ANESTHETIC EFFICACY OF 3.6 ML OF 4% ARTICAINE WITH 1:100,000 EPINEPHRINE COMPARED TO 1.8 ML OF 4% ARTICAINE WITH 1:100,000 EPINEPHRINE AS PRIMARY BUCCAL INFILTRATIONS IN MANDIBULAR POSTERIOR TEETH

A Thesis

Presented in Partial Fulfillment of the Requirements for

The Degree of Master of Science in the

Graduate School of The Ohio State University

By

Matthew Joshua Martin, D.D.S.

Graduate Program in Dentistry

The Ohio State University 2010

Master’s Examination Committee

Dr. John M. Nusstein, Advisor

Dr. Al Reader

Dr. Melissa Drum

Dr. F. Michael Beck

Copyright by

Matthew J. Martin

2010 ABSTRACT

The purpose of this prospective, randomized, single-blind study was to compare the anesthetic efficacy of 3.6 mL of 4% articaine with 1:100,000 epinephrine to 1.8 mL of 4% articaine with 1:100,000 epinephrine in mandibular buccal infiltration injections given next to the first molar. Using a cross-over design, 86 adult subjects (43 males and

43 females) randomly received two primary buccal mandibular infiltration injections given next to the first molar of 3.6 mL of 4% articaine with 1:100,000 epinephrine and

1.8 ml of 4% articaine with 1:100,000 epinephrine, in two separate appointments, spaced at least one week apart. The second molar through the first premolar were tested with an electric pulp tester every 3 minutes for a total of 90 minutes. The pain of injection and any postoperative discomfort over the next three days was rated by the subjects on a

Heft-Parker visual analogue scale.

Each test tooth had a higher percentage of 80/80 readings for each test time when the 3.6 mL volume was injected but not all differences reached statistical significance.

Anesthetic success was defined as two consecutive 80/80 readings at any point during the testing time. The incidence of anesthetic success was 65.1% and 48.8% of second molars,

75.6% and 52.3% of first molars, 92.9% and 87.1% of second premolars, and 91.9% and

81.4% of first premolars for Group 1 (3.6 mL volume) and Group 2 (1.8 mL volume), respectively: There was no statistically significant difference in anesthetic success

ii between Groups 1 and 2 for the second premolar (p=0.1797), but the second molar, first

molar, and first premolar were significantly different (p=0.0129, <0.0001, and =0.0234, respectively).

The incidence of anesthetic failure was 34.9% and 51.2% in the second molars,

24.4% and 47.7% in the first molars, 7.1% and 12.9% in the second premolars, and 8.1%

and 18.6% in the first premolars for Group 1 and Group 2, respectively. There was no

statistically significant difference between Groups 1 and 2 for the second premolar

(p=0.1797), but the second molar, first molar, and first premolar were significantly

different (p=0.0129, <0.0001, and =0.0234, respectively).

The percentages of short duration of anesthesia was significantly higher for

second molar, first molar, second premolar, and first premolar in Group 2 (1.8 mL

volume) compared to Group 1 (3.6 mL volume) (p=0.0215, 0.0068, <0.0001, and

=0.0001, respectively). There were no significant differences between Groups 1 and 2

for any of the four teeth tested for slow onset of anesthesia or for incidences of non-

continuous anesthesia.

There were no significant differences in pain ratings between the two volumes for

needle insertion, needle placement, or anesthetic deposition. The 3.6 mL volume had

significantly higher pain ratings at each post-operative period, but the average pain

ratings were still in the mild category.

In conclusion, the anesthetic efficacy of 3.6 mL of 4% articaine with 1:100,000

iii epinephrine was superior to 1.8 mL of 4% articaine with 1:100,000 epinephrine in a single primary mandibular buccal infiltration injection given next to the first molar.

iv

Dedicated to my parents Michael and Julie Martin. Your love and inspiration allowed me to chase my dreams. Without your support and sacrifice none of this would have been possible for me. I love you more than you could ever know and continue to miss you more with every passing day, Dad.

v

ACKNOWLEDGMENTS

I wish to specially thank my advisor, Dr. John Nusstein. Thank you for your hard work, dedication to teaching, and your guidance over the last two years. You are an incredible teacher and mentor, and your passion for endodontics, Ohio State, and your residents shows through in all of your teaching efforts. I will miss the slow afternoons that enabled us to talk about sports and life.

I thank Dr. Al Reader for your great humor and love of teaching. Your experience and dedication to our program is an integral part to the success of all who are fortunate enough to attend Ohio State. Thank you for teaching me about how to hire staff people (the elbow test), and for all of your support over the years. You are a huge part of the reason Ohio State Endo has the excellent, and well deserved, reputation it does.

I thank Dr. Melissa Drum for helping to teach me everything Endo. Your great personality and love of what you do made residency fun. I hope I’ve made Yoda proud with my endodontic knowledge and clinical skills. We need more people like you in education. I am relieved to know that you will continue the great tradition of OSU Endo for the decades to come.

I thank Dr. William Meyers for your amazing stories of every historical person in endodontics. Your wisdom, kindness, and dedication to teaching young dental students and residents is inspiring. I hope you continue to shape the minds of students for many more years to come.

I thank Dr. Michael Beck for your commitment and support. Thank you for making my life easier and taking the time to explain stats to me. Your continued dedication to the College of Dentistry and specifically the Division of Endodontics is appreciated more than you could ever know.

I thank my co-residents Sara Fowler, Kevin Wells, and Mike Simpson. You have become like a dysfunctional family to me over the last two years. I will cherish the time I spent with you for the rest of my life. I hope life continues to bring each of you everything you are searching for.

I thank all of the dental students who helped me complete my research including Jonathan Mason, Spencer Fullmer, Matt Balasco, Vivian Kaufman, and Josh Melton. Without your help I would still be pulp testing teeth.

vi VITA

February 28, 1982……………………….....Born – Peoria, Illinois

2004………………………………………..B.A. Psychology, University of Michigan

2008………………………………………..D.D.S., University of Michigan

2010……….……………………………….Specialization in Endodontics Post-Doctoral Certificate, The Ohio State University

FIELDS OF STUDY

Major Field: Dentistry

Specialization: Endodontics

vii TABLE OF CONTENTS

Page Abstract…………………………………………………………………………………....ii Dedication………………………………………………………………………………....v Acknowledgments………………………………………………………………………..vi Vita………………………………………………………………………………………vii

List of Tables……………………………………………………………………………...x List of Figures……………………………………………………………………………xii

Chapters:

1. Introduction……………………………………………………………………………..1

2. Literature Review………………………………………………………………………5 Mechanism of Action of Local Anesthetics……………………………………....5 Pharmacology of Local Anesthetics...... 8 Articaine...... 11 Safety of Articaine…………………………………...... ………17 Efficacy of Articaine……………………………………………………..32 Onset and Duration of Articaine…………………………………...... 49 Vasoconstrictors………………………………………………………………….53 Mandibular Buccal Infiltration Injection………………………………………..57 Effect of Volume on Anesthesia…………………………………………………65 The Electric Pulp Tester………………………………………………………….68 The Visual Analogue Scale………………………………………………………71

