nerve blocks in patients withsymptomatic versus asymptomatic irreversible pulpitis. Gen Dent2012;60:e39–e43.

3. Bhuyan AC, Latha SS, Jain S, Kataki R. Anesthetic efficacy of thesupplemental X-tip intraosseous injection using 4% articaine with1:100,000 adrenaline in patients with irreversible pulpitis: an in vivostudy. J Conserv Dent 2014;17:522–525.

4. Bigby J, Reader A, Nusstein J, et al. Articaine for supplementalintraosseous anesthesia in patients with irreversible pulpitis. JEndod 2006;32:1044–1047.

5. Sakkir N, Naik KG, JayaramNK, Idris M. Intraosseous injection as anadjunct 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 ofintraligamentary injection techniques on mandibular molarsdiagnosed with asymptomatic irreversible pulpitis: a retrospectivestudy. Aust Endod J 2017;43:34–37.

7. Matthews R, Drum M, Reader A, Nusstein J, Beck M. Articaine forsupplemental buccal mandibular infiltration anesthesia in patientswith irreversible pulpitis when the inferior alveolar nerve block fails. JEndod 2009;35:343–346.

8. Nusstein J, Claffey E, Reader A, Beck M, Weaver J. Anestheticeffectiveness of the supplemental intraligamentary injection,administered with a computer-controlled local anesthetic deliverysystem, in patients with irreversible pulpitis. J Endod 2005;31:354–358.

9. Nusstein J, Kennedy S, Reader A, et al. Anesthetic efficacy of thesupplemental X-tip intraosseous injection in patients with irreversiblepulpitis. J Endod 2003;29:724–728.

10. Nusstein J, Reader A, Nist R, et al. Anesthetic efficacy of thesupplemental intraosseous injection of 2% lidocaine with 1:100,000epinephrine in irreversible pulpitis. J Endod 1998;24:487–491.

11. Parente SA, Anderson RW, Herman WW, et al. Anesthetic efficacyof the supplemental intraosseous injection for teeth with irreversiblepulpitis. J Endod 1998;24:826–828.

12. Walton R, Reisman D, Nist R, et al. Anesthetic efficacy of thesupplemental intraosseous injection of 3 % mepivacaine in

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SUPPLEMENTARY TABLE S3 - Continued

Reasons for exclusion References

irreversible pulpitis. Oral Surg Oral Med Oral Pathol Oral RadiolEndod 1997;84:676–682.

13. Subbiya A, Pradeepkumar AR, Vivekanandhan P, Karthick A.Comparative efficacy evaluation of articaine as buccal infiltration andlignocaine as IANB in the mandibular first molar with irreversiblepulpitis. Indian J Multidiscip Dent 2011;2:370–373.

14. Talati A, Bidar M, Sadeghi G, Nezami H. A comparative study oflidocaine and lidocaine-mannitol in anesthetizing human teeth withinflamed pulps. Int Endod J 2006;1:19–23.

15. Vangheluwe J, Walton R. Intrapulpal injection: factors related toeffectiveness. Oral Surg Oral Med Oral Pathol Oral Radiol Endod1997;83:38–40.

16. Verma PK, Srivastava R, Kumar MR. Anesthetic efficacy of X-tipintraosseous injection using 2% lidocaine with 1:80,000 epinephrinein patients with irreversible pulpitis after inferior alveolar nerve block:a clinical study. J Conserv Dent 2013;16:162–166.

17. Webster S Jr, Drum M, Reader A, et al. How effective issupplemental intraseptal anesthesia in patients with symptomaticirreversible pulpitis? J Endod 2016;42:1453–1457.

Retrospective studies 1. Fowler S, Drum M, Reader A, Beck M. Anesthetic success of aninferior alveolar nerve block and supplemental articaine buccalinfiltration for molars and premolars in patients with symptomaticirreversible pulpitis. J Endod 2016;42:390–392.

2. Fowler S, Reader A. Is a volume of 3.6 ml better than 1.8 ml forinferior alveolar nerve blocks in patients with symptomaticirreversible pulpitis? J Endod 2013;39:970–972.

Ongoing trials from clinicaltrials.gov and WHO ICTRP 1. Anesthetic Efficacy of 1,8mL and 3,6mL of Articaine in InferiorAlveolar Nerve Block in Irreversible Pulpitis (ClinicalTrials.govIdentifier: NCT02422823)

2. Comparison of Anesthetic Efficacy of Dexmedetomidine andEpinephrine With Lidocaine in Irreversible Pulpitis (ClinicalTrials.govIdentifier: NCT03415724)

3. Diclofenac Potassium on IANB Efficacy in Symptomatic IrreversiblePulpitis (ClinicalTrials.gov Identifier: NCT03163420)

4. Effect of Lidocaine With Magnesium Sulfate on the Success of theInferior Alveolar Nerve Block (ClinicalTrials.gov Identifier:NCT03262857)

5. Efficacy of Block Injection of an Anti-Inflammatory Medicine inPatients With Mandibular Dental Pain (ClinicalTrials.gov Identifier:NCT03410212)

6. Efficacy of Two Injection Techniques on Success Rate of InferiorAlveolar Nerve Anesthesia (ClinicalTrials.gov Identifier:NCT02543619)

7. Ketorolac Premedication for Anesthetic Efficiency of IANB &Postendodontic Pain in TeethWith Irreversible Pulpitis (ClinicalTrials.gov Identifier: NCT02940405)

8. Success of Inferior Alveolar Nerve Block in Women Taking SelectiveSerotonin Reuptake Inhibitors (ClinicalTrials.gov Identifier:NCT02884596)

9. Comparison of two anesthestic agents in irreversible pulpitis casesof upper first molar (WHO ICTRP main ID CTRI/2016/12/007610);

10. Painless Anesthesia for mandibular teeth (WHO ICTRP main IDCTRI/2016/12/007546)

11. Effect of Dexamethasone on the efficacy of anesthesia in painfulteeth (WHO ICTRP main ID CTRI/2017/05/008544)

12. 4% Articaine and 2% Lidocaine by Intraligamentary Technique inIrreversible Pulpitis (ClinicalTrials.gov Identifier: NCT02807298)

13. Evaluation of Anesthetic efficacy of injection technique in single visitroot canal therapy (WHO ICTRP main ID CTRI/2017/05/008632)

14. A clinical trial to study the effects of adding magnesium sulfate withlocal anesthetic injection on evaluating shooting tooth pain during

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Reasons for exclusion References

and after the treatment (WHO ICTRP main IDIRCT2015011020238N2)

15. Comparison of anesthetic efficacy of articaine in different anestheticadministration methods in the lower jaw molars (trial id:IRCT2014120820238N1)

16. Comparison of anesthetic efficacy of articaine in different anestheticadministration methods and volumes in maxillary first molars (WHOICTRP main ID IRCT2015011020238N)

17. Comparison of the anesthetic efficacy of Articaine 4% in twosupplemental anesthetic injections (WHO ICTRP main IDIRCT2015072023253N1)

18. The efficacy of three different anesthetic technique in mandibularmolars (WHO ICTRP main ID IRCT2015073023412N1)

19. Comparison of Articaine and Lidocaine as an anestheticsupplemental injection (WHO ICTRP main IDIRCT2015100523253N2)

20. Anesthetic efficacy of Articaine/Clonidine for inferior alveolar nerveblock in patients with irreversible pulpitis (WHO ICTRP main IDIRCT201706022541N6)

Results not binary 1. Shetkar P, Jadhav GR, Mittal P, et al. Comparative evaluation ofeffect of preoperative alprazolam and diclofenac potassium on thesuccess of inferior alveolar, Vazirani-Akinosi, and Gow-Gatestechniques for teeth with irreversible pulpitis: Randomized controlledtrial. J Conserv Dent 2016;19:390–395.

2. Sooraparaju SG, Abarajithan M, Sathish ES, et al. Anaestheticefficacy of topical benzocaine gel combined with hyaluronidase forsupplemental intrapulpal injection in teeth with irreversible pulpitis- adouble blinded clinical trial. J Clin Diagn Res 2015;9:ZC95–ZC7.

Results reported in another study 1. Rogers BS, Botero TM, Mcdonald NJ, et al. Efficacy of articaineversus lidocaine as a supplemental buccal infiltration in mandibularmolars with irreversible pulpitis: a prospective, randomized, double-blind study. J Endod 2014;40:753–758.

Single-arm studies 1. Abazarpoor R, Parirokh M, Nakhaee N, Abbott PV. A comparison ofdifferent volumes of articaine for inferior alveolar nerve block formolar teeth with symptomatic irreversible pulpitis. J Endod2015;41:1408–1411.

2. Aggarwal V, Singla M, Miglani S, Kohli S. Comparison of theanaesthetic efficacy of epinephrine concentrations (1 : 80,000 and 1: 200,000) in 2% lidocaine for inferior alveolar nerve block in patientswith symptomatic irreversible pulpitis: a randomized, double-blindclinical trial. Int Endod J 2014;47:373–379.

3. Aggarwal V, Singla M, Miglani S, et al. A prospective, randomizedsingle-blind evaluation of effect of injection speed on anestheticefficacy of inferior alveolar nerve block in patients with symptomaticirreversible pulpitis. J Endod 2012;38:1578–1580.

4. Aggarwal V, Singla M, Miglani S, et al. Comparative evaluation of 1.8mLand3.6mLof 2% lidocainewith 1:200,000 epinephrine for inferioralveolar nerveblock in patientswith irreversible pulpitis: a prospective,randomized single-blind study. J Endod 2012;38:753–756.

5. Aggarwal V, Singla M, Subbiya A, et al. Effect of preoperative pain oninferior alveolar nerve block. Anesth Prog 2015;62:135–139.

6. Kennedy S, Reader A, Nusstein J, et al. The significance of needledeflection in success of the inferior alveolar nerve block in patientswith irreversible pulpitis. J Endod. 2003;29(10):630–3.

7. Pereira LAP, Groppo FC, Bergamaschi Cde C, et al. Articaine (4%)with epinephrine (1:100,000 or 1:200,000) in intraosseous injectionsin symptomatic irreversible pulpitis of mandibular molars: anestheticefficacy and cardiovascular effects. Oral Surg Oral Med Oral PatholOral Radiol 2013;116:85–91.

8. Shadmehr E, Aminozarbian MG, Akhavan A, et al. Anaestheticefficacy of lidocaine/clonidine for inferior alveolar nerve block inpatients with irreversible pulpitis. Int Endod J 2017;50:531–539.

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SUPPLEMENTARY TABLE S3 - Continued

Reasons for exclusion References

Using pharmacologic agents that require mixing/extra preparation or itsuse is restricted to those who meet special qualifications

1. Akhlaghi NM, Hormozi B, Abbott PV, Khalilak Z. Efficacy of ketorolacbuccal infiltrations and inferior alveolar nerve blocks in patients withirreversible pulpitis: a prospective, double-blind, randomized clinicaltrial. J Endod 2016;42:691–695.

2. Bigby J, Reader A, Nusstein J, Beck M. Anesthetic efficacy oflidocaine/meperidine for inferior alveolar nerve blocks in patientswith irreversible pulpitis. J Endod 2007;33:7–10.

3. Jalali S, Majd NM, Torabi S, et al. The effect of acupuncture on thesuccess of inferior alveolar nerve block for teeth with symptomaticirreversible pulpitis: a triple-blind randomized clinical trial. J Endod2015;41:1397–1402.

4. Khademi AA, Saatchi M, Minaiyan M, et al. Effect of preoperativealprazolam on the success of inferior alveolar nerve block for teethwith irreversible pulpitis. J Endod 2012;38:1337–1339.

5. Kreimer T, Kiser Ii R, Reader A, et al. Anesthetic efficacy ofcombinations of 0.5 mol/L mannitol and lidocaine with epinephrinefor inferior alveolar nerve blocks in patients with symptomaticirreversible pulpitis. J Endod 2012;38:598–603.

6. Lindemann M, Reader A, Nusstein J, et al. Effect of sublingualtriazolam on the success of inferior alveolar nerve block in patientswith irreversible pulpitis. J Endod 2008;34:1167–1170.

7. Rodriguez-Wong L, Pozos-Guillen A, Silva-Herzog D, Chavarria-Bolanos D. Efficacy of mepivacaine-tramadol combination on thesuccess of inferior alveolar nerve blocks in patients withsymptomatic irreversible pulpitis: a randomized clinical trial. IntEndod J 2016;49:325–333.

8. Saatchi M, Khademi A, Baghaei B, Noormohammadi H. Effect ofsodium bicarbonate-buffered lidocaine on the success of inferioralveolar nerve block for teethwith symptomatic irreversible pulpitis: aprospective, randomized double-blind study. J Endod 2015;41:33–35.