3. Materials and Methods………………………………………………………………...73

4. Results…………………………………………………………………………………80

5. Discussion of Materials and Methods...... 92

6. Discussion of Results...... 114 Subject Biographical Information………………………………………114 Sex Differences in Pain…………………………………………………115 Pain of Injection...... 118 Pain during needle insertion…………………………………….118 Pain during needle placement…………………………………...122

viii Pain during solution deposition…………………………………124 Anesthetic Efficacy…………………………...... 130 Frequency of Pulpal Anesthesia………………………………………...131 Anesthetic Success……………………………………………………...137 Anesthetic Failure……………………………………………………….149 Onset of Pulpal Anesthesia……………………………………………...152 Duration of Pulpal Anesthesia…..……………………………………...154 Slow Onset of Anesthesia, Short Duration of Anesthesia, and Non-continuous Anesthesia………………………………..157 Postoperative Pain………………………………………………………162

7. Summary and Conclusions…………………………………………………………..174

Appendices A. Tables…………………………………………………………...178 B. Figures…………………………………………………………..204 C. Biographical Data………………………………………………211 D. Medical History Form……..……………………………………213 E. Consent…………………………………………………………216 F. HIPAA………………………………………………………….223 G. Random code list………………………………………………..227 H. VAS form and raw VAS pain score data……………………….232 I. Electric pulp testing form and raw EPT data…………………...234

References…………………………………………………….………….……...…...…240

ix LIST OF TABLES

Table Page

1. Biographical data for all subjects…………………………………....………….179

2. Mean VAS values (mm) for infiltration injection………………………………180

3 Mean VAS values (mm) for infiltration by gender…………………………….181

4. Frequency of pain ratings for needle insertion……………………….………...182

5. Frequency of pain ratings for needle placement………………………………..183

6. Frequency of pain ratings for solution deposition……………………………...184

7. Between-solution comparisons of percent 80/80 for the second molar...... 185

8. Between-solution comparisons of percent 80/80 for the first molar…...... 186

9. Between-solution comparisons of percent 80/80 for the second premolar…….187

10. Between-solution comparisons of percent 80/80 for the first premolar…...... 188

11. Adjusted odds ratios for pulpal anesthesia…………………………………..….189

12. Anesthetic success by group and definition of success…..…………………….190

13. Anesthetic failure by tooth and group…………………………………………..191

14. Mean Onset of pulpal anesthesia by tooth and group…….…………………….192

15. Slow onset of anesthesia by group and by tooth………………………………..193

16. Short duration of anesthesia by group and by tooth……………………………194

17. Non-continuous anesthesia by group and by tooth……...……………………...195

18. Mean VAS values (mm) of postoperative discomfort ratings…………………196

x

19. Mean VAS values (mm) of post-op pain ratings by gender...... 197

20. Summary of pain ratings for Post-op Day 0…………………………………...198

21. Summary of pain ratings for Post-op Day 1……………………………………199

22. Summary of pain ratings for Post-op Day 2…………………………………...200

23. Summary of pain ratings for Post-op Day 3………………………………….. 201

24. Frequency of subject-reported postoperative complications by day…………...202

25. Postoperative complications associated with buccal infiltration injection……..203

xi LIST OF FIGURES

Figure Page

1. Mean pain ratings by group and stage of injection……….……….…...……….205

2. Second molar pulpal anesthesia by postinjection time…...….….……...………206

3. First molar pulpal anesthesia by postinjection time………….…………………207

4. Second premolar pulpal anesthesia by postinjection time….…………………..208

5. First premolar pulpal anesthesia by postinjection time……..…………………..209

6. Postoperative pain by group and period………………………………………...210

xii

CHAPTER 1

INTRODUCTION

Selected portions of the following have been adapted from previous theses by

McEntire (1) and Pabst (2) from the Division of Endodontics at The Ohio State

University College of Dentistry.

“Articaine [4-methyl-3 (2[propylamino] propionamido)-2 thiophenecarboxylic

acid, methyl ester hydrochloride] was first synthesized in 1969 by H. Rushing et al. (3) and was originally known as carticaine. The drug was approved in 1976 for use in both Germany and Switzerland and in 1984 had its name changed to articaine (3).

Approval for use was granted in Canada in 1983 and in the United Kingdom in 1998

(3). In 2000, the FDA approved the drug for use in the United States. The formulation that gained approval was a 4% solution which contained a 1:100,000

concentration of epinephrine. The formulation is known as Septocaine (Septodont,

Inc., New Castle, DE) and is now available as either a 4% solution with 1:100,000 epinephrine or a 4% solution with 1:200,000 epinephrine.

Successful anesthesia requires a local anesthetic that can produce a loss of sensation in a peripheral area into which it is injected or applied (4). The inferior alveolar nerve block is the most frequently used injection technique for achieving local anesthesia for mandibular restorative and surgical procedures. However, the inferior alveolar nerve block does not always result in successful pulpal anesthesia (5-22).

1 Clinical anesthetic studies in endodontics have found failure with the inferior alveolar

nerve block occurring between 38% and 81% of the time (19-21). Anesthetic failure

rates (a positive response when tested with an electric pulp tester) of 10% to 57% have

been reported in experimental studies (8,14,18,19,21-26).” (1)

Articaine has a reputation for providing improved local anesthetic efficacy.

Research has shown that buccal infiltrations of lidocaine and prilocaine solutions are not very effective for pulpal anesthesia in adult mandibular posterior teeth (27). However,

articaine has the clinical reputation of penetrating bone allowing successful pulpal

anesthesia of mandibular teeth. If this is indeed true, the practitioner could use this

injection routinely to anesthetize the mandibular teeth and avoid the lip numbness which

comes with an inferior alveolar nerve block. Articaine buccal infiltration injections may

also be useful as supplemental injections when the inferior alveolar nerve block fails to

achieve pulpal anesthesia.

“Kanaa et al. (28) compared the pulpal anesthesia produced by one cartridge of

2% lidocaine with 1:100,000 epinephrine to one cartridge of 4% articaine with 1:100,000

epinephrine for mandibular buccal infiltration injections. Success was defined as having

two consecutive negative readings with the electric pulp tester at any time during the 30-

minute testing period. Articaine had 64.5% success while lidocaine had only 38.7%

success in producing mandibular first molar anesthesia.” (1)

“Robertson et al. (29) has reported an increased success rate and faster onset time with an articaine solution, when compared to a lidocaine solution, when used for buccal

infiltration injections in mandibular posterior teeth. Anesthetic success (obtaining two

consecutive 80 readings during post-injection testing) for articaine and lidocaine were,

2 respectively, as follows: 75% and 45% of the second molars; 87% and 57% for the first

molars; 92% and 67% of the second premolars; and 86% and 61% of the first premolars.”

(1) These results were found to be significantly different (p<0.05) between the solutions

with each tooth type (29).

“Haase and co-workers (30) compared the degree of pulpal anesthesia obtained

with 4% articaine with 1:100,000 epinephrine and 2% lidocaine with 1:100,000

epinephrine in buccal infiltrations of the mandibular first molar following an inferior

alveolar nerve block. At each appointment all subjects received an inferior alveolar

nerve block of 1.8 mL of 4% articaine with 1:100,000 epinephrine. Then after 15

minutes, the subjects received a buccal infiltration injection of either 1.8 mL of 2%

lidocaine with 1:100,000 epinephrine or 1.8 mL of 4% articaine with 1:100,000 epinephrine. Anesthetic success for the first molar was 81% with articaine and 65% with

lidocaine. This difference was found to be significant (p=0.0075). Anesthetic success

was also generally greater with articaine for the second molar, second premolar, and first

premolar, however, the differences were not significant (30).” (1)

“Pabst (2) studied the anesthetic efficacy of a repeated infiltration injection of articaine given 25 minutes following a primary articaine infiltration injection in mandibular posterior teeth. The repeated infiltration of articaine increased the anesthetic

success (two consecutive 80 readings) from 69.8% to 84.9% in the second molar, from

66.3% to 83.7% in the first molar, from 78.8% to 97.7% in the second premolar and from

80.7% to 92.8% in the first premolar. A repeated injection of articaine significantly

(p<0.05) increased the anesthetic success for all teeth when compared to a repeated mock injection.” (1)

3 Nuzum (207) studied the anesthetic efficacy of a combination labial plus lingual infiltration compared to a labial infiltration in mandibular anterior teeth. This prospective, randomized, single-blinded study included eighty-two subjects that randomly received mandibular lateral incisor infiltrations, either a combination of labial and lingual (totaling 3.6 mL) or labial and mock (totaling 1.8 mL), utilizing 4% articaine with 1:100,000 epinephrine at two separate appointments spaced at least 1 week apart.