9. Sakhaeimanesh V, Khazaei S, Kaviani N, et al. Anesthetic efficacy ofarticaine and ketamine for inferior alveolar nerve block insymptomatic irreversible pulpitis: a prospective randomized double-blind 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 inpatients 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 ofcombination of two percent lidocaine with 1: 80,000 epinephrineand 0.5 mol/l mannitol for inferior alveolar nerve blocks in patientswith symptomatic irreversible pulpitis: an in vivo study. Int Res JPharm 2013;4:161–163.

12. Shetty KP, Satish SV, Kilaru KR, et al. Comparison of anestheticefficacy between lidocaine with and without magnesium sulfate USP50% for inferior alveolar nerve blocks in patients with symptomaticirreversible pulpitis. J Endod 2015;41:431–433.

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Chapter 3

Efficacy and safety of post-operative medications in reducing pain following nonsurgical endodontic treatment: a systematic review and network meta-analysis

REVIEW ARTICLE

Efficacy and Safety ofPostoperative Medications inReducing Pain afterNonsurgical EndodonticTreatment: A SystematicReview and NetworkMeta-analysis

ABSTRACT

Introduction: The purpose of this study was to evaluate the efficacy and safety ofpostoperative medications in decreasing pain after nonsurgical endodontic treatment using anetwork meta-analytic approach. Methods: MEDLINE, Embase, CENTRAL, CINAHL, andScopus were searched (until July 31, 2019). Two reviewers selected eligible randomizedcontrolled trials and extracted and meta-analyzed data to estimate the treatment effects ofpain assessed on a 0–100 scale (mean difference [MD]); 95% credible interval [CrI], andsurface under the cumulative ranking curve [SUCRA]) at 6–8, 12, 24, and 48 hours post-operatively after the administration of various interventions. The Cochrane risk of bias tool wasapplied to eligible trials. The overall quality of evidence was assessed using the Grading ofRecommendations Assessment, Development and Evaluation approach obtained from theCINeMAWeb application (University of Bern, Bern, Switzerland).Results: Eight interventionsamong 11 studies were identified: nonsteroidal anti-inflammatory drugs (NSAIDs), NSAIDs1acetaminophen, NSAIDs 1 benzodiazepines, NSAIDs 1 opioids, corticosteroids, opioids,acetaminophen, and placebo. Compared with placebo, nonsurgical endodontic treatmentpain 6–8 hours postoperatively improved with NSAIDs 1 acetaminophen (MD 5 222; 95%CrI,238 to27.2; SUCRA5 73%; moderate confidence) and NSAIDs (MD5221; 95% CrI,234 to 27.6; SUCRA 5 68%; very low confidence). At 12 and 24 hours, only NSAIDs wereeffective in decreasing postoperative pain. At 48 hours, no treatment resulted in significantpain reduction. Corticosteroids and opioids did not significantly decrease pain. No majorsafety concerns were reported. Conclusions: Very low- to moderate-quality evidencesuggests that NSAIDs or NSAIDs 1 acetaminophen administered after nonsurgical end-odontic treatment lead to a clinically relevant decrease in postoperative pain for patients withirreversible pulpitis or pulpal necrosis and are the most effective treatments available. Post-operative corticosteroids or opioids did not significantly decrease postoperativepain. (J Endod 2020;46:1387–1402.)

KEY WORDS

Endodontic treatment; efficacy; oral medications; postoperative pain

Pain is a subjective unpleasant experience associated with tissue damage1. Dental pain is associatedwith a lower quality of life, with 27% of patients frequently reporting it2–4. Patients undergo nonsurgicalendodontic treatment to relieve pain of pulpal origin; yet, 21%–40%5,6 of patients report immediate

SIGNIFICANCE

Compared with placebo,postoperative NSAIDs, aloneor in combination withacetaminophen, areefficacious in decreasing painafter nonsurgical endodontictreatment for patients withirreversible pulpitis or pulpalnecrosis.

From the *Faculty of Dentistry,xDepartment of Pediatrics, Faculty ofMedicine, and {Clinical Epidemiology andHealth Care Research, Institute of HealthPolicy, Management and Evaluation,University of Toronto, Toronto, Ontario,Canada; †Faculty of Dentistry, New YorkUniversity, New York, New York;‡Department of Dentistry, SunnybrookSciences Health Centre, Toronto, Ontario,Canada; and Departments of kPediatricsand #Dentistry, Mount Sinai Hospital,Toronto, Ontario, Canada

Address requests for reprints to Dr AmirAzarpazhooh, 455–124 Edward Street,Toronto, ON M5G 1G6, Canada.E-mail address: amir.azarpazhooh@dentistry.utoronto.ca0099-2399/$ - see front matter

Copyright © 2020 American Associationof Endodontists.https://doi.org/10.1016/j.joen.2020.07.002

Maryam Zanjir, DDS,*

Adam Sgro, HBSc,†

Nima Laghapour Lighvan,HBSc,* Carilynne Yarascavitch,

BSc, DDS, MSc, DIP. ADBA,*‡

Prakesh S. Shah, MSc, MBBS,

MD, DCH, MRCP, FRCPC,xk{

Bruno R. da Costa, BScPT,

MScPT, MScMedStat, PhD,{

and Amir Azarpazhooh, DDS,

MSc, PhD, FRCD(C)*{#

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postoperative pain, whereas 7%7 reportpersistent pain of more than 6 months. Be itspontaneous or provoked by biting, palpation,or percussion7, this pain originates from theinflamed periapical tissues because ofchemical, mechanical, or microbial injury afterendodontic treatment 8. The presence ofpreoperative pain increases the incidence ofpostoperative pain9, which may be explainedby the prolonged and intense input of C-nociceptors resulting in central sensitization10.

Evidence from randomized controlledtrials (RCTs) is typically pooled in systematicreviews using pair-wise meta-analysis topreserve within-trial randomization, increasepower, and provide a more precise estimate ofthe treatment effect11. However, when acertain condition has more than 1 possibleintervention, performing multiple pair-wisemeta-analyses that compare only 2interventions at a time is of limited use fordecision making and does not allow forcoherent and transparent decisions12. Severalpharmacologic modalities for the treatment ofpostendodontic pain have been studied inRCTs13,14, including analgesics, nonsteroidalanti-inflammatory drugs (NSAIDs),corticosteroids, and opioids14,15. Availablesystematic reviews and pair-wise meta-analyses are inconclusive as to the superiorityof one approach over another because they failto rank the different classes of drugs and donot determine the most efficacious drug typebecause of their pair-wise design16–19.

Network meta-analysis (NMA) is ananalytical well-established method thathas been implemented in endodonticsresearch20–22. It is used to compare and rankany number of treatments for a particularcondition, as well as treatments that have notbeen investigated in RCTs, as long as there is acommon comparator across trials andproduces consistent estimates of the relativeeffects of all interventions23. NMA can be usefulin studies that report different treatment effectsor similar effects but different conclusions andcan be used to draw conclusions on the besttreatments possible12. According to anNMAbyNagendrababu et al22, only preoperativecorticosteroids offered a significant decrease inpostoperative pain after endodontic treatment,whereas NSAIDs were ranked as the leasteffective class of drugs. Their results conflictedwith a meta-analysis by Smith et al16 and anoverview of systematic reviews by Mooreet al18, who concluded that NSAIDs areeffective in reducing postoperative pain. Todate, nopreviousNMA investigated theeffect ofpostmedication on pain after endodontictreatment.

The purpose of this study was tosystematically review pharmacotherapeutic

agents used in the management ofpostoperative pain in patients who underwentnonsurgical initial endodontic treatment usinga network meta-analytic approach. Ourfocused question was as follows: “Amongadult patients who received nonsurgicalendodontic treatment, what is the mostefficacious and safe postoperative medicationto reduce postoperative pain?”

MATERIALS AND METHODS

The Preferred Reporting Items for SystematicReviews and Meta-Analyses extensionstatement for NMA was used to report ourmethodology and results24. The eligibilitycriteria were the following:

� Design: RCTs� Population: adults who had nonsurgicalendodontic treatment for any type ofpermanent tooth with any pulpal orperiapical diagnosis

� Interventions: any commonly usedpharmacologic intervention administeredpostoperatively for preventing or reducingpain after nonsurgical endodontictreatment in their recommendedtherapeutic dosage25, excluding antibioticsfor pain management because they contestcurrent standards for antibioticstewardship as per the American DentalAssociation (ADA), consistent with theAmerican Association of Endodontists(AAE), who recommends against usingantibiotics for dental painmanagement26,27.

� Outcomes

B Primary: pain after nonsurgicalendodontic treatment measured by anyform of verbal or visual analog scales.Studies were excluded if they did notinclude the primary outcome.

B Secondary: safety of the interventions,which was assessed qualitatively asreported in the included studies basedon adverse effects.

Search Methods for theIdentification of StudiesWe searched 5 major electronic databases:MEDLINE, Embase, Cochrane CENTRAL,CINAHL, and Scopus from inception until July31, 2019, for English language studiesavailable through the University of Toronto’slibraries (Supplemental Table S1 is availableonline at www.jendodon.com). We searchedfor completed and ongoing trials through theWorld Health Organization InternationalClinical Trials Registry Platform andClinicalTrials.gov trials registries andunpublished studies (or gray literature, such

as technical reports or dissertations) throughProQuest (Ann Arbor, MI), Google Scholar(Google, Mountain View, CA) (the first 100hits), and the OpenGrey database. Abstractsfrom the annual meetings of the AAE, theInternational Federation of EndodonticAssociation, and the European Society ofEndodontology were searched from inceptionuntil July 31, 2019. Reference lists of previousreviews in the same topic, included studies,and a major textbook10 were manuallysearched. We attempted to contact theauthors in case of missing information.

Study Selection and Data CollectionTwo authors (M.Z. and A.S.) independentlyreviewed selected trials from searches andextracted the data. Another review authorreviewed the selection of the trials and dataextraction (N.L.L.). Disagreements wereresolved through discussion and consensus orby consulting a fourth reviewer (A.A.). Anyreason for exclusion was reported(Supplemental Table S2 is available online atwww.jendodon.com). The information outlinedin Table 1 was extracted from each study toverify the inclusion criteria.

Risk of Bias AssessmentTwo authors (MZ and NLL) independentlyevaluated the risk of bias following theCochrane’s risk of bias assessment tool28

based on the reported information in thestudies in the following seven domains for eachstudy: random sequence generalization,allocation concealment, blinding of participantsand personnel, blinding of outcomeassessment, incomplete outcome data,selective reporting and other bias. Adetermination of ‘low risk’ was indicated if alldomains were judged as low bias risk;‘moderate risk’ if any domain was judged asunclear bias risk; ‘high risk’ if any domain wasjudged as high bias risk. Any study with unclearrisk of bias in the blinding of outcomeassessors was considered to be high bias risk.Disagreements were resolved by consulting athird reviewer (PS).