The labial plus lingual infiltration of articaine increased the anesthetic success (two consecutive 80 readings) from 76% to 98% in the mandibular lateral incisor, from 82% to

99% in the mandibular central incisor and from 74% to 93% for the mandibular canine.

The labial plus lingual infiltration injection of articaine significantly (p<0.05) increased the anesthetic success for all teeth when compared to a labial plus mock infiltration injection.

No objective study has addressed the addition of an additional volume of articaine to a primary infiltration injection over the mandibular first molar. Therefore, the purpose of this prospective, randomized, single-blinded study was to determine the anesthetic efficacy of an infiltration of a 3.6 mL volume of 4% articaine with 1:100,000 epinephrine in mandibular posterior teeth.

4

CHAPTER 2

LITERATURE REVIEW

Selected portions of the following have been adapted from previous theses by

McEntire (1) and Pabst (2) from the Division of Endodontics at The Ohio State

University College of Dentistry.

MECHANISM OF ACTION OF LOCAL ANESTHETICS

“The primary action of a local anesthetic is interference with the excitation- conduction process of nerve fibers and endings (31). A nerve fiber has the capability to respond to a stimulus by excitation and to propagate this stimulus along the nerve fiber to its point of termination (47). This conduction of the stimulus is temporarily interfered with by the action of the local anesthetic (31).

The electrophysiological properties of the neuronal membrane are a result of the permeability of the membrane to specific electrolytes, as well as the concentration of these electrolytes in the cytoplasmic and extracellular fluid (31). A nerve cell membrane is fully permeable to potassium and chloride ions in its resting state and relatively impermeable to proteins, amino acids, and sodium ions (31,32). As a result of this selective permeability, sodium and chloride ions are concentrated extracellularly.

5 Potassium ions and anions other than chloride are concentrated intracellularly. The permeability of the nerve cell membrane combines with the concentrations of cytoplasmic and extracellular electrolytes to determine the electrophysiologic properties of the nerve cell membrane. The electrochemical gradient between the inside and outside of the nerve membrane results in an electrical potential of approximately -70 to -90 mV across the cell membrane (48). Stimulating the nerve results in increased sodium permeability which is facilitated by a transitory widening of the transmembrane channels.

This widening allows sodium ions to rapidly diffuse to the interior of the cell resulting in depolarization of the neural cell membrane to a firing threshold of approximately -50 to

-60 mV. Upon reaching the firing threshold, sodium permeability increases markedly and a rapid influx of sodium ions occurs across the cell membrane. At the end of the depolarization phase, the electrical potential is actually reversed across the membrane to approximately +40 mV (4,31).

Once depolarization is complete, the permeability of the nerve membrane to sodium ions decreases and the high permeability to potassium is restored. This results in movement of sodium ions out, and potassium ions in, by passive diffusion, restoring the

normal resting potential of the nerve cell membrane. When the resting potential is

achieved, there is a relatively high concentration of sodium ions intracellularly and of

potassium ions extracellularly (48). The ‘sodium pump’ actively transports the excess

sodium ions out of the cell. This process is energy dependent. Adenosine triphosphate

(ATP) is oxidatively metabolized to provide the necessary energy (32,48). Once the

normal ionic gradient is restored, the nerve is again in its resting state. This

repolarization process takes approximately 0.7 msec. The nerve cell membrane’s normal

6 resting potential of approximately -90 mV is thereby restored (32).” (1)

“The exact mechanism of action of local anesthetics is unknown. The generally accepted theory is that they prevent depolarization by blocking the transmembrane sodium channels. This is believed to be accomplished by either of the following mechanisms: the specific receptor mechanism and/or the membrane expansion mechanism (31-34,49-51).

The specific receptor theory is based on four proposed binding sites within the sodium channel to which local anesthetic molecules can attach. Molecules may bind to the inner mouth of the channel pore resulting in a tonic block. Binding to a second site deeper within the pore will result in a use-dependent block (51). The other two proposed sites are located at the gate of the sodium channel and are related to the action of scorpion venom (33). Only the charged, or ionized, forms of the local anesthetic can bind to the first two sites, but this form is unable to cross the nerve membrane (31,49,51).” (1) “The nonionized, lipid-soluble local anesthetic molecules diffuse across the membrane and are present in high amounts inside the nerve initially. However, the molecules cannot exist only in this nonionized form at the intracellular pH of 7.4, and equilibrium is immediately established between the ionized and nonionized forms within the cell. Approximately

75% of the nonionized molecules are converted to the ionized form. It is this ionized form of the anesthetic molecule that is capable of binding to receptor sites on the sodium channel, thereby decreasing membrane permeability to sodium and preventing the propagation of action potentials (31,32,49).” (2)

“The alternative explanation of local anesthetic action is known as the membrane expansion theory. According to this theory, the anesthetic agent acts by penetrating the

7 nerve membrane, resulting in an expansion of the membrane and a decrease in the diameter of the sodium channel, thereby preventing sodium permeability (31,32,50).

This theory offers an explanation for the action of anesthetics such as benzocaine that do not exist in an ionized form (32).

Local anesthetics consist of an aromatic group (benzoic acid or aniline) with an ester or amide linkage to an intermediate hydrocarbon chain, and a secondary or tertiary amino group (31,34). The local anesthetic’s hydrophilic properties are due to the secondary or tertiary amino groups, while the lipophilic properties are derived from the aromatic residue which originates from benzoic acid or aniline (34). The ester or amide linkage between the aromatic residue and the intermediate carbon chain determines the anesthetic’s metabolism, allergenicity, and classification (31,51). Each compound’s anesthetic properties are dependent on its lipid solubility, protein binding capacity, pKa, pH, tissue diffusibility, and intrinsic vasodilating properties (31).” (1)

“The potency of the anesthetic compound is primarily determined by its ability to penetrate the nerve cell membrane, which is directly related to its lipid solubility. Highly lipid-soluble anesthetic compounds can easily penetrate the nerve membrane. Relatively lower concentrations are therefore efficacious (31,32,34). Lidocaine and articaine are considered to be of intermediate potency.