Data Synthesis and AnalysisThe data from the included studies wereentered into a standardized Excel (Microsoft,Redmond, WA) spreadsheet. The primaryoutcome was reported as mean values withassociated standard deviations (SDs). MissingSDs were calculated from the availableconfidence interval or standard error and thenumber of participants29. If only the mean wasreported, the SDwas imputed from the medianSD from all the interventions in the samenetwork. Data from figures were extracted

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TABLE 1 - The Characteristics of the Included Studies

ID

Author,year,

countryOral medication

(dose) Instructions

Age in years(mean ±SD/range)

Samplesize (male/female)

Preoperativepain level

(mean ± SD) Tooth type/diagnosisEvaluation

scaleOutcomemeasured Safety

Escapedrug

1 Baradaran,2014, Iran

Placebo Single dose immediatelyafter endodontictreatment

30.6667.26 (20–45)

15 (26/19) 8.2 6 1.01 Molars/symptomaticirreversible pulpitis

10-point VAS 6, 12, 24, 48,and 72 hours

— Twoacetaminophentablets(325 mg)

Ibuprofen (400 mg) 31.4664.4 (20–45)

15 7.6 6 0.99

Ibuprofen 1 alprazolam(400/0.5 mg)

29.1367.18 (20–45)

15 8.2 6 1.26

2 Doroschak,1999, US

Placebo 10 tablets every 6 h, theloading dose to betaken when thepatient reacheshome afterendodontictreatment

18–65 12 66.2 6 5 (SE) Symptomaticirreversible pulpitis orpulpal necrosis andapical diagnosis ofnormal apical tissues,acute apicalperiodontitis, oracute apical abscess

100-mm VAS 6, 24, and48 hours

1 patient had nausea,emesis, or dyspepsia;1 patient hadsedation, light-headedness,headache, oreuphoria; and 1patient hadxerostomia, "feltwarm," tachycardia,or “itchy"

Acetaminophen(650 mg)

Flurbiprofen (loadingdose 100 mg,subsequent 50 mg)

12 70.66 5 (SE) 3 patients haddyspepsia and 1 hadheadache

Tramadol (loading dose100 mg subsequent100 mg)

12 68.3 6 4 (SE) Sedation, nausea,emesis, andeuphoria, and 3patients had CNS/GIsymptoms; 3 hadxerostomia,tachycardia, oritchiness

Flurbiprofen 1 tramadol(loading dose 100 mgsubsequent 50/100mg)

13 70.2 6 5 (SE) GI/CNS includinginclude nausea,emesis, dyspepsia;sedation, light-headedness,headache, euphoria;xerostomia,tachycardia, anditchiness

3 Elzaki, 2016,Sudan

Placebo Single dose immediatelyafter endodontictreatment

33610.5 (18–65)

34 8 (median) Maxillary andmandibular anteriorsand premolars/symptomaticirreversible pulpitisand normal apicaltissues

Numericalratingscale 0–11

1, 2, 3, 4, 6,and 8 hours

— Ibuprofen(800 mg)Acetaminophen (1000

mg)34

Ibuprofen 1acetaminophen (600/1000 mg)

33

Mefenamic acid 1acetaminophen (500/1000 mg)

34

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TABLE 1 - Continued

ID

Author,year,

countryOral medication

(dose) Instructions

Age in years(mean ±SD/range)

Samplesize (male/female)

Preoperativepain level

(mean ± SD) Tooth type/diagnosisEvaluation

scaleOutcomemeasured Safety

Escapedrug

Diclofenac K 1acetaminophen (50/1000 mg)

35

4 Glassman,1989, US

Placebo Loading doseimmediately aftertreatment and 2every 4 h

— 18 — Asymptomaticirreversible pulpitis

100-mm VAS 8, 24, and48 hours

— —

Dexamethasone (4 mg) 19

5 Krasner,1986, US

Placebo 3 tablets immediatelyafter endodontictreatment then 4tablets each every 4 h

— 23 33.76 Not been previouslyendodonticallytreated with nopurulent drainage orclinical signs ofcellulitis

100-mm VAS 8 and24 hours

Dizziness, stomachupset, swelling of theface, and tachycardia

—

Dexamethasone (0.75mg)

25 33.47

6 Makkar,2011,India

Placebo Single dose immediatelyafter endodontictreatment

37.9 10 (6/4) 4.7 6 1.23 Anteriors andpremolars/symptomaticirreversible pulpitis

10-cm VAS 6, 12, and24 hours

— —

Ibuprofen 1acetaminophen (400/325 mg)

39.6 10 (7/3) 5.3 6 1.29

Diclofenac sodium 1acetaminophenl (50/500 mg)

41.3 10 (6/4) 5.5 6 1.54

7 Mehrvarzfar,2012, Iran

Placebo Single dose immediatelyafter endodontictreatment

31.4 6 10.7 24 (15/9) 5.6 6 2.24 Maxillary or mandibularanteriors andmandibular single-rooted teeth/symptomaticirreversible pulpitiswith normal apicaltissues

10-point VAS 6, 12, and24 hours

— —

Tramadol (100 mg) 29.5 66.9/20–60

24 (13/11) 5.1 6 2.249

Acetaminophen 1ibuprofen caffeineanhydrous (Novafen[Brown & Burk,Richmond, UK]) (325/200/40 mg)

29.6 68.1/20–60

23 (11/12) 5.8 6 2.814

Naproxen (500 mg) 28.4 67.6/20–60

24 (14/10) 5.8 6 2.24

8 Menhinick,2004, US

Placebo Single dose immediatelyafter endodontictreatment

42/24–-80 19 (8/11) 80 6 3.9 Maxillary andmandibular anteriors,premolars andmolars/symptomaticirreversible pulpitis orpulpal necrosis andapical diagnosis ofnormal apical tissuesor symptomaticapical periodontitis orasymptomatic apicalperiodontitis or acute

apical abscess

100-mm VAS First 8 hoursaftertreatments

4 GI symptoms (nausea,emesis), 10 CNSsymptoms(headache, dizziness,drowsiness)

8 acetaminophenand codeinephosphatetablets(300/30 mg)

Ibuprofen (600 mg) 40/21–61 20 (6/14) 69 6 3.8 1 GI symptoms (nausea,emesis), 6 symptoms(headache, dizziness,drowsiness), 3 othersymptoms (sweating,rash, wheezing,tightness in chest)

Ibuprofen 1acetaminophen (600/1000 mg)

35/19–58 18 (2/16) 81 6 4.2 1 GI symptom (nausea,emesis), 5 symptoms(headache, dizziness,drowsiness)

(continued on next page )

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TABLE 1 - Continued

ID

Author,year,

countryOral medication

(dose) Instructions

Age in years(mean ±SD/range)

Samplesize (male/female)

Preoperativepain level

(mean ± SD) Tooth type/diagnosisEvaluation

scaleOutcomemeasured Safety

Escapedrug

9 Ryan,2008, US

Placebo 1 capsule immediatelyafter treatment andthen 4 capsules every6 h for 24 hours

— 14 (8/6) 70.03 Symptomaticirreversible pulpitis orpulpal necrosis, andapical diagnosis ofnormal apical tissues,acute, apicalperiodontitis, oracute apical abscess

100-mm VAS 0, 6, 12,18, and 24hours aftertreatment

— —

Ibuprofen (600 mg) 15 (7/8) 68.04 —

Pentazocine 1naloxone (Talwin[Sanofi Winthrop,Morrisville, PA]) (50/0.5 mg)

14 (8/6) 73.64 1 or more of thefollowing: dizziness,light-headedness,sedation, nausea,and emesis

10 Salarpoor,2013, Iran

Placebo 1 capsule immediatelyafter treatment andthen 4 capsules every6 h for 24 hours

29 20 (6/14) 7.6 6 1.2 Single canals anteriorsand single premolars/symptomaticirreversible pulpitis

10-point VAS 6, 12, 24, and48 hours

4 reported nausea and 7reported headache

8 acetaminophencodeinetablets(300/10 mg)

Ibuprofen (400 mg) 31.33 19 (6/13) 6.4 6 1.9 1 reported nausea, 2reported headache,and 1 reportedsweating

Indomethacin (75 mg) 27.93 22 (7/15) 6.7 6 1.6 3 reported nausea and 2reported headache

11 Wells,2011, US

Ibuprofen (150 mg) 4 capsules every 6 hdaily as needed

34.36 14.0 36 (17/19) 130.1 6 23.8 Maxillary andmandibular molarsand premolars/symptomaticnecrotic teeth withperiapicalradiolucency of atleast 2 ! 2 mm

170Heft-ParkerVAS

0–5 days 6 required antibioticsbecause of thedevelopment ofsignificant facialswelling

hydrocodone/acetaminophen(5/500 mg)

Ibuprofen 1acetaminophen (150/250 mg)

37.3 6 14.7 35 (20/15) 118.3 6 22.3 1 required antibioticsbecause of thedevelopment ofsignificant facialswelling

CNS, central nervous system; GI, gastrointestinal; SE, standard error; VAS, visual analog scale.

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using the WebPlotDigitizer (Ankit Rohatgi,Pacifica, CA) Version 4.230.

A Bayesian NMA was performed undera hierarchical random effects framework andunified generalized linear model with a normallikelihood and identity link function31–33. Weused the program R (Version 3.5.0; R Projectfor Statistical Computing, Vienna, Austria) withthe gemtc version 0.8.2 and rjags packages,which interface with Just Another GibbsSampler software (Version 4.0.0, developed byMartyn Plummer) for Markov Chain MonteCarlo modeling. Treatment effects of theprimary outcome were estimated as meandifferences (MDs) with associated 95%credible intervals (CrIs) at 6–8 hours, 12, 24,and 48 hours. A 95% CrI is the interval withinwhich the underlying treatment effect isexpected to lie with 95% probability in a newtrial comparing a specific pair of treatments.From posterior probabilities, we calculated thesurface under the cumulative ranking curve(SUCRA) to simplify the information about theeffect of each treatment, rank its effectiveness,and identify the best treatment. SUCRA is asimple numerical summary that ranges from0% (when the treatment is certain to be worst)

to 100% (when the treatment is certain to bebest)34. Heterogeneity was assessed using theI2 statistic, and the node-splitting method wasused to calculate the inconsistency of themodel through the direct and indirect evidencewith its Bayesian P value35. The mostefficacious adjunctive treatments were thosewith higher SUCRA values and CrIs thatexcluded the null effect. CrIs that included thenull effect were considered irrelevant becauseof their imprecise treatment effect estimates.We conducted 2 sensitivity analyses. The firstexcluded studies that recruited patients withasymptomatic teeth because preoperativepain has a significant impact on postoperativepain9, and the second excluded high risk ofbias studies. We conducted a subgroupanalysis for patients who could not takeNSAIDs.

Quality of EvidenceTwo authors (M.Z. and N.L.L.) used theCINeMA web application (University of Bern,Bern, Switzerland)36 to judge the confidence inthe main results obtained from our NMAconsidering 6 domains: within- and across-

studies bias, indirectness, imprecision,heterogeneity, and incoherence. Each domainwas judged as having no concerns, majorconcerns, or minor concerns. The latter woulddowngrade the level of evidence. An overalljudgment of high, moderate, low, or very lowconfidence would be given to each result37.Consensus was reached by consulting a thirdreviewer (P.S.).

RESULTS

Search ResultsFrom the initial search of 969 records, 166duplicates were removed, and 758 recordswere excluded based on the title and abstractscreening. A total of 45 records were screenedin full text, and 11 RCTs met our inclusioncriteria (Fig. 1). There were 6 RCTs from theUnited States15,38–42, 3 from Iran14,43,44, and 1each from India45 and Sudan46.

Study CharacteristicsPopulationA total of 706 adult patients (18–68 years old)were included. Four trials did not specify theirpopulation’s mean age15,38,40,41 but

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

1392 Zanjir et al. JOE � Volume 46, Number 10, October 2020

mentioned they were treating permanent teeth(Table 1). Maxillary and mandibular teeth wereincluded. All trials were performed in auniversity setting, except for 1 in a privatepractice setting45 and another in bothuniversity and private practice settings 15.

Diagnosis was confirmed by thermaltests14,42,46, electric pulp tests14,42,44,45,radiographs15,42,44, and patientsymptoms14,15,40,42,44–47; 3 trials did not report

how they confirmed their diagnosis38,41,43, and1 mentioned confirmation of diagnosis byclinical and radiographic examination39.

Pulpal diagnoses included irreversiblepulpitis (symptomatic14,38–40,43–46 orasymptomatic15) and pulpal necrosis38–40,42,and periapical diagnoses included normalapical tissues14,38–40,46, apical periodontitis(symptomatic38–40,42 or asymptomatic39), andacute apical abscess38–40. One trial did not

report the pulpal diagnosis41, and 5 did notreport the apical diagnosis15,41,43–45. All trialsrecruited patients with moderate to severepreoperative pain, except 1 that recruitedasymptomatic patients15.

InterventionsThe oral medications administered wereclassified based on their pharmacologic

TABLE 2 - The Patients’ Mean Pain Levels in the Included Studies at 6, 12, 24, and 48 Hours Estimated as Mean Values with Standard Deviations (SDs) Based on a 100-mm VisualAnalog Scale

ID Study Intervention Sample size

6–8 hours 12 hours 24 hours 48 hours

Mean ± SD Mean ± SD Mean ± SD Mean ± SD

1 Baradaran, 2014 Placebo 15 38 6 17.4 36 6 22.9 15.8 6 9 1 6 1Ibuprofen (400 mg) 15 30.0 6 13.6 25.3 6 10.6 10.7 6 12.2 0.9 6 1.3Ibuprofen 1 alprazolam (400/0.5mg)

15 23.3 6 10.5 16 6 9.1 13.3 6 9 0.9 6 0.9

2 Doroschak, 1999 Placebo 12 43.5 6 13.5 — 26.3 6 19 9.9 6 20.1Flurbiprofen (loading dose 100 mg,subsequent 50 mg)

12 36.8 6 13.5 — 20.3 6 19 15.5 6 20.1

Tramadol (loading dose 100 mgsubsequent 100 mg)

12 35.5 6 13.5 — 33.9 6 19 21.9 6 20.1

Flurbiprofen 1 tramadol (loadingdose 100mg subsequent 50/100mg)

13 22.9 6 13.5 — 8.8 6 19 4.7 6 20.1

3 Elzaki, 2016 Placebo 34 24.8 6 13.5 — — —

Ibuprofen 1 acetaminophen (600/1000 mg)

33 12.2 6 13.5 — — —

Mefenamic acid 1 acetaminophen(500/1000 mg)

34 13.3 6 13.5 — — —

Acetaminophen (1000 mg) 34 27.8 6 13.5 — — —

Diclofenac K1 acetaminophen (50/1000 mg)

35 12.6 6 13.5 — — —

4 Glassman, 1989 Placebo 18 29.7 6 13.5 — 7.4 6 19 7.4 6 20.1Dexamethasone (4 mg) 19 25.1 6 13.5 — 1 6 19 0.8 6 20.1

5 Krasner, 1986 Placebo 23 37.9 6 13.5 — 28.5 6 19 —

Dexamethasone (0.75 mg) 25 13.7 6 13.5 — 5.6 6 19 —

6 Makkar, 2011 Placebo 10 13.5 6 7.5 5.5 6 7.8 0 6 19 —

Diclofenac 1 acetaminophen (50/500 mg)

10 5 6 7.5 0 6 11.7 0.5 6 1.2 —

Ibuprofen 1 acetaminophen (400/325 mg)

10 7 6 5.4 1 6 3.2 2 6 4.8 —

7 Mehrvarzfar, 2012 Placebo 24 48 6 33.7 37 6 15 32 6 16.2 —

Naproxen (500 mg) 24 8 6 11.2 5 6 5 7 6 10 —

Acetaminophen 1 ibuprofen 1caffeine anhydrous (Novafen),(325/200/40 mg)

23 6 6 9.8 7 6 12.2 4 6 8.6 —

Tramadol (100 mg) 24 32 6 27.5 21 6 15 22 6 23.7 —

8 Menhinick, 2004 Placebo 19 32 6 28.9 — — —

Ibuprofen (600 mg) 20 17 6 11.4 — — —

Ibuprofen 1 acetaminophen (600/1000 mg)

18 3 6 6.5 — — —

9 Ryan, 2008 Placebo 14 48.9 6 30.7 48.2 6 28.1 27.1 6 30.2 —

Ibuprofen (600 mg) 15 17.2 6 20.5 18.1 6 25.6 12.4 6 22.2 —

Pentazocine 1 naloxone (Talwin),(50/0.5 mg)

14 33.4 6 29.6 21.7 6 25.4 27.1 6 30.2 —

10 Salarpoor, 2013 Placebo 20 63 6 12.6 52 6 13.2 0 6 19 19 6 16.6Ibuprofen (400 mg) 19 33 6 13.4 13 6 11.2 36 6 16.3 0 6 20.1Indomethacin (75 mg) 22 13.1 6 13.9 2 6 4.5 0 6 19 0 6 20.1

11 Wells, 2011 Ibuprofen 1 acetaminophen (600/1000 mg)

35 — — 32.1 6 25.5 20.6 6 20.8

Ibuprofen (150 mg) 36 — — 36.9 6 29.6 18.1 6 24.2

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groups (Table 2). Eight were identified (Fig. 2A–D), including NSAIDs, corticosteroids, opioids,acetaminophen, placebo, NSAIDs 1

acetaminophen, NSAIDs 1 benzodiazepines,and NSAIDs 1 opioids.

Outcome AssessmentAll patients underwent nonsurgical endodontictreatment up until instrumentation orobturation (Table 1). Patients’ pain levels werereported as continuous values (mean and SD).The majority of the studies used a 100-mmvisual analog scale (Table 1). In studies inwhich different ranges of pain scales wereused, we converted the reportedmean and SDvalues to a 0–100 scale.

Risk of BiasFive studies were graded as low risk ofbias, 5 as moderate, and 1 as high risk(Fig. 3A). Overall, an unclear risk of biaswas found in the random sequencegeneration; allocation concealment; andblinding of patients, operators, andoutcome assessors (Fig. 3B).

Data SynthesisThe treatment effects for all the interventionswere estimated at 6–8, 12, 24, and 48hours after endodontic treatment (Table 3).The quality of evidence is summarized inTable 4. In comparison with placebo, theinterventions that ranked highest for efficacyin decreasing postoperative pain were asfollows:

� At 6–8 hours: NSAIDs 1 acetaminophen(MD 5 222; 95% CrI, 238 to 27.2;SUCRA5 73%; moderate confidence) andNSAIDs (MD 5 221; 95% CrI, 234 to27.6; SUCRA 5 68%; very lowconfidence)

� At 12 hours: NSAIDs (MD5228; 95% CrI,249 to 27; SUCRA 5 75%; very lowconfidence)

� At 24 hours: NSAIDs (MD5215; 95% CrI,227 to 22.3; SUCRA 5 65%; very lowconfidence)

Other interventions that did not result insignificant pain reduction after endodontictreatment were the following:

� 6–8 hours: opioids (MD 5 28.5; 95% CrI,227 to 9.8; SUCRA 5 33%; very lowconfidence), corticosteroids (MD 5 215;95% CrI, 237 to 8.4; SUCRA5 50%; verylow confidence), NSAIDs 1 opioids (MD 5

225; 95%CrI,254 to 3.1; SUCRA5 75%;very low confidence), NSAIDs 1

benzodiazepines (MD 5 221; 95% CrI,251 to 8.1; SUCRA 5 66%; very lowconfidence), and acetaminophen (MD 5

22.2; 95%CrI,231 to 26; SUCRA5 23%;low confidence)

� 12 hours: NSAIDs1 acetaminophen (MD5

219; 95% CrI,247 to 8.1; SUCRA5 51%;low confidence), opioids (MD5217; 95%CrI,246 to 10; SUCRA5 44%; very lowconfidence), and NSAIDs1benzodiazepines (MD5230; 95%CrI,268to 8.6; SUCRA5 74%; very low confidence)

� 24 hours: NSAIDs 1 acetaminophen (MD5 215; 95% CrI, 232 to 0.77; SUCRA 5

66%; moderate confidence), opioids (MD5 21.6; 95% CrI, 218 to 14; SUCRA 5

20%; low confidence), corticosteroids (MD5 215; 95% CrI, 235 to 5.1; SUCRA 5

FIGURE 2 – The network geometry of the different interventions used to decrease pain after nonsurgical endodontic treatment. Interventions compared at (A ) 6–8 hours, (B ) 12hours, (C ) 24 hours, and (D ) 48 hours. The black lines connect interventions that have been compared within a trial directly head-to-head. The thickness of the black lines representshow many trials compared the corresponding pair of interventions.

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63%; very low confidence), NSAIDs 1

opioids (MD5223; 95%CrI,248 to 0.98;SUCRA 5 66%; low confidence), andNSAIDs 1 benzodiazepines (MD 5 22.1;95% CrI, 227 to 22; SUCRA 5 49%; verylow confidence)

At 48 hours, all the interventions’ CrIsincluded the null effect; thus, no interventionresulted in significant pain reduction.

Supplemental Table S3 (availableonline at www.jendodon.com) summarizesthe relative treatment effects for all possible

comparisons at the different time pointsexpressed by MDs with 95% CrIs. Table 3summarizes the treatment effects of allinterventions compared with the placebo.Moderate to major heterogeneity andsome inconsistency, although not

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

JOE � Volume 46, Number 10, October 2020 Postoperative Medications in Reducing Postendodontic Pain 1395

TABLE 3 - The Relative Treatment Effects for All Interventions Compared with Placebo Expressed by the Mean Difference for Postoperative Pain with 95% Credible Intervals (CrIs) and Ranked Using Surface under the Cumulative Ranking Curve(SUCRA) Values

ID Intervention

6–8 hours 12 hours 24 hours 48 hours

SUCRA(%)

Meandifference(95% CrI)

SUCRA(%)

Meandifference(95% CrI)

SUCRA(%)

Meandifference(95% CrI)

SUCRA(%)

Meandifference(95% CrI)

Primary analysis1 NSAIDs 68 221 (234 to 27.6)* 75 228 (249 to 27)* 65 215 (227 to 22.3)* 57 24.1 (220 to 11)2 NSAIDs 1 acetaminophen 73 222 (238 to 27.2)* 51 219 (247 to 8.1) 66 215 (232 to 0.77) 48 21.7 (235 to 31)3 NSAIDs 1 benzodiazepines 66 221 (251 to 8.1) 74 230 (268 to 8.6) 39 27.1 (231 to 17) 49 22.1 (227 to 22)4 NSAIDs 1 opioids 75 225 (254 to 3.1) — — 66 223 (248 to 0.98) 73 210 (235 to 31)5 Corticosteroids 50 215 (237 to 8.4) — — 63 215 (235 to 5.1) 62 26.6 (234 to 21)6 Opioids 33 28.5 (227, 9.8) 44 217 (246 to 10) 20 21.6 (218 to 14) 22 7.2 (218 to 32)7 Acetaminophen 23 22.2 (231 to 26) — — — — — —

8 Placebo 12 — 5 — 13 — 39 —

Subgroup analysis exploring the efficacy of interventions for patients who cannot take NSAIDs1 Corticosteroids 79 215 (235 to 5.4) — — 89 215 (234 to 4.2) — —

2 Opioids 76 214 (231 to 4) — — 46 24.9 (220 to 13) — —

3 Acetaminophen 21 3.0 (224 to 30) — — — — — —

4 Placebo 24 — — — 15 — — —

First sensitivity analysis excluding studies that recruited patients with asymptomatic teeth1 NSAIDs 64 221 (235 to 27.1)* 75 228 (249 to 27)* 61 215 (227 to 22.1)* 61 24.1 (220 to 11)2 NSAIDs 1 acetaminophen 69 223 (239 to 27)* 51 219 (247 to 8.1) 62 215 (232 to 1.2) 49 21.8 (234 to 31)3 NSAIDs 1 benzodiazepines 63 221 (251 to 8.7) 74 230 (268 to 8.6) 37 27.1 (232 to 1.2) 51 22 (227 to 22)4 NSAIDs 1 opioids 72 225 (255 to 3.2) — — 80 224 (249 to 1.7) 76 210 (235 to 15)5 Corticosteroids 68 224 (257 to 8.5) — — 77 223 (25.1 to 5.3) — —

6 Opioids 31 28.4 (228 to 10) 44 217 (246 to 10) 20 21.6 (218 to 15) 22 7.1 (218 to 32)7 Acetaminophen 22 22.4 (232 to 27) — — — — — —

8 Placebo 11 — 5 — 13 — 41 —

Second sensitivity analysis excluding high risk of bias studies1 NSAIDs 74 223 (238 to 28.5)* 89 233 (258 to 28.8)* 67 218 (231 to 23.2)* 64 29.1 (228 to 13)2 NSAIDs 1 acetaminophen 75 223 (239 to 27.7)* 56 221 (249 to 7.1) 64 217 (234 to 20.20)* 54 26.7 (240 to 30)3 NSAIDs 1 benzodiazepines — — — — — — — —

4 NSAIDs 1 opioids 78 227 (256 to 2.1) — — 82 225 (252 to 2.0) 71 213 (240, 16)5 Corticosteroids 50 215 (238 to 9.1) — — 57 215 (236 to 6.2) 55 26.6 (236 to 23)6 Opioids 37 22.6 (232 to 27) 51 219 (249 to 8.8) 21 20.9 (223 to 21) 23 4.6 (223 to 34)7 Acetaminophen 26 22.6 (232 to 26) — — — — — —

8 Placebo 12 — 4 — 9 — 33 —

NSAIDs, nonsteroidal anti-inflammatory drugs.SUCRA estimates the surface under the cumulative ranking line for each treatment. It would be 100% when a treatment is certain to be the best and 0 when a treatment is certain to be the worst. A 95% credible interval is the interval within which theunderlying treatment effect is expected to lie with 95% probability in a new trial comparing a specific pair of treatments.*Statistical significance.

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statistically significant, were noted in theNMA results.

Sensitivity AnalysesIn the first sensitivity analysis, excluding studiesthat recruitedpatientswith asymptomatic teeth, 1study was excluded15, and the results confirmedthe findingsof theprimary analysis (Table3). In thesecondsensitivity analysis, excludingstudieswitha high risk of bias, only 1 study was excluded43,and the results also confirmed the findings of theprimary analysis, except at 24 hourspostoperatively, when a combination of NSAIDs1 acetaminophen also significantly reducedpostoperative pain (Table 3).

Subgroup AnalysisFor patients who could not take NSAIDs, nosignificant pain reduction was observed at 6–8and 24 hours postoperatively. Data at 12 and48 hours postoperatively were unavailable.

SafetySix studies included data on safety andreported that the interventions were safe withno major concerns (Table 1); 17.6% of patientstaking NSAIDs (flurbiprofen or ibuprofen) in 3studies38,39,44 reported headache ordrowsiness, and 9.9% suffered fromgastrointestinal symptoms including emesis ornausea.