Duration of action is primarily determined by the local anesthetic’s protein- binding characteristics. The stronger the binding ability is, the longer the duration will be. Poor protein binding results in a short duration of anesthesia. Lidocaine and articaine are rated as having intermediate duration of action: two to four hours for maxillary infiltration injections and four to five hours for inferior alveolar nerve (IAN) block

8 injections (31,33).” (1)

“A chemical compound's pKa is defined as the pH at which the ionized and nonionized forms exist in equilibrium. The pKa is constant for each specific anesthetic molecule and ranges from a low for mepivacaine at 7.6 to a high for procaine at 9.1

(31,32,34,35). Lidocaine has a pKa of 7.9, and articaine has a pKa of 7.8. Anesthetic onset time is strongly related to the pKa. It is the nonionized form of the drug that penetrates the neuronal membrane (31). At a tissue pH of 7.4, 2-40% of an anesthetic

will exist in the nonionized form, depending on the anesthetic’s pKa. The lower the pKa

value and the closer it gets to the pH of the injected tissues, the faster the onset time because a larger portion of the particles will be in the nonionized form and can easily penetrate the nerve membrane. Lidocaine and articaine have relatively fast clinical onset times (from one to three minutes for maxillary infiltration injections and one to four minutes for IAN block injections) because their pKa’s are close to the pH of the injected tissue (31,33,36).

Anesthetic compounds can only act on nerve membranes after they diffuse through non-nervous tissue to reach the nerve. Tissue diffusibility has a direct relationship to the rate of onset. Despite their importance, the factors that determine the rate of diffusibility through non-nervous tissues are poorly understood (31).” (1)

“Vasodilator activity of anesthetic compounds influences their potency and duration. Increased blood flow caused by vasodilation results in quicker removal of the anesthetic compound from the injection site, thereby decreasing the amount available to act upon the nerve. With the exception of cocaine, all local anesthetic agents have vasodilator properties (48).” (1) “Both lidocaine and articaine are potent vasodilators and

9 would be ineffective and more toxic if given as plain solutions (32). Therefore, in order to improve duration and safety, a vasoconstrictor such as epinephrine is added to the anesthetic cartridges. In contrast, other anesthetics, such as prilocaine, are less potent and can be given safely as plain solutions.

Local anesthetic compounds exist in cartridges in the form of hydrochloride salt solutions (31,48). These preparations have a pH of 4.5 to 6.0 (4). Not only does such a low pH improve water solubility, but stability of the local anesthetic is also increased.

Epinephrine and other vasoconstrictors become progressively unstable as pH increases; therefore, solutions with vasoconstrictors are required to have a pH in the range of 3.3 to

5.5 (52). Within this range, vasoconstrictor concentration will be within USP regulated levels for up to a year, whereas solutions with a pH much higher than this will deteriorate in several hours (52). Therefore, this pH is most optimal for storage. Because the compounds have pKa values greater than these pH values, most of the solutions are in the ionized form. Once injected, however, fluid buffers of the surrounding tissues quickly neutralize the acidic local anesthetic solution. This increases the pH of the anesthetic solution and increases the amount of free base (nonionized) anesthetic available to diffuse through the nerve sheath (31,32).” (2)

“Various instances of local anesthetic toxicity have been reported. The earliest and most common response to a local anesthetic overdose is central nervous system excitation. Initially, a feeling of light-headedness or dizziness occurs. Auditory and visual disturbances may also be noted. The patient may become disoriented and develop slurred speech, tremors, muscle twitching and generalized convulsions. Generalized central nervous system depression follows, with loss of consciousness and respiratory

10 arrest. At even higher doses, the cardiovascular depressant effects of local anesthetics, such as decreased myocardial contractility, decreased peripheral resistance, hypotension, and circulatory collapse, will also result (53).” (1)

ARTICAINE

“Carticaine [4-methyl-3(2[propylamino] propionamido)-2 thiophenecarboxylic acid, methyl ester hydrochloride] was first synthesized in 1969 by Rushing et al. when experimenting with thiophene derivatives (3). The drug was approved for use in both

Germany and Switzerland in 1976 and had its name changed from carticaine to articaine in 1984 (3). Approval for use was granted in Canada in 1983 and in the United Kingdom in 1998 (3). In Germany, articaine accounts for 90% of all local anesthetics used (54). In

Canada, a 1993 survey showed that articaine was the most frequently used local anesthetic, accounting for almost 38% of all dental injections (55). In Canada, a 2007 survey showed that articaine accounted for 44.2% of all dental injections (209). Pogrel reported that articaine sales accounted for approximately 25% of the U.S. market in 2003

(208). Malamed estimated that articaine accounted for 26% of the U.S. market in 2005

(211).

Articaine’s action is similar to that of other currently available local anesthetics.

Like other amide local anesthetics (e.g. lidocaine), articaine blocks sodium and potassium channels in the nerve membrane to such an extent that the nerve resting membrane potential cannot reach the electrical threshold needed to fire an action potential (56).

This prevents the nerve from sending a signal to the brain (57). The epinephrine in dental cartridges produces localized vasoconstriction which slows absorption of the articaine.

11 This ensures prolonged maintenance of an active tissue concentration of the anesthetic

while minimizing the systemic absorption of both active compounds (56).” (1)

“In 2000, the Food and Drug Administration (FDA) approved articaine for use in

the United States. The articaine formulation that gained approval in the United States was a 4% solution which contained a 1:100,000 concentration of epinephrine. The formulation is known as Septocaine (Septodont, Inc., New Castle DE). Septocaine is distributed in a 1.7 mL dental cartridge and contains many components with specific functions: articaine hydrochloride 40 mg/mL as the local anesthetic, epinephrine tartrate

0.018 mg/mL for vasoconstriction, sodium chloride 1.6 mg/mL for isotonicity, sodium metabisulphite 0.5 mg/mL as an antioxidant for the vasoconstrictor, and distilled water

1.0 mL volume for injection (3). Sodium chloride is added to the cartridge to make the solution isotonic with the tissues of the body and sterile water is added to the cartridge to

provide the correct volume of solution. A small bubble of nitrogen gas is also included in the cartridge during manufacturing to prevent oxygen from being trapped in the cartridge and potentially destroying the vasoconstrictor (32).” (1) “Sodium metabisulfate is a chemical added as an antioxidant whenever a vasoconstrictor is present, including articaine preparations. People allergic to bisulfites (most often steroid-dependent asthmatics) may develop allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes (68). Sodium metabisulfate is not present in dental anesthetics without a vasoconstrictor. The overall prevalence of sulfite sensitivity in the general population is unknown.” (1) “Original articaine formulations contained a bacteriostatic agent, an antifungal agent, and methylparaben as an antioxidant preservative for the local anesthetic. Methylparaben has a high potential for allergenicity

12 and it was not until 1994 that methylparaben was removed from articaine formulations

sold in Canada. A similar methylparaben-free formula is sold in the United States (58).”

(1)

“Berlin (69) reported that although the 4% articaine with 1:100,000 epinephrine

solution is supplied in a cartridge labeled 1.7 mL, the volume is 1.8 mL. Weaver (67)

also acknowledged that articaine anesthetic cartridges actually contain 1.8 mL of

solution. The FDA requires the manufacturer to indicate the solution as a 1.7 mL

cartridge because some anesthetic cartridges were found to occasionally contain slightly

less than 1.8 mL of solution (67). Therefore, the apparent difference in anesthetic volume between the two solutions is very likely not different at all.” (1)

“Articaine has been available since 1984 in Europe and Canada in two formulations: 4% articaine with 1:100,000 epinephrine and 4% articaine with 1:200,000

epinephrine. Articaine is now available in the United States with 1:200,000 epinephrine.

The basic ingredients are the same, but the higher concentration of epinephrine in the

1:100,000 epinephrine formulation may provide a longer duration of analgesia (75

minutes vs. 45 minutes with the 1:200,000 epinephrine formulations) (32).” (2) Several

studies have recently shown no differences in anesthetic efficacy, onset, or duration

between the two formulations (44-46).

“Articaine is classified as an amide, similar to lidocaine and all other local

anesthetics currently available in dentistry. Articaine has a molecular weight of 320.84

and has an intermediate chain with a trivalent bonded nitrogen attached to a carboxylic

acid (3). Articaine, however, differs from all other amide local anesthetics in that it is

derived from thiophene. Therefore, the molecule does not contain a benzene ring as do

13 other amide local anesthetics but instead contains a thiophene ring (3). A second

molecular difference between articaine and other amide local anesthetics is the extra ester

linkage incorporated into the articaine molecule (3).

Borchard et al. (59) studied the action of local anesthetics on myelinated nerve

fibers. He stated that a lower concentration of the thiophene derivative (articaine) was

sufficient to block an action potential, compared to benzene derivatives (all other amide

anesthetics).” (1)

“Degradation of articaine is initiated primarly in the plasma by plasma esterase

hydrolysis of the carboxylic acid and ester groups to yield free carboxylic acid (56,60).

A small amount is also metabolized in the liver by hepatic microsomal enzymes.

Articainic acid is the primary metabolite (60).” (2) “Additional metabolites including

articainic acid glucoronide have been detected in animal studies (3). In contrast to

lidocaine, which has known active metabolites, it is unclear whether articainic acid has

biologic activity (3). This is important because an active metabolite may cause toxicity

and may lead to undesirable side-effects (3). Van Oss et al. (61) administered articainic

acid intravenously to a single volunteer to determine the clinical effects and

pharmacokinetics of the major metabolite of articaine. They found no change in

electrocardiography, blood pressure, or heart rate in this subject. Though the study had only one subject, it provided evidence that the metabolite may be inactive, unlike the metabolites found after breakdown of lidocaine. The other metabolite, articainic acid glucoronide, also appears to be inactive (3).” (1)

“High performance liquid chromatography has been used to determine the concentrations of articaine and its metabolite articainic acid in the serum. Oertel and

14 Rahn (62) studied the clinical pharmacokinetics of articaine and found that the maximum drug concentration of articaine is reached about 10 to 15 minutes after submucosal injection of an 80 mg, 4% articaine solution, irrespective of the addition of epinephrine.

They also found the mean maximum plasma drug concentration to be about 400 μg/L for articaine with 1:200,000 epinephrine, and 580 μg/L for articaine without epinephrine.

Oertel and Rahn (62) concluded that the rapid breakdown of articaine to its inactive metabolite articainic acid results in a very low systemic toxicity, giving articaine a wide therapeutic range. They also concluded that articaine can be safely administered using repeated doses because the use of articaine in higher doses is safer than other amide-type local anesthetics (62). Isen et al. (3) also concluded that re-injection with articaine is safe after 30 minutes should the patient require additional local anesthetic, since the majority of the initial dose would already be metabolized. If more lidocaine were administered 30 minutes after the first injection, it would be additive to the first dose because its half-life is 3 times longer than articaine.” (1)

“Biotransformation of articaine occurs in both the plasma (hydrolysis by plasma cholinesterase) and the liver (hepatic microsomal enzymes) (56). It has been shown that a higher percentage of articaine is metabolized in the blood than in the liver. Van Oss

(60) found protein binding of articaine in patients varied between 50% and 70% while protein binding of the metabolite articainic acid varied between 60% and 90% (60). Isen

(3) states that 90% to 95% of articaine is metabolized in the blood and only 5% to 10% is broken down by the microsomal P450 enzyme system in the liver (3). The half-life of articaine has been reported to be as low as 20 minutes (60), while the half-life of lidocaine is approximately 90 minutes (63). Oertel and Rahn (62) studied the clinical

15 pharmacokinetics of articaine and also found the elimination half-life to be 20 minutes.

Jakobs et al. (64) evaluated the pharmacokinetics of both 2% and 4% articaine in children

and found plasma half-lives of 18.5 and 23.6 minutes, respectively. Muller et al. (65)

studied the pharmacokinetics of articaine in mandibular nerve block anesthesia using 2

mL of 4% articaine with 1:200,000 epinephrine in 10 alert patients and 10 patients under general anesthesia. Blood samples from peripheral veins showed a half-life of approximately 20 minutes. Muller concluded that compared to other local anesthetics, whose plasma half-lives may vary between 1 and 3.6 hours, the 20 minute value found for articaine was very low. The reason for such a short half-life is explained, in part, by its structure. Plasma esterases can degrade articaine due to its ester group. This is a rapid process compared to the microsomal P450 enzyme system of the liver (2).

Articaine is eliminated via the kidneys (56). Van Oss et al. (60) found 2-5% of articaine is excreted unchanged, 30-70% as articainic acid, and 4-15% as articainic acid

glucoronide. Renal clearance of articaine ranges from 12 to 28 mL/min and that of

articainic acid ranges from 84 to 160 mL/min (60).” (1)

“Potocnik and co-authors (66) compared the effectiveness of 2% and 4%

lidocaine, 3% mepivacaine, and 2% and 4% articaine solution in blocking the action

potential of rat sensory nerves. After application of an anesthetic solution and

stimulation of the nerve with a supramaximal electrical stimulus, a complete

disappearance of the compound action potential of the C fibers, but not of the A fibers,

was observed in all the experimental groups. Both 2% and 4% articaine more effectively

depressed the compound action potential of the A fibers than did other anesthetic

solutions (66).” (2)

16 SAFETY OF ARTICAINE

“Articaine has a maximum safe dose of 7 mg/kg for uncompromised patients.

Articaine has a maximum milligram dose of 500 mg for an average, healthy, 70 kg adult

(67). A 1.7 mL cartridge of 4% articaine contains almost twice the amount of drug (68 mg) as a 1.8 mL cartridge of 2% lidocaine (36 mg). The maximum number of cartridges of articaine that a patient can be safely given would therefore be about half the number of cartridges that the same patient could receive if lidocaine were selected (67). At a body weight of 70 kg, an average adult’s maximum dose would be 490 mg of articaine, which translates into 7.2 cartridges of 4% articaine with 1:100,000 epinephrine (67).” (1)

“The rapid breakdown of articaine and the apparent inactivity of its metabolites imply that it may be a safer anesthetic than other currently available anesthetics, including lidocaine. In his editorial on articaine, Weaver (67) noted the excellent safety record for articaine worldwide. Weaver stated that although lidocaine and other amides have been implicated in a number of pediatric deaths, there are few reports of overdose mortalities attributed to articaine. He raised the question: ‘is articaine inherently safer despite its higher concentration?’ Weaver attributed articaine’s reputation of safety to possible underreporting of overdose reactions and acknowledged that the mg/kg maximum dose for articaine may be very conservative. In addition, Weaver also stated that dentists in those countries in which articaine is commonly used may meticulously calculate the maximum recommended dose for each patient; these dentists avoid high blood levels of articaine by spreading out their injections over the entire appointment; and these dentists have better training and are better able to recognize and appropriately treat overdose reactions. Weaver (67) stated that articaine is safe and effective when

17 used in appropriate doses for dental patients.” (1)

Cardiovascular Safety

“Malamed et al. (70) investigated the safety of articaine compared to lidocaine in

adult dental patients. A total of 1325 patients undergoing general dental procedures were evaluated for adverse effects of the injected anesthetic solutions. The subjects were randomized in a 2:1 ratio to maximize trials with articaine. Subjects received comparable volumes of articaine and lidocaine for both simple and complex procedures, but higher mg/kg doses of articaine in both types of procedures due to the higher concentration of articaine at 4% versus lidocaine being 2%. Safety was evaluated by measuring vital signs

before administration of the anesthetic, at 1 and 5 minutes post-administration, and at the

end of the procedure. Information about any adverse events was also collected by

follow-up telephone calls both 24 hours and 7 days after the procedure. The incidence of

adverse events was 22% (191 of 882 patients) for the articaine group and 20% (89 of 443

patients) for the lidocaine group. One patient in the lidocaine group had to discontinue

the study due to chest pain and dizziness. No deaths were reported associated with either

anesthetic in this study. The most common adverse event in the articaine group was post-

procedural pain (13%). Other reported adverse events associated with articaine included

headache (4%), facial edema (1%), infection (1%), gingivitis and paresthesia (1%). The

most commonly reported adverse events which were considered by the investigator to be

drug-related were paresthesia (0.9%), hypoesthesia (0.7%), headache (0.55%), infection

(0.45%), rash (0.3%), and pain (0.3%). Heart rate and respiratory rates increased slightly

at 1 and 5 minutes but by post-procedural times had decreased slightly below the baseline

18 values. Adverse events reported for lidocaine were similar to those reported for articaine.