DISCUSSION

In this systematic review and NMA, NSAIDs orNSAIDs 1 acetaminophen appear to be themost efficacious strategies in reducing painafter nonsurgical endodontic treatment inpatients with irreversible pulpitis or pulpalnecrosis. The quality of evidence ranged frommoderate to very low. No major safetyconcerns were reported in the includedstudies.

Our primary outcome was pain afternonsurgical endodontic treatment. Despite abroad search strategy, no eligible RCTs inwhich patients underwent nonsurgicalretreatment were found. Thus, all patients in

TABLE 4 - Confidence in the Top Interventions’ Effect Estimates Compared with Placebo Based on the Grading of Recommendations Assessment, Development and EvaluationApproach Obtained from the CINeMA Web Application

InterventionNumberof studies

Within-studybias

Across-studiesbias Indirectness Imprecision Heterogeneity Incoherence

Confidencerating

At 6–8 hoursNSAIDs 6 Major concerns Undetected No concerns No concerns Major concerns Major concerns Very lowNSAIDs 1

acetaminophen2 No concerns Undetected No concerns No concerns Major concerns Some concerns Moderate

NSAIDs 1benzodiazepines

1 Major concerns Undetected No concerns Major concerns No concerns Major concerns Very low

NSAIDs 1 opioids 1 Major concerns Undetected No concerns No concerns Major concerns Major concerns Very lowCorticosteroids 2 Major concerns Undetected No concerns Major concerns No concerns Major concerns Very lowOpioids 3 Major concerns Undetected No concerns Major concerns No concerns Major concerns Very lowAcetaminophen 1 No concerns Undetected No concerns Major concerns No concerns Major concerns Low

At 12 hoursNSAIDs 4 Major concerns Undetected No concerns No concerns Major concerns Major concerns Very lowNSAIDs 1

acetaminophen2 No concerns Undetected No concerns Major concerns No concerns Major concerns Low

NSAIDs 1benzodiazepines

1 Major concerns Undetected No concerns No concerns Major concerns Major concerns Very low

Opioids 2 Major concerns Undetected No concerns Major concerns No concerns Major concerns Very lowAt 24 hours

NSAIDs 5 Major concerns Undetected No concerns No concerns Major concerns Major concerns Very lowNSAIDs 1

acetaminophen2 Major concerns Undetected No concerns Major concerns No concerns No concerns Moderate

NSAIDs 1benzodiazepines

1 Major concerns Undetected No concerns Major concerns No concerns Major concerns Very low

NSAIDs 1 opioids 1 No concerns Undetected No concerns No concerns Major concerns Major concerns LowCorticosteroids 2 Major concerns Undetected No concerns Major concerns No concerns Major concerns Very lowOpioids 3 Major concerns Undetected No concerns Major concerns No concerns Some concerns Low

At 48 hoursNSAIDs 3 Major concerns Undetected No concerns Major concerns No concerns Major concerns Very lowNSAIDs 1

acetaminophen0 Major concerns Undetected No concerns Major concerns No concerns Major concerns Very low

NSAIDs 1benzodiazepines

1 Major concerns Undetected No concerns Major concerns No concerns Some concerns Low

NSAIDs 1 opioids 1 Major concerns Undetected No concerns Major concerns No concerns Major concerns Very lowCorticosteroids 1 Major concerns Undetected No concerns Major concerns No concerns Major concerns Very lowOpioids 1 Major concerns Undetected No concerns Major concerns No concerns Major concerns Very low

NSAIDs, nonsteroidal anti-inflammatory drugs.Grading of Recommendations Assessment, Development and EvaluationWorking Group grades of evidence: high confidence, we are very confident that the true effect lies close to that ofthe 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 possibilitythat 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 lowconfidence, we have very little confidence in the effect estimate (the true effect is likely to be substantially different from the estimate of effect).

JOE � Volume 46, Number 10, October 2020 Postoperative Medications in Reducing Postendodontic Pain 1397

our included population underwent initial rootcanal treatment.

Pain after nonsurgical endodontictreatment steadily decreased over time48

(Supplemental Fig. S1 is available online atwww.jendodon.com). At 6–8, 12, and 24hours, compared with preoperative pain,postoperative pain in patients taking placebodropped by 27%, 29%, and 66% respectively,and taking any type of medication dropped by68%, 79%, and 72% at 6–8, 12, and 24 hours,respectively. At 48 hours postoperatively, theaverage pain levels in all groups dropped by86%. This is consistent with systematic reviewfindings of Pak and White48 that mean painlevels drop more than 90% by day 7 regardlessof whether or not medications are used.Hence, the first few hours are the most criticaltime to manage pain after endodontictreatment.

Patients receiving NSAIDs 1

acetaminophen had significant postoperativepain reduction at 6–8 hours. Synergisticinteractions between NSAIDs (which inhibit thesynthesis and release of prostaglandins49,50)and acetaminophen (which reinforcesdescending inhibitory pain pathways51 result inmore analgesia52,53. Significant pain reductionwas not observed in the remaining time points(12, 24, and 48 hours) compared with the useof NSAIDs alone, except in the secondsensitivity analysis in which pain significantlydecreased at 24 hours. This suggests thatproper initial pain management may eliminatepain up to 24 hours, and after 24 hoursNSAIDs alone are sufficient to improvepatients’ symptoms. We could notrecommend a specific NSAID because therewere insufficient studies to explore the effectsof different doses and types. Ibuprofenremains the drug of choice because it is mostinvestigated and has a high safety profile; 200–400 mg ibuprofen is recommended for mildpain and 600–800 mg ibuprofen or 600 mgibuprofen 1 1000 mg acetaminophen formoderate to severe pain, without exceedingthe maximum daily dosage of 3200 mg foribuprofen and 90 mg/kg up to a total of 4000mg for acetaminophen54.

NSAIDs 1 opioids had no significantpostoperative pain reduction and should beavoided as a first-line therapy in patients ableto take NSAIDs. An increased prescription ofopioids has caused widespread misuse andrelated overdoses, accounting for .40% ofUnited States opioid overdose deaths in201655. The ADA states that dental careproviders should use nonnarcotics as the first-line therapy for acute dental pain56.

The subgroup analysis for patients whocould not take NSAIDs determined noalternative to significantly reduce pain (Table 3).

Tramadol 100 mg was the only opioidcompared, and no trial investigated theefficacy of acetaminophen 1 opioidspostoperatively. Until further studies areconducted, guidelines recommended byHargreaves and Abbott54 and Haas49 shouldbe followed, including the use ofacetaminophen for mild pain and opioids oracetaminophen 1 opioid for moderate tosevere pain.

Corticosteroids suppress inflammationand relieve pain57 by blocking the release ofmembrane phospholipids (ie, arachidonicacid), thereby reducing the biosynthesis ofboth cyclooxygenase and lipoxygenaseproducts, including prostaglandins,leukotrienes, and thromboxane-relatedsubstances58. Based on our results,corticosteroids had no effect on painreduction, contradicting the NMA byNagendrababu and colleagues22, whichreported that preoperative corticosteroidssignificantly reduced postoperative pain at 6,12, and 24 hours. This may be because of thesmall number of studies included, themoderate to very low quality of evidencegenerated, and the significant heterogeneity inthe direct evidence estimates. Two studies intheir NMA used interventions (gabapentin 600mg59 and piroxicam 40 mg60) exceeding themaximum recommended dosages25, and 1had an intervention (rofecoxib 50 mg61)withdrawn from the United States market in2004. The preoperative pain level was also notreported for the included population norexplored in a sensitivity analysis. Two meta-analyses by Shamszadeh et al62 and Nathet al63 also yielded contradictory results, likelybecause of the unrestricted corticosteroidadministration time or method compared withour limited inclusion guidelines topostoperative oral intervention. Thus, theyincluded 1862 and 963 compared with our 2corticosteroid studies. Shamszadeh et al62 didnot evaluate the quality of evidence generated,whereas Nath et al63 used Grading ofRecommendations Assessment, Developmentand Evaluation, and evidence ranged from lowto moderate. Additionally, neither explored theeffect of including studies judged to be of highrisk of bias on the outcome. Despitecorticosteroid use for pain relief with no majorside effects reported62–64, high doses andlonger durations can induce immunesuppression64. Corticosteroids could beconsidered adjunct to dental treatment whenno other anti-inflammatory medication hashelped, and there are no signs or possibility ofan infection developing56.

We identified 3 studies investigating theeffect of antibiotics on postoperative painmanagement65–67 and 1 administering

antibiotics to patients while investigating theeffects of liposomal bupivacaine on painmanagement68. Fouad et al66 includedpatients with pulpal necrosis and periapicalpain and/or localized swelling and randomizedthem into 3 groups (penicillin VK, placebo, andcontrol), yielding no significant difference for upto 72 hours. Henry et al65 also deduced thatpostoperative penicillin administration had nosignificant effect on pain or swelling. Both trialswere included in the ADA guidelines onantibiotic use for postoperative painmanagement27 and, in agreement with theAAE recommendations26, advocated againstantibiotic use for pain relief because the risks ofsuperinfections caused by antibiotic-resistantbacteria outweigh the benefits. Additionally,they recommend reserving antibiotic treatmentas an adjunct to nonsurgical endodontictreatment for immunocompetent adultssuffering from pain and swelling in cases ofpulpal necrosis and acute apical abscess withsystemic involvement or at high risk ofdeveloping systemic involvement and lackingimmediate access to care26,27.

Preoperative pain is considered astrong predictor for postoperativepain7,69,70. All included studies recruitedpatients with symptomatic irreversiblepulpitis or pulpal necrosis experiencingmoderate to severe preoperative pain,except 1 study that recruited asymptomaticirreversible pulpitis patients15. Our sensitivityanalysis, excluding this study, did not impactthe overall findings. Given the wide variety ofperiapical diagnoses in our includedpopulation and the fact that some includedstudies did not report their population’speriapical diagnosis or reported varyingperiapical diagnoses results in aggregate,we could not conduct further analysis toinvestigate the effect of periapical diagnosison the outcome.

This study included a robust searchstrategy and strict inclusion criteria, whichhelped us identify as much evidence aspossible, reduce publication and selectionbias, and meet the NMA assumption ofsimilarity29. Bibliographic databasesconsidered mandatory by the Cochranecollaboration29 and “gray literature” weresearched, and we attempted to contact theauthors of the included studies in case ofmissing information; this is of high importanceto enhance precision and reduce the impact ofreporting biases in the review29. No significantthreats from inconsistency and heterogeneitywere identified. Some study limitations includea relatively small number of studies comparedwith the number of interventions, resulting insome degree of imprecision in the treatmenteffects and estimated ranks; levels of evidence

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ranging frommoderate to very low, indicating apotential discrepancy between the estimatedand true effect; limited findings regarding thesafety of the included interventions; andassumed transitivity between interventions.Variations between interventions and baselinecharacteristics of the included populationcannot be ignored.

Future clinical trials should implementa low risk of bias approach in order toproduce strong recommendations and highquality of evidence. Failure to do so can leadto over- or underestimating the effect of theintervention. Our risk of bias assessment,following Cochrane’s approach (Fig. 3),estimated half of the included studies tohave an unclear risk of bias in the randomsequence generation and allocationconcealment domains because ofinadequate information reported. Additionally,as per Supplemental Table S2 (available

online at www.jendodon.com), some trialswere excluded because of inadequatereporting of the outcome measure, outcomedata, or sample size. Accordingly, to ensurea more precise assessment, it is highlyrecommended for investigators to report indetail the conduct and methods of their trialsand perhaps follow the ConsolidatedStandards of Reporting Trials statement,which is an evidence-based, minimum set ofrecommendations for reporting randomizedtrials71.

Given the current state of evidence,we believe there is no need for futurestudies to investigate therapies that lackefficacy such as opioids alone oracetaminophen alone in patients who cantake NSAIDs. The future well-designedRCTs should focus on the best approach tomanage pain for patients for whom NSAIDsare contraindicated.

CONCLUSION

Very low to moderate quality of evidencesuggests that postoperative medications usinga combination of NSAIDs1 acetaminophen orNSAIDs alone lead to a clinically relevantdecrease in postoperative pain afternonsurgical endodontic treatment for patientswith irreversible pulpitis or pulpal necrosis.

ACKNOWLEDGMENTS

The authors deny any conflicts of interestrelated to this study.

SUPPLEMENTARY MATERIAL

Supplementary material associated with thisarticle can be found in the online version atwww.jendodon.com (10.1016/j.joen.2020.07.002).

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66. Fouad AF, Rivera EM,Walton RE. Penicillin as a supplement in resolving the localized acute apicalabscess. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81:590–5.

67. Zarrabi MH, Ghaziani P, Salarpoor M. Clinical evaluation of various medication methods on theincidence of post-treatment endodontic pain in necrotic teeth. J Dent Sch 2007;25:174–81.