However, one case of mouth infection and one case of mouth ulceration rated at severe intensity were reported from the articaine group. Malamed et al. (70) concluded that 4% articaine with 1:100,000 epinephrine had a low risk of toxicity that appeared comparable to other local anesthetics.” (1)

“Simon et al. (71) investigated differences between three anesthetics during intravenous regional anesthesia in a double-blind randomized clinical trial. Thirty patients received either 0.5% articaine, 0.5% lidocaine, or 0.5% prilocaine intravenously, and differences in side effects and maximum drug concentrations were evaluated. The plasma drug concentration was evaluated by high performance liquid chromatography.

The peak levels were found immediately after release of the tourniquet and gradually decreased over time. The maximum concentrations were 1.85, 8.5, and 4.4 μg/mL for articaine, lidocaine, and prilocaine, respectively. Articaine had the lowest peak concentration of the three local anesthetics when used for intravenous regional anesthesia. The authors speculate that the low plasma levels of articaine may be a result of hydrolysis by plasma esterase. In addition, no signs of local anesthetic toxicity of the cardiovascular or central nervous system were seen when using articaine.” (1)

“Hidding and Khoury (63) evaluated the safety of 4% articaine with 1:100,000 epinephrine and 4% articaine with 1:200,000 epinephrine when used for an inferior alveolar block. With the 4% articaine with 1:100,000 epinephrine, 7.6% of the patients experienced an increase in blood pressure equal to or greater than 20 mm Hg as compared to 4% articaine with 1:200,000 epinephrine where 6.3% of the subjects experienced a similar increase. There were no differences among the groups with respect

19 to changes in blood pressure or heart rate. One subject who received 4% articaine with

1:100,000 epinephrine experienced diplopia after injection, which resolved after 15

minutes.” (1)

“Daublander et al. (54) investigated the incidence of complications associated

with local anesthetic use in dentistry. Articaine was reported to have been administered

in over 90% of all local anesthetic injections in Germany, with a low incidence of complications. In this study, 2731 patients receiving local anesthesia were evaluated for complications associated with the administration of articaine in an oral surgery clinic in

Germany. The overall incidence of complications was 4.5%, with the incidence higher for at-risk patients (5.7%) than non-risk patients (3.5%). Severe complications, including seizure and bronchospasm, occurred in only two cases, a 0.07% incidence. The most frequently observed complications were dizziness, tachycardia, agitation, nausea, and tremor. These were transient and did not require treatment.

Moller (72) examined the cardioelectrophysiologic effects of articaine in

comparison to those of bupivacaine and lidocaine in isolated rabbit heart preparations.

The effects of the three local anesthetics on action potentials from the Purkinje fiber and

ventricular muscle tissues were determined. Moller et al. found that articaine, at ten

times its observed clinical blood concentration, was significantly less cardiodepressive

than bupivacaine at only five times its observed clinical blood concentration.” (1)

“Elad et al. (73) studied the cardiovascular safety profiles of 4% articaine with

1:200,000 epinephrine versus 2% lidocaine with 1:100,000 epinephrine in cardiovascular patients. The study was a prospective, randomized, double blinded study in which 50 patients received 1.8 mL of each anesthetic at separate appointments. There were no

20 adverse clinical effects. There were also no statistically significant differences between the two groups in heart rate, systolic or diastolic blood pressure, or oxygen saturation

(73).” (1)

Children

“Articaine has been shown to be safe in children over 4 years of age. Articaine is not recommended for children under the age of 4 because, according to the articaine product monograph (68), no data exists to support its use. However, recent clinical studies have shown articaine to be safe even in children under 4 years of age (64,74).

Wright et al. (75) evaluated the use of articaine administered in children under 4 years old in a retrospective survey of dental records from 2 pediatric dental offices in

Ontario, Canada. Two hundred and eleven children (59 also receiving preoperative sedation with chloral hydrate, hydroxyzine hydrochloride, and nitrous-oxide) from 12 months to 48 months of age who received articaine as a maxillary infiltration or mandibular block were evaluated for any observed or reported adverse reactions. The

211 patients received a combined total of 240 doses of articaine without any reported adverse effects.” (1)

“Jakobs et al. (64) measured the serum levels of articaine at multiple time intervals after administration of the drug. The study was carried out on a total of 27 children, aged 3 to 12 years, undergoing general anesthesia. Venous blood samples were gathered before local anesthesia and then 2, 5, 10, and 20 minutes after infiltration with either 2% articaine with 1:200,000 epinephrine or 4% articaine with 1:200,000 epinephrine. It was observed that the pharmacokinetic profile of articaine was similar to

21 that observed in adults. The maximum serum concentration in the children was 1060

μg/mL for the 2% articaine group and 1382 μg/mL for the 4% articaine group. These

values are consistent with the results of a study by Kirsch et al. (76), in which maximum

serum concentrations in adults were approximately 1170 μg/mL after injection of 240 mg of articaine. The Tmax (time to maximum plasma concentration) values were 7.44

minutes in the 2% group and 7.78 in the 4% group. These values were comparable with

investigations of pharmacokinetic characteristics of articaine in adults. Muller (65) found

average Tmax values to vary between 16.9 and 17.7 minutes in adults. Jakobs et al. (64)

claims that the Tmax values in children are distinctly earlier and the plasma clearance is

distinctly increased in comparison to adults. Jakobs et al. found no particular adverse

events, side-effects, or untoward incidents. Jakobs et al. concluded that there is no reason

to adjust the mg/kg dose limit for children as compared to adults. However, it is

important to remember that for a small child (15 kg or approximately 30 pounds) the

toxic dose can be reached with less than two cartridges of a 4% articaine solution (3).”

(1)

“Malamed and Gagnon (77) investigated the safety of articaine compared to

lidocaine for pediatric dental patients. Subjects aged 4 to 13 years undergoing general

dental procedures were evaluated for any adverse effects of the injected anesthetic

solutions. Fifty subjects were randomized in a 2.5:1 ratio to maximize information

gathered about articaine. Subjects received comparable volumes of articaine and

lidocaine for both simple and complex procedures, but higher mg/kg doses of articaine in

both types of procedures due to the higher concentration of articaine at 4% versus

lidocaine at 2%. Safety was evaluated by measuring vital signs before administration, at

22 1 and 5 minutes post-administration of the medication, and at the end of the procedure.