68. Glenn B, Drum M, Reader A, et al. Does liposomal bupivacaine (Exparel) significantly reducepostoperative pain/numbness in symptomatic teeth with a diagnosis of necrosis? A prospective,randomized, double-blind trial. J Endod 2016;42:1301–6.

69. Sadaf D, Ahmad MZ. Factors associated with postoperative pain in endodontic therapy. Int JBiomed Sci 2014;10:243–7.

70. Law AS, Nixdorf DR, Aguirre AM, et al. Predicting severe pain after root canal therapy in theNational Dental PBRN. J Dent Res 2015;94:37S–43S.

71. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updatedguidelines for reporting parallel group randomised trials. Int J Surg 2012;10:28–55.

1402 Zanjir et al. JOE � Volume 46, Number 10, October 2020

SUPPLEMENTAL FIGURE S1 – Patients’ average preoperative and postoperative pain levels at 6, 12, 24, and 48 hours based on a 100-mm visual analog scale.

JOE � Volume 46, Number 10, October 2020 Postoperative Medications in Reducing Postendodontic Pain 1402.e1

SUPPLEMENTAL TABLE S1 - The Search Strategy of the Online Databases from Their Inception until July 31, 2019

Database Search strategy

Ovid MEDLINE: Epub Ahead of Print,In-Process & OtherNon-Indexed Citations, Ovid MEDLINEDaily and Ovid MEDLINE

#1: "analgesic*".mp. or exp ANALGESICS/#2: Anti-Inflammatory Agents.mp. or exp Anti-Inflammatory Agents/#3: Anti-Bacterial Agents.mp. or exp Anti-Bacterial Agents/#4:"antibiotic*".mp. #5: exp Acetaminophen/#6: paracetamol.mp. #7: corticosteroids.mp. or expAdrenal Cortex Hormones/#8: "opioid*".mp. #9: "medication*".mp. #10: 1 or 2 or 3 or 4 or 5 or 6 or7 or 8 or 9 #11: "Root Canal Therap*".mp. or exp "Root Canal Therapy"/#12: "root endresection".mp. #13: Endodontics.mp. or exp ENDODONTICS/#14: apicoectomy.mp. or expAPICOECTOMY/#15: "pulpectomy".mp. or exp PULPECTOMY/#16: symptomatic irreversiblepulpitis.mp. #17: exp Dental Pulp Diseases/#18: 11 or 12 or 13 or 14 or 15 or 16 or 17 #19: expPAIN/#20: Pain Measurement.mp. or exp Pain Measurement/#21: Pain Management.mp. or expPain Management/#22: preoperative pain.mp. #23: postoperative pain.mp. or exp Pain,Postoperative/#24: 19 or 20 or 21 or 22 or 23 #25: 10 and 18 and 24

Embase Classic 1 Embase #1: "analgesic*".mp. or exp ANALGESICS/#2: Anti-Inflammatory Agents.mp. or exp Anti-Inflammatory Agents/#3: Anti-Bacterial Agents.mp. or exp Anti-Bacterial Agents/#4:"antibiotic*".mp. #5: exp Acetaminophen/#6: paracetamol.mp. #7: corticosteroids.mp. or expAdrenal Cortex Hormones/#8: "opioid*".mp. #9: "medication*".mp. #10: 1 or 2 or 3 or 4 or 5 or 6 or7 or 8 or 9 #11: "Root Canal Therap*".mp. or exp "Root Canal Therapy"/#12: "root endresection".mp. #13: Endodontics.mp. or exp ENDODONTICS/#14: apicoectomy.mp. or expAPICOECTOMY/#15: "pulpectomy".mp. or exp PULPECTOMY/#16: symptomatic irreversiblepulpitis.mp. #17: exp Dental Pulp Diseases/#18: 11 or 12 or 13 or 14 or 15 or 16 or 17 #19: expPAIN/#20: Pain Measurement.mp. or exp Pain Measurement/#21: Pain Management.mp. or expPain Management/#22: preoperative pain.mp. #23: postoperative pain.mp. or exp Pain,Postoperative/#24: 19 or 20 or 21 or 22 or 23 #25: 10 and 18 and 24

Cochrane #1: "analgesic*" #2: "anti-inflammatory agents" #3: "anti-bacterial agents" #4: "antibiotic*" #5:"acetaminophen" #6: "paracetamol" #7: "corticosteroids" #8: "opioid*" #9: "medication*" #10: #1OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 #11: "root canal therap*" #12: "root endresection" #13: "endodontics" #14: "apicoectomy" #15: "pulpectomy" #16: "symptomaticirreversible pulpitis" #17: "Dental Pulp Diseases" #18: #11 OR #12OR #13OR #14OR #15OR #16OR #17 #19: "pain" #20: "Pain Measurement" #21: "Pain Management" #22: "preoperative pain"#23: "postoperative pain" #24: #19 OR #20 OR #21 OR #22 OR #23 #25: #10 AND #18 AND #24

CINAHL (("analgesic*") OR ("anti-inflammatory agents") OR ("anti-bacterial agents") OR ("antibiotic*") OR("acetaminophen") OR ("paracetamol") OR ("corticosteroids") OR ("opioid*") OR ("medication*"))AND (("root canal therap*") OR ("root end resection") OR ("endodontics") OR ("apicoectomy") OR("pulpectomy") OR ("symptomatic irreversible pulpitis") OR ("Dental Pulp Diseases")) AND (("pain")OR ("Pain Measurement") OR ("Pain Management") OR ("preoperative pain") OR ("postoperativepain"))

Scopus (TITLE-ABS-KEY("analgesic*") OR TITLE-ABS-KEY("anti-inflammatory agents") OR TITLE-ABS-KEY("anti-bacterial agents") OR TITLE-ABS-KEY("antibiotic*") OR TITLE-ABS-KEY("acetaminophen") OR TITLE-ABS-KEY("paracetamol") OR TITLE-ABS-KEY("corticosteroids")OR TITLE-ABS-KEY("opioid*") OR TITLE-ABS-KEY("medication*")) AND (TITLE-ABS-KEY("rootcanal therap*") OR TITLE-ABS-KEY("root end resection") OR TITLE-ABS-KEY("endodontics") ORTITLE-ABS-KEY("apicoectomy") OR TITLE-ABS-KEY("pulpectomy") OR TITLE-ABS-KEY("symptomatic irreversible pulpitis") OR TITLE-ABS-KEY("Dental Pulp Diseases")) AND (TITLE-ABS-KEY("pain") OR TITLE-ABS-KEY("Pain Measurement") OR TITLE-ABS-KEY("PainManagement") OR TITLE-ABS-KEY("preoperative pain") OR TITLE-ABS-KEY("postoperativepain"))

World Health Organization InternationalClinical Trials Registry Platform

Title: - ; Condition: pulpitis OR pain; Intervention: root canal therapy OR root end resection ORapicoectomy OR pulpectomy

ProQuest (("analgesic*") OR ("anti-inflammatory agents") OR ("anti-bacterial agents") OR ("antibiotic*") OR("acetaminophen") OR ("paracetamol") OR ("corticosteroids") OR ("opioid*") OR ("medication*"))AND (("root canal therap*") OR ("root end resection") OR ("endodontics") OR ("apicoectomy") OR("pulpectomy") OR ("symptomatic irreversible pulpitis") OR ("Dental Pulp Diseases")) AND (("pain")OR ("Pain Measurement") OR ("Pain Management") OR ("preoperative pain") OR ("postoperativepain"))

ClinicalTrial.gov ("analgesics" OR "anti-inflammatory agents" OR "anti-bacterial agents" OR "antibiotic*" OR"corticosteroids") AND ("root canal therapy" OR "apicoectomy" OR "pulpectomy") AND ("pain")

1402.e2 Zanjir et al. JOE � Volume 46, Number 10, October 2020

SUPPLEMENTAL TABLE S2 - The Excluded Studies at the Full-text Stage with Reasons

Reasons for exclusion References

Population not randomized Negm MM. Management of endodonticpain with nonsteroidal anti-inflammatoryagents: a double-blind, placebo-controlled study. Oral SurgOral MedOralPathol 1989;67:88–95.

Sample size not reported; contactedauthors, no response

Nekoofar M, Sadeghipanah M, Dehpour A.Evaluation of meloxicam (a COX-2inhibitor) for management ofpostoperative endodontic pain: adouble-blind placebo-controlled study. JEndod 2003;29:634–637.

Administered intervention (intraoralmuscular injections) is notcommonly performed by the generaldentist

Liesinger A, Marshall FJ, Marshall JG. Effectof variable doses of dexamethasone onposttreatment endodontic pain. J Endod1993;19:35–39.

Utilized drug dosages beyond themaximum recommended

Fuller M, Younkin K, Drum M, et al.Postoperative pain management withoral methylprednisolone in symptomaticpatients with a pulpal diagnosis ofnecrosis: a prospective randomized,double-blind study. J Endod2018;44:1457–1461.

Mean values cannot be derived for eachgroup

TorabinejadM, Cymerman JJ, FranksonM,et al. Effectiveness of variousmedications on postoperative painfollowing complete instrumentation. JEndod 1994;20:345–354.

Outcome measure not defined Torabinejad M, Dorn SO, Eleazer PD, et al.Effectiveness of various medications onpostoperative pain following root canalobturation. J Endod. 1994;20:427–431.

Outcome data reported at different timepoints

Kusner G, Reader A, Beck FM, et al. Astudy comparing the effectiveness ofibuprofen (Motrin), Empirin with Codeine#3, and Synalgos-DC for the relief ofpostendodontic pain. J Endod1984;10:210–214.

Binary outcome Parirokh M, Sadr S, Nakhaee N, et al.Comparison between prescription ofregular or on-demand ibuprofen onpostoperative pain after single-visit rootcanal treatment of teeth with irreversiblepulpitis. J Endod 2014;40:151–154.

JOE � Volume 46, Number 10, October 2020 Postoperative Medications in Reducing Postendodontic Pain 1402.e3

SUPPLEMENTAL TABLE S3 - The Relative Treatment Effects of Postoperative Pain between Interventions for All Possible Comparisons Expressed by the Mean Differences with 95% Credible Intervals

Interventions compared at 6–8 hours

Corticosteroids — — — — — — —

6.10 (220.36, 32.98) NSAIDS — — — — — —

6.75 (230.45, 43.68) 0.56 (228.56, 29.38) NSAIDs 1 benzodiazepines — — — — —

10.83 (225.5, 47.39) 4.66 (223.75, 33.64) 4.08 (234.99, 44.23) NSAIDs 1 opioids — — — —

8.08 (219.48, 35.83) 1.9 (215.39, 19.21) 1.23 (230.73, 33.54) 22.81 (233.86, 27.99) NSAIDs 1 acetaminophen — — —

26.03 (235.51, 23.71) 212.14 (230.76, 6.35) 212.8 (245.78, 20.74) 216.83 (246.65, 13.15) 213.98 (235.78, 7.26) Opioids — —

212.32 (249, 25.14) 218.41 (249.19, 12.2) 219.07 (259.65, 21.81) 223.06 (263.09, 16.87) 220.26 (249.42, 8.26) 26.23 (239.72, 27.19) Acetaminophen —

214.48 (237.52, 8.42) 220.62 (234.03, 27.41)* 221.26 (250.29, 7.88) 225.28 (253.97, 3.04) 222.52 (238.08, 27.37)* 28.46 (227.16, 10.15) 22.18 (231.2, 26.65) Placebo

Interventions compared at 12 hours

NSAIDs — — — —

28.78 (239.21, 22.48) NSAIDs 1 acetaminophen — — —

1.68 (236.29, 38.57) 10.37 (235.58, 54.51) NSAIDs 1 benzodiazepines — —

211.24 (239.47, 18.08) 22.38 (236.12, 31.46) 212.89 (256.18, 32.97) Opioids —

227.99 (248.63, 26.82)* 219.31 (246.64, 8.2) 229.64 (266.64, 9.16) 216.74 (245.37, 11.03) Placebo

Interventions compared at 24 hours

Corticosteroids — — — — — —

20.17 (223.31, 22.92) NSAIDs — — — — —

27.72 (238.99, 23.77) 27.58 (231.66, 16.92) NSAIDs 1 benzodiazepines — — — —

8.71 (222.76, 40.74) 8.85 (215.63, 33.78) 16.38 (217.31, 50.13) NSAIDs 1 opioids — — —

0.42 (224.61, 26.49) 0.63 (215.77, 17.72) 8.15 (219.67, 36.21) 28.25 (236.07, 19.69) NSAIDs 1 acetaminophen — —

213.27 (238.23, 12.39) 213.04 (228.68, 3.12) 25.48 (233.08, 22.34) 221.88 (247.35, 3.6) 213.68 (233.43, 5.99) Opioids —

214.85 (234.23, 5.07) 214.64 (226.68, 22.28)* 27.07 (231.57, 16.98) 223.45 (248.58, 1.24) 215.18 (231.87, 0.65) 21.57 (217.68, 14.37) Placebo

Interventions compared at 48 hours

Corticosteroids — — — — — —

22.44 (233.71, 29.14) NSAIDs — — — — —

24.45 (240.62, 31.96) 22.03 (226.4, 22.36) NSAIDs 1 benzodiazepines — — — —

3.4 (233.56, 40.05) 5.88 (219.25, 30.81) 7.88 (225.6, 41.1) NSAIDs 1 opioids — — —

24.91 (247.15, 37.82) 22.44 (230.85, 26.26) 20.39 (237.58, 37.27) 28.37 (245.94, 30.4) NSAIDs 1 acetaminophen — —

213.74 (250.79, 22.96) 211.31 (236.7, 13.6) 29.3 (242.68, 23.96) 217.19 (244.62, 10.07) 28.9 (246.79, 28.4) Opioids —

26.6 (233.61, 20.13) 24.18 (220.1, 11.46) 22.11 (226.7, 21.95) 210.01 (234.83, 14.88) 21.62 (234.81, 30.68) 7.14 (217.74, 32.54) Placebo

NSAIDs, nonsteroidal anti-inflammatory drugs.This table contains estimated relative treatment effects and 95% credible intervals for all pair-wise comparisons. Estimates are for the column-defining intervention compared to the row-defining intervention (ie, the intervention in the row is the referenceintervention). For example, reading from the top left of the table, it is estimated that people taking corticosteroids have postoperative pain reduction estimated as a mean difference of 6.1 (220.36, 32.98) compared with people taking NSAIDs.*Statistical significance.