Information about any adverse events was also collected during telephone call follow-up both 24 hours and 7 days after the procedure. At least one minor adverse event was reported by 8% of the articaine subjects and by 10% of the lidocaine subjects. The adverse events noted were post-procedural pain (2%), headache (2%), injection site pain

(2%), and accidental injury/lip bite (2%). There were no serious adverse events. One

patient received more than the recommended maximum dosage of 7.0 mg/kg of articaine

and reported no adverse effects. Mean supine blood pressure values increased slightly

from baseline after administration of articaine, but the changes were not clinically

significant and were not associated with any adverse events. Malamed et al. (77)

concluded that 4% articaine with 1:100,000 epinephrine is safe when administered by

injection to children at least 4 years of age.” (1)

“Adewumi et al. (78) reported the incidence of adverse reactions following the

use of 4% articaine in children. Follow-up phone interviews were conducted with the

parents of 2 to 14 year-olds at 3, 5, 24 and 48 hours regarding prolonged paresthesia, soft

tissue injury and pain. The incidence of prolonged paresthesia was 40% at 3 hours

postinjection and 11% at 5 hours postinjection. Soft tissue injury occurred in 14% of the

patients at 3 hours postinjection and was the highest in children under 7 years old.

Twenty percent of the children reported post procedural pain at 3 and 5 hours post-

treatment (78).” (1)

Pregnant, Elderly and Medically Compromised Patients

“Malamed et al. (77) advised caution with the use of articaine in patients with

23 hepatic disease or significant impairments in cardiovascular function because amide-type

local anesthetics undergo biotransformation in the liver and possess myocardial depressant properties.

Oertel and Rahn (80) investigated the pharmacokinetics of articaine in elderly

patients. The premise investigated was that physiologic changes that occur with age may

affect the pharmacokinetics of local anesthetics. Submucosal infiltration of two different

dosages of 4% articaine without epinephrine was compared between healthy young and healthy elderly adults. Articaine’s clearance and volume of distribution after infiltration were significantly lower in the elderly subjects compared to the young. However, the maximum drug concentration and the area under the serum concentration-time curve did not differ significantly with age. Likewise, no changes in terminal half-life or T max were observed. The measured levels of the metabolite articainic acid were also similar in the young and elderly subjects. The authors concluded that no change of articaine dosage should be necessary for elderly patients (80).” (1)

“Articaine has been classified by the Food and Drug Administration as a pregnancy category C drug. There have not been adequate well-controlled studies with pregnant women. Leuschner et al. (81) studied the toxicological profile of articaine. The toxicity of 4% articaine with 1:100,000 epinephrine was examined in vitro and in vivo for repeated dose toxicity, reproduction toxicity, mutagenic potential, and local tolerance.

Rats and dogs were subjected to repeated subcutaneous administration of articaine and none of the animals demonstrated pathomorphological systemic changes even at doses considered toxic. The no-effect level was found to be 25 mg/kg/day for the rat and 40 mg/kg/day for the dog. Reproduction studies with rats and rabbits using doses ten times

24 the maximum recommended human dose of 7 mg/kg/day demonstrated no evidence of harm to the fetus or to other aspects of reproduction. This was true even when the doses were toxic to the parental animals. The mutagenicity studies also showed no mutagenic potential up to cytotoxic concentrations or up to the maximum tolerated dose levels. The authors concluded that local tolerance of articaine is very good. The data indicated that articaine did not possess any notable side effects or toxicity and can be considered a safe local anesthetic. Animal reproduction studies are not always predictive of human response (67). Therefore, articaine should be used during pregnancy only if the potential

benefit justifies the potential risk to the fetus. Likewise, it is not known if articaine is

excreted in human milk. Because many drugs are excreted in human milk, caution should

be exercised when articaine is administered to nursing women (67).” (1)

“Articaine, like prilocaine, is capable of producing methemoglobinemia at very

high doses (3). Methemoglobinemia has been observed, although rarely, when articaine

is administered intravenously for regional anesthesia (32). However, when used within

the recommended dosages for dental anesthesia, the occurrence of this side effect is

unlikely and there have been no cases reported following administration for dental

anesthesia (3).” (1)

Allergic Reaction

“A few cases of allergic reaction to articaine have been reported. Malanin and

Kalimo (87) described a case of an acute cutaneous reaction after administration of local

anesthesia using 4% articaine with 1:200,000 epinephrine. The patient was a 38-year-old

female in good health with no history of atopy. She had visited the dentist on several

25 occasions over the course of a year and was administered articaine local anesthetic

without any adverse reaction. On this particular occasion, however, she was

administered an infiltration of 1.7 mL articaine, and after 15 minutes experienced itching

on her skin and redness and papules developed on her chest, abdomen, axillae, hands, and

groin. The rash disappeared after a few hours. Two weeks later, 2% lidocaine with and

without epinephrine were tested in a similar manner and no reaction was seen. Malain

and Kalimo explain the allergic reaction as a complement-mediated mechanism involving

liberation of anaphylatoxins and degranulation of mast cells. Klein et al. (88) reported a

case of a slow anaphylactoid reaction to lidocaine. The same patient was able to tolerate

articaine without reaction. Likewise, the patient in the Malainin and Kalimo case had no

crossreactivity with lidocaine. They concluded that although both local anesthetics are of

the amide type they both have marked differences in their chemical structures.

Warrington and McPhillips(89) reported on a case of articaine hypersensitivity. A

35-year-old female dental patient developed generalized, large hives about 5 minutes

after receiving an injection of articaine. She received 50 mg of intramuscular

diphenhydramine and her symptoms resolved after 1 to 2 hours. She had neither

angioedema nor breathing problems. The patient had most recently received articaine at

the dentist 3 years earlier without problem. Warrington stated that when type-I

hypersensitivity is observed, there is extensive cross-reactivity among the local

anesthetics of the amide group. Warrington concluded that the subject’s history and

positive skin test strongly suggest that she had an immediate hypersensitivity reaction to

articaine, and that the reaction exhibited crossreactivity with other amide local anesthetics.” (1)

26 Paresthesia

Local anesthetics are capable of causing temporary or permanent nerve damage.

“The term paresthesia is defined as numbness or tingling of the lips or mouth, persistent

anesthesia, or a painful neuropathy known as dysethesia.” (210) The injection of local anesthetics for an IAN block has been associated with paresthesia of the IAN and/or

lingual nerve. To date, no published studies or case reports have linked any local

anesthetic agents with permanent paresthesia following mandibular buccal infiltration

injections.

“The incidence of paresthesia is extremely low when articaine is used for a

mandibular block. However, the use of a 4% solution of both articaine and prilocaine has

been found to be associated with a statistically higher risk of paresthesia following a

mandibular block compared to a 2% lidocaine solution (3).

Haas and Lennon (83) and Miller and Lennon (84) investigated the incidence of

local anesthetic-induced neuropathies following administration of different types of local

anesthetics. In these two retrospective studies, cases were reviewed from different time

periods in Ontario, Canada to determine if articaine and prilocaine were significantly

more likely to be associated with permanent neuropathies. The incidence of reported

cases of neuropathies from 1994 to 1998 (84) was 1 out of 765,000 injections, or 1.3

injections per million. A high level of statistical significance was observed for the

incidence of post-injection paresthesia associated with articaine and prilocaine compared

to other agents. The incidence of permanent neuropathies associated with articaine and

prilocaine was approximately five times that found with either lidocaine or mepivacaine.

The neuropathies observed in all cases involved the lip and/or tongue. These results are

27 consistent with other previously published data (83) and suggest that articaine may have

the potential for mild neurotoxicity.

Malamed et al. (70) also obtained data regarding paresthesia after injection of

articaine based on Haas and Lennon's report (83). A total of 1325 patients undergoing general dental procedures were evaluated for adverse effects of the injected anesthetic solutions. The subjects were randomized in a 2:1 ratio to maximize information gathered about articaine. The total number of subjects who reported paresthesia 4 to 8 days after the procedure was 8 (1%) for the articaine group and 5 (1%) for the lidocaine group.

However, in 4 cases of the articaine group and 1 case of the lidocaine group, the symptoms did not begin on the day of the study. This suggests that the paresthesias were caused by the procedure rather than by the anesthetic itself (70). In all cases the paresthesia ultimately resolved.” (1)

“A review by Haas discussed the epidemiological evidence regarding incidence of paresthesia with articaine (85). Paresthesia is considered irreversible when resolution does not take place within eight weeks. Haas and Lennon published the first study to suggest the possibility that articaine is more highly associated with paresthesia than other local anesthetics (83). Since then, other studies have shown incident rates with articaine up to twenty-fold higher than lidocaine, usually associated with the lingual nerve (86).

Haas attributed the increased incidence not to the drug itself, but to the higher concentrations of anesthetic. Articaine is marketed as a 4% solution, which means that the concentration of the drug is 40 mg/mL. This is twice the concentration of lidocaine, which is most frequently used as a 2% solution. The author recommended that articaine

and other high-concentration anesthetics such as prilocaine should be avoided for

28 mandibular and lingual blocks.” (2)

Pogrel et al. (214) evaluated 83 cases of permanent nerve involvement following

IAN block. The authors determined that only rarely does an IAN block cause permanent alteration of sensation of the lingual nerve, the IAN, or both. When paresthesia does occur, the authors reported that the lingual nerve was affected 79% of the time while the

IAN was affected 21% of the time. The authors also stated that 85-94% of cases of paresthesia caused by local anesthetics resolved within an eight week period, but if recovery did not occur quickly, approximately two-thirds of those suffer permanent damage.

Pogrel (208) reported on 57 patients that presented to the Department of Oral and

Maxillofacial Surgery at the University of California, San Francisco, for evaluation of permanent paresthesia resulting from an IAN block. The author reported that lidocaine accounted for 35% of the cases, prilocaine accounted for 29.8% of the cases, and articaine accounted for 29.8% of the cases of permanent paresthesia. The author also provided the approximate percentage sales of local anesthetics in the U.S. over that period, and lidocaine accounted for 54% of sales, articaine accounted for 25% of sales, and prilocaine accounted for 6% of sales. The author concluded that there is not disproportionate nerve involvement from articaine, but stated that there could be a higher incidence of paresthesia with prilocaine. The author failed to evaluate the percentage of use of lidocaine, articaine, or prilocaine for IAN blocks, which could drastically change the percent incidence of paresthesia for the different local anesthetic agents. The author also looked only at permanent paresthesia and made no attempt to evaluate the rate of temporary paresthesia associated with the different local anesthetic agents.

29 Malamed (211) in 2006 wrote an update on local anesthetics. He stated that “little to no evidence-based medicine exists demonstrating any superiority of articaine over other available local anesthetics.” He went on to mention that despite the lack of evidence demonstrating advantages over other local anesthetics, articaine is believed to work faster, work better, miss blocks less often, and get patients numb when other anesthetic agents fail. The author also stated that at that time, there was absolutely no scientific evidence to demonstrate there was a greater risk of paresthesia associated with administration of a 4% concentration of local anesthetic. Malamed reiterated that when paresthesia occurred following administration of local anesthetics, that the IAN block is the most common injection technique resulting in paresthesia and that the lingual nerve is the most commonly affected site of paresthesia (83, 214).

Malamed (212) provided an update of what is new in local anesthesia in 2009.

The author discussed the statistically significant difference in the ability of articaine to provide profound pulpal anesthesia when administered in a mandibular buccal infiltration adjacent to the first molar as shown by Robertson et al. and Kanaa et al. (29,100). The author went on to discuss the issue of local anesthetic induced paresthesia associated with

IAN block. He compared the findings of Haas (55) to those of Pogrel (208) and determined that Pogrel had the most scientific look at the question to date.

“Mikesell et al. (79) investigated the incidence post-injection sequelae when using articaine for inferior alveolar nerve blocks. There were no reports of paresthesia. The most common complaint was trismus (9% incidence), followed by soreness (4-5% incidence) and swelling (0-2% incidence) at the injection site (79).

Robertson et al. (29) reported the incidence of post-injection complications

30 following mandibular buccal infiltrations with 4% articaine with 1:100,000 epinephrine.

The only reported post-injection complication was slight swelling (4% of the subjects) in

the area of the injection. Haase et al. (30) reported the incidence of post-injection

complications when using 4% articaine with 1:100,000 epinephrine as a supplementary

buccal infiltration after an inferior alveolar nerve block with 4% articaine with 1:100,000

epinephrine. Six percent of the subjects reported swelling and 3% of the subjects

reported bruising. No subjects reported paresthesias with the inferior alveolar nerve blocks or infiltrations (30).” (1)

“Pabst et al. (204) investigated the incidence of post-injection complications when a repeated mandibular buccal infiltration of 4% articaine with 1:100,000 epinephrine was administered 25 minutes following a primary articaine infiltration injection in mandibular posterior teeth. There were no reports of any incidence of anesthesia, paresthesia, or hematoma following any of the injections. The most frequent complications were tenderness to touch at the site of the injection (22%) and swelling (8-14%) (204).” (1)

Nuzum (207) investigated the incidence of post-injection complications when a mandibular lingual infiltration was performed in addition to a mandibular labial infiltration for mandibular anterior teeth. There were no reports of any incidence of anesthesia, paresthesia, or hematoma following any of the injections. The most frequent complication was tenderness to touch at the site of the injection (23 - 31%). In most categories of postoperative complications, the labial injection produced more

complications than the lingual. Although relatively few patients reported complications,

soreness to chewing was more commonly noted at the lingual injection site when

compared to the labial (1.2 - 2.5% versus 0.6 - 1.2%, respectively).

31 McEntire (1) investigated the incidence of post-injection complications when a

comparing a buccal infiltration of 4% articaine with 1:100,000 epinephrine to a buccal

infiltration of 4% articaine with 1:200,000 epinephrine in mandibular posterior teeth.

The majority of subjects did not report any complications. There were no reports of any incidence of anesthesia, paresthesia, or hematoma following any of the injections. The most frequent complication was a tenderness to touch at the site of injection (11.8 -

15.3%).

EFFICACY OF ARTICAINE

“The available literature indicates that articaine is at least comparable to other

existing local anesthetics in achieving pulpal anesthesia (3). Due to the inherent chemical

differences between articaine and the other amide anesthetics, many case reports and

empirical evidence have claimed more profound anesthesia and longer duration of

activity when using articaine. Articaine is the only amide local anesthetic that contains a

thiophene ring. This configuration is consistent with a high lipid solubility. Therefore,

articaine should theoretically cross lipid barriers, including nerve membranes, quite easily

(3). It may also diffuse through soft tissue and bone better than other local anesthetics,

including lidocaine (62).” (1)

“A partition coefficient measures the differential solubility of a compound

between two solvents. It is often used to describe the distribution of drugs in the body,

measuring how hydrophobic or hydrophilic a substance is based on its preferential

distribution into specific body tissues. More lipid-soluble