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Chapter 4

Discussion

Multiple interventions have been investigated in RCTs to manage pain during and following

endodontic treatment, and most were being compared to placebo or control. Having a common

intervention between these trials allows to indirectly compare all the interventions to one another

in order to estimate their relative treatment effects and rank them according to their efficacy.

Network meta-analysis synthesizes evidence by comparing interventions that were directly and

indirectly investigated in RCTs for a given condition; this aids in evidence-based clinical decision-

making (103). In both of our network meta-analyses, direct and indirect comparisons contributed

to the overall results, and a Bayesian model was adopted to incorporate heterogeneity between

trials for precise results that would assist clinicians to reach a sound clinical decision on the most

effective intervention.

To conduct NMA and produce valid results, we carefully examined three assumptions: transitivity,

coherence and homogeneity. Transitivity means whether it was equally likely that any patient in

the network could have been given any of the treatments in the network. While there is no statistical

test to check for or measure transitivity, our multi-disciplinary team of experts with knowledge in

endodontics, dental anesthesia, evidence-based Dentistry, clinical epidemiology and statistics

ensured practicing the best judgment for assessing comparability. Consequently, we had strict

inclusion criteria and only included RCTs measuring the same treatment effect. Since indirect

estimates are not protected by randomization and are impacted by effect modifiers, we included

only studies that were clinically and methodologically similar. In the first NMA, all the patients in

the included population were adults above the age of 18 years, had the diagnosis of symptomatic

irreversible pulpitis in a mandibular molar tooth and were undergoing nonsurgical endodontic

treatment. In the second NMA, all the patients in the included population were adults above the

age of 18 years, had the diagnosis of symptomatic irreversible pulpitis or symptomatic pulpal

necrosis with varying periapical diagnoses, and preoperative pain. To test for coherence, also

called inconsistency, we used the node splitting method and noted some inconsistency in the

network that was not significant. Heterogeneity was assessed using the I2 statistic. Although some

heterogeneity was found in our results, it was not statically significant. Hence, no major threats

from heterogeneity or inconsistency were found in our network.

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4.1 Summary of findings

Our first NMA identified supplemental intraosseous (IO) injections with 2% lidocaine or 4%

articaine and supplemental BI and LI using 4% articaine as the top-ranked interventions to achieve

successful pulpal anesthesia during endodontic treatment of permanent mandibular molars with

symptomatic irreversible pulpitis. Our second NMA identified NSAIDs alone or combined with

acetaminophen to be the most efficacious in reducing postoperative pain following nonsurgical

endodontic treatment in patients with irreversible pulpitis or necrotic teeth. The evidence level

generated from both NMAs ranged from very low to moderate based on GRADE. We did not

identify major safety concerns or side effects from these interventions.

4.2 Agreements and disagreements with other systematic reviews and meta-analyses or network meta-analyses

4.2.1 The efficacy and safety of pulpal anesthesia strategies during endodontic treatment

In line with previous meta-analyses (34-36) and NMA (40), our results demonstrated no significant

difference between 2% lidocaine and 4% articaine in achieving successful anesthesia when IANB

or supplemental BI or LI were administered during nonsurgical endodontic treatment for patients

with irreversible pulpitis. On the contrary, other meta-analyses reported that articaine was superior

in IANB (38, 104) or infiltration anesthesia (37, 38). This is probably due to the low number of

studies included and differences in patients’ characteristics. Kung et al (37) showed that articaine

was superior in supplementary BI by including three studies, no significant effect was observed

on IANB when 5 studies were included. Although de Geus et al included 17 studies, patients with

various preoperative pain (symptomatic and asymptomatic) and tooth types (molars and

premolars) were included, which could have impacted anesthetics’ efficacy. Su et al (38) did not

report the preoperative pain level for the included patients. Our results also confirmed

Nagendrababu et al (40) conclusion that only mepivacaine local anesthetics were superior for

IANB injection when compared with lidocaine but not significantly different from articaine,

prilocaine or bupivacaine in terms of efficacy.

Concerning injection techniques, significant increase in achieving successful anesthesia in patients

with symptomatic irreversible pulpitis undergoing endodontic treatment resulted when using both

supplemental IO using 2% lidocaine with 1:100,000 epinephrine or 4% articaine with 1:100,000

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epinephrine. This finding was novel since no previous NMA or MA compared the efficacy of IO

to IANB or other injection techniques. Other injection techniques yielding an increase in the

efficacy of pulpal anesthesia were supplemental BI and LI using 4% articaine with 1:100,000

epinephrine. Contrary to our findings, Corbella et al (34) found that administering BI using 4%

articaine with 1:100,000 epinephrine did not lead to successful anesthesia. However, they only

included two studies comparing BI to IANB. Furthermore, Tupyota et al (36) showed that BI and

LI using 2% articaine with 1:200,000 epinephrine may be effective in increasing the efficacy of

IANB injection while BI using various medications (4% articaine with 1:100,000 epinephrine, 30

mg of ketorolac tromethamine, 4 mg of dexamethasone) were insignificant. However, they did not

take into account investigating only similar medications in one analysis. Other injection techniques

(i.e. intraligamentary injection, gow-gates, and vazirani-akinosi) were not compared in previous

meta-analyses and based on our NMA results, only supplemental intraligamentary injection using

2% lidocaine or 4% articaine could lead to significant increase in achieving successful anesthesia

when compared to IANB.

In the event of IANB failure, we found that 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 result ties well with previous studies wherein suboptimal

success rates of 13%-54% for IANB using 2% lidocaine as a primary injection (11-14) or success

rates of 13% for repeating IANB as a supplemental injection (13, 14) were reported.

We verified previous findings that increasing anesthetic volume does not increase the efficacy of

achieving successful anesthesia (34, 105, 106). In our subgroup analysis, we compared the effect

of administering anesthetic volume up to 1.8ml versus more than 1.8ml and found no significant

difference. Nevertheless, our results were different from one meta-analysis (107) that concluded

increasing the volume of anesthetic solution from 1.8 to 3.6 ml improved the success. Possible

reasons for this disagreement are likely due to the number of studies included. Nagendrababu et al

included 4 trials whereas we 33 trials using 1.8 ml and 20 trials using 3.6 ml.

In accordance with previous studies (34, 36, 108-110), we found that premedication with NSAIDs

significantly increases the success of IANB success in achieving pulpal anesthesia. Our results go

beyond previous reports showing that premedication with NSAIDs, NSAIDs and acetaminophen,

and opioids up to 1 hour preoperatively may increase the efficacy of supplemental IO injections

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using 2% lidocaine or 4% articaine, supplemental BI and LI using 4% articaine or 2% lidocaine,

and IANB using 2% lidocaine or 4% articaine or 2% mepivacaine.

4.2.2 The efficacy and safety of post-operative medications in reducing pain following nonsurgical endodontic treatment

Pak et al (111) showed that mean pain levels drop by drop by half on day 1, and by more than 90%

by day 7 regardless of whether or not medications are used. Our results seem to confirm this

observation. In fact we found that pain following nonsurgical endodontic treatment steadily

decreased over time. In comparison to preoperative pain, postoperative pain in patients taking

placebo dropped by 27, 29 and 66% at 6-8, 12, and 24 hours respectively. On the contrary, in those

taking any type of medication pain dropped by 68, 79 and 72% at 6-8, 12, and 24 hours

respectively. At 48 hours postoperatively, average pain levels in all groups dropped by 86%.

Hence, it can be suggested that the first few hours are considered the most critical time to manage

pain following endodontic treatment.

Consistent with previous systematic reviews (71, 112) and meta-analyses (70, 72) we showed that

administering NSAIDs and NSAIDs+acetamninophen had a clinically relevant decrease in

postoperative pain following nonsurgical endodontic treatment. Based on our results,

administering NSAIDs+acetaminophen decreased pain at 6-8 hours postoperatively while

administering NSAIDs decreased postoperative pain up to 24 hours. This suggests that proper

initial pain management may be able to eliminate pain phenomena up to 24 hours, and that for

subsequent pain after 24 hours NSAIDs alone are sufficient to improve patients’ symptoms. This

finding was consistent with Smith et al (70) who showed that ibuprofen+acetaminophen were

effective in relieving pain at 6 hours postoperatively. In addition, Shirvani et al (72) concluded

that NSAIDS with or without acetaminophen were effective in relieving postoperative pain up to

24 hours.

On the other hand, we compared NSAIDs+benzodiazepines, NSAIDs+opioids, corticosteroids,

opioids, acetaminophen, and corticosteroids, and none could significantly decrease postoperative

pain when compared with placebo. Contrary to our findings, in an NMA investigating the efficacy

of preoperative medications to manage post-endodontic pain, Nagendrababu et al (73) concluded

that preoperative corticosteroids offered a significant decrease in postoperative pain following

nonsurgical endodontic treatment, whereas NSAIDs were ranked as the least effective class of

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drugs. Additionally, in another meta-analysis, Suneelkumar et al (113) reported that corticosteroids

were effective for the relief of postoperative endodontic pain. This may be due to the small number

of studies included in both, moderate to very low quality of evidence generated, and significant

heterogeneity assessed by the I2 statistic in the direct evidence estimates. Furthermore, the

preoperative pain level was not reported for the included NMA population (73) whereas we had

symptomatic patients with irreversible pulpitis or pulp necrosis. A similar conclusion was reached

by Shamszadeh et al (64) and Nath et al (65) stating that corticosteroids were effective in reducing

post-endodontic pain. It must be pointed out that they pooled RCTs with various administration

times (e.g., preoperative and postoperative) and routes that are not commonly used by the general

dental practitioner (e.g., intraligamentary, intracanal, intramuscular, supraperiosteal). This resulted

in the inclusion of a high number of studies that could have overestimated the treatment effect of

steroids, which may not be applicable to general dental practice. Moreover, neither explored the

effect of including studies judged to be of high risk of outcome bias.

4.3 Challenges

4.3.1 Risk of bias

To generate valid results and draw conclusions from NMA for decision making, it is important to

include studies with valid data and results. Therefore it is essential to assess the validity of the

trials included and ensure they are free of bias. In both our NMAs, we followed the Cochrane’s

risk of bias assessment tool to appraise the methodological quality of the included studies in which

includes seven domains: random sequence generalization, allocation concealment, blinding of

participants and personnel, blinding of outcome assessment, incomplete outcome data, selective

reporting and other bias. We had two review authors to assess each trial methodological quality

against this tool, and a third author to consult in case of disagreements. A determination of ‘low

risk’ was indicated for a study if all domains were judged as low bias risk; ‘moderate risk’ if any

domain was judged as unclear bias risk; ‘high risk’ if any domain was judged as high bias risk.

Furthermore, in the second NMA, any study with unclear risk of bias in the blinding of outcome

assessors was considered to be high bias risk.

In our first NMA, we included 46 RCTs where 23 trials were graded as low risk, 20 as moderate

risk, and three as high risk. In the second NMA, we included 11 RCTs where five studies were

graded as low risk of bias, five as moderate and one as high risk. Overall, moderate and high risk

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of bias in the judgment was found in the random sequence generation, allocation concealment and

blinding of patients and operators domains.

In both NMA’s primary analyses, we included all the studies with the various ROB judgments. To

explore the effect of high risk of bias studies on our results and conclusions and increase the

validity of our results, we performed a sensitivity analysis where we repeat the primary analysis

while excluding studies judged to have high ROB. The results of the sensitivity analysis in the first

NMA confirmed the findings of the primary analysis. While the second NMA also confirmed the

results primary analysis for all the treatments except for a combination of NSAIDs+acetaminophen

which emerged to be a significant treatment to reduce postoperative pain at 24 hours.

4.3.2 Quality of evidence

Application of NMA results requires understanding the quality of the evidence generated, in other

words, the degree of confidence or certainty we can place in estimates of treatment effects (114).

Patients and clinicians may prefer a lower ranked treatment with strong supporting evidence they

can trust over a higher ranked treatment with supporting evidence they cannot trust (114). To

evaluate the quality of evidence for the outcomes reported in both our NMAs, we used the

CINeMA web application (University of Bern, Bern, Switzerland) (115) which considers six

domains based on GRADE approach: within- and across-studies bias, indirectness, imprecision,

heterogeneity and incoherence. Each domain was judged as having no concerns, major or minor

concerns. The latter would downgrade the level of evidence. An overall judgment of either high,

moderate, low or very low confidence would be given to each result (101). For example, we would

judge the quality of evidence as high (that is, we can be confident that the true effect lies close to

that of the estimate of the effect). If all the included trials for a given comparison were at low risk

of bias; if all included populations, interventions, and outcomes are applicable to practice; if trials

show similar estimates of treatment effects; if the effect estimates from meta-analysis are precise

(for example, narrow 95% confidence interval); and if suspicion of publication bias is low (114).

Two review authors assessed each domain and a third review author was consulted in case of

disagreements.

The quality of evidence generated from our both NMAs ranged from moderate to very low. This

means we have moderate to very little confidence in the effect estimates, suggesting that there may

be potential discrepancy between the estimated and true effect.

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4.4 Outcome measure

Pain is a subjective sensory experience that is difficult to be quantified. No objective method has

been identified for measuring its intensity. Thus, the most valid and reliable approach to measure

pain is through patients’ reports and self-assessments, in which they rate their sensations on

different types of scales (116). To investigate pain during and following endodontic treatment,

unidimensional scales were adopted including visual analogue scales (VAS), categorical verbal

rating scales, and categorical numerical rating scales.

Categorical verbal rating scales are easy to use because they classify pain intensity into categories

such as “none, mild, moderate, and severe”. Categorical numerical rating scales use numbers, for

example 1 to 10, where 1 represents “no pain” and 10 “worst pain”. Both of these scales are simple

and validated to be used in assessing pain. Another more common scale used among most included

studies in both our NMAs was the visual analogue scale, which is a continuous scale that ranges

from 0 to 100mm, or 0 to 170mm. The accuracy of results obtained from any of these scales depend

on the proper instructions being given to patients, and ensuring they understand how to use them.

In the first NMA, the outcome was binary, reported as a success rate in which patients with no

pain or mild pain based on VAS were considered to have had successful anesthesia. The majority

of studies used Heft-Parker VAS of 170-mm where mild pain was considered when a reading from

0 to 54mm was reported indicating successful anesthesia. Other scales were 100mm VAS, 10cm

VAS, 4 points categorical scale and VAS without specifying categories. Two studies were

excluded for the outcome was not in binary format.

In the second NMA, the outcome was continuous, where the mean value with associated SD of the

VAS measurement were obtained per intervention. The majority of the studies used 100mm VAS.

In studies where different ranges of pain scales were used, we converted the reported mean and

SD values to 0-100 scale. One study was excluded because the outcome was in binary format.

4.5 Future clinical trials methodological and reporting quality

Future clinical trials should be of high methodological quality in order to produce strong

recommendations and high quality of evidence. Any flaw in the conduct or reporting of a clinical

trial may cause an overestimate or underestimate of the effect of an intervention. According to

Cochrane’s risk of bias tool, investigators should ensure they implement low risk of bias approach

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in every step while conducting a clinical trial. Starting with participants’ assignments, investigators

need to consider a random component when assigning participants to the intervention and

comparison groups to ensure balancing both known and unknown prognostic factors. This can be

best achieved by referring to a random number table (30) or using a computer random number

generator (11, 117). Next, investigators should maintain a concealed randomization to minimize

selection bias by either implementing central allocation (including telephone, web-based and

pharmacy-controlled randomization) (118); or sequentially numbering drug containers of identical

appearance (11, 30, 118); or sequentially numbering opaque, sealed envelopes (117, 119).

Following that, both the participants and operators need to be blinded to avoid performance bias,

and the outcome assessors need to be blinded while assessing the outcome to avoid detection bias

especially when the outcome is likely to be influenced by the lack of blinding (11). In studies

assessing the efficacy of injection techniques in achieving anesthesia during endodontic treatment,

having another person administering the injections to be different from the operator performing

endodontic treatment would blind the operator and the outcome assessor (11). In studies assessing

the different anesthetic solutions while administering the same injection technique, the operator

may be the outcome assessor with low risk of bias if the operator was blinded by masking the

anesthetic solutions (117, 118) or having a different person delivering anesthesia (120). In studies

assessing postoperative pain, operators may provide the patients with VAS to assess their pain

levels independently at the different time points following endodontic treatment and collect it in

the next appointment (119). Finally, all outcomes need to be reported whether they were

dichotomous or continuous, and any missing data need to be justified. Following all the above

steps results in a strong internal validity of a clinical trial and more confidence in the results

reported.

Investigators should also ensure transparency when reporting the conduct and methods of their

trials in order for the review authors to accurately judge the risk of bias when assessing the

methodological quality of each trial. This possibly can be achieved by following the CONSORT

Statement, which is an evidence-based, minimum set of recommendations for reporting

randomized trials (121). It offers a standard way for authors to prepare reports of trial findings,

facilitating their complete and transparent reporting, and aiding their critical appraisal and

interpretation. The CONSORT Statement comprises a 25-item checklist that focuses on reporting

how the trial was designed, analyzed, and interpreted; and a flow diagram that displays the progress

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of all participants through the trial. In our first NMA, out of 46 studies, 20 were judged to have

moderate risk of bias. While in our second NMA, out of 11 studies, five were judged to have

moderate risk of bias. The judgment of moderate risk was reached when we had unclear risk of

bias in any ROB domain, which is mainly due to insufficient information provided to make a

judgment of high or low risk of bias. As a result, the quality of evidence was impacted and our

confidence in the results ranged from moderate to very low.

We encourage future investigators studying pain during and following endodontic treatment to

report in detail the characteristics of their included population, such as sample size per group,

diagnosis, age, preoperative pain levels, drug types and dosages. This will allow further analyses

to be conducted to explore the effect of each characteristic on the outcome. Also, treatment effects

of the treatment or intervention being investigated need to be reported in the results section in a

format that allows it to be meta-analyzed; for continuous outcomes, the mean and standard

deviations must be reported per group and if not normally distributed then they must report median,

range and interquartile range. For binary outcomes, success or failure rates are required along with

correct denominator.

4.6 Strengths and limitations of our NMAs

We ran a robust search strategy that included major databases and grey literature. Our inclusion

criteria were strict to ensure the included population characteristics were as similar as possible in

order to meet NMA assumption of similarity and reduce selection bias. We identified no significant

threats from inconsistency and heterogeneity in both NMAs. Furthermore, we explored

heterogeneity by conducting subgroup analyses when applicable. Our sensitivity and subgroup

analyses were informative from the standpoint of the potential impact of covariates that might have

affected the outcome.

There are some potential limitations related to this study that need to be considered. To begin with,

the number of included studies was small in relation to the number of interventions compared.

This resulted in some degree of imprecision and uncertainty in the treatment effects and estimated

ranks. We had limited findings on safety of the included interventions. Additionally, we had to

group all the drugs under their pharmacological group due to the high number of interventions

available, and we could not run additional analyses to explore the efficacy of postoperative

medications based on the drug type or dosage due to the limited number of studies investigating

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each type. Therefore, we could not recommend a specific drug type or dosage and reported our

results based on the pharmacological group. Furthermore, we could not conduct further analyses

to investigate the effect of periapical diagnosis on the postoperative pain because the included

studies either did not report their population’s periapical diagnosis or reported varying periapical

diagnoses results in aggregate. Finally, we could not recommend any analgesic to reduce

postoperative pain in patients who could not take NSAIDs because we did not have enough studies

that investigated alternatives to NSAIDs.

4.7 Implications for clinical practice

In assessing the efficacy and safety of pulpal anesthesia strategies during endodontic treatment of

permanent mandibular molars with symptomatic irreversible pulpitis, we found IO injections with

2% lidocaine or 4% articaine and supplemental BI and LI using 4% articaine to be the top-ranked

interventions. In assessing the efficacy and safety of post-operative medications in reducing pain

following nonsurgical endodontic treatment, we found NSAIDs alone or combined with

acetaminophen to be the most efficacious in patients with symptomatic irreversible pulpitis or

necrotic teeth. These findings were supported by very low quality of evidence. Thus, no practice

recommendation can be made. The main reasoning is lack of direct evidence for most comparisons

and further high quality RCTs are needed. However, until further studies are available, clinicians

can choose to use supplemental IO using 2% lidocaine or supplemental BI and LI using 4%

articaine when the primary IANB injection fails in achieving successful anesthesia during

endodontic treatment of permanent mandibular molars with symptomatic irreversible pulpitis.

Postoperatively, clinicians can choose to administer NSAIDs alone or combined with

acetaminophen to reduce pain in patients with symptomatic irreversible pulpitis or necrotic teeth.

However, it is possible that some clinicians may not prefer that option.

4.8 Implications for future research

As per the findings of our first NMA, additional large and well-designed RCTs are needed to

further assess the efficacy and safety of IO interventions in patients with symptomatic irreversible

pulpitis undergoing endodontic treatment for mandibular molars. More trials are also needed to

explore the efficacy and safety of IANB or IO with mepivacaine for these patients.

101

Concerning our second NMA, future RCTs should focus on investigating the best approach to

managing postoperative pain for patients who cannot take NSAIDs. In addition, large and high

quality RCTs are needed to investigate NSAIDs and NSAIDs+acetaminophen ability to manage

postoperative pain at 6-8, 12 and 24 hours in order to elevate the quality of evidence. Moreover, a

larger NMA could be conducted comparing the efficacy of both preoperative and postoperative

medications in relieving postoperative pain following endodontic treatment. This would increase

the sample size and the number of interventions compared, which would increase precision and

the confidence of the results. With this larger data set, a subgroup analysis to explore the effect of

the time of drug administration (i.e., preoperative versus postoperative) may yield additional

insights on postoperative pain management.

Finally, NMA can provide clarity for clinicians when RCTs have heterogeneous methods or

conflicting results by combining the results of all the RCTs in a statistical model to identify the

best treatment and rank the remaining treatments according to their relative efficacy. Undertaking

NMA in these studies to compare multiple treatments demonstrates its potential for knowledge

translation. NMA is therefore useful in other areas in dentistry, especially where a given condition

has multiple treatments options. Nevertheless, NMA validity depends on the quality of included

studies, and caution should be exercised when interpreting NMA results and making conclusions

especially in the presence of heterogeneity or inconsistency in the network, or when small number

of studies or poor-quality studies are included. Thus, it is important to always assess the quality of

evidence before making conclusions based on NMA results and rankings.

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Chapter 5

Conclusion

This research was the first to use a novel statistical method, namely, NMA, to compare the most

efficacious strategies to achieve successful pulpal anesthesia for adult patients diagnosed with

symptomatic irreversible pulpitis in a mandibular molar tooth and undergoing endodontic

treatment, and to manage pain postoperatively. In our first NMA, we showed that supplemental

IO using 2% lidocaine with 1:100,000 epinephrine or 4% articaine with 1:100,000 epinephrine

followed by supplemental BI and LI using 4% articaine with 1:100,000 epinephrine are the most

efficacious interventions to achieve successful pulpal anesthesia during endodontic treatment of

mandibular molar with symptomatic irreversible pulpitis. In our second NMA, we showed that

postoperative medications using a combination of NSAIDs+acetaminophen or NSAIDs alone lead

to a clinically relevant decrease in postoperative pain following non-surgical endodontic treatment

for patients with irreversible pulpitis or pulpal necrosis. The level of evidence generated from both

our NMAs ranged from very low to moderate which means we have moderate to very little

confidence in the evidence generated, and further research is likely to have an important impact

on our confidence in the estimate of effect and may change the estimate.

103

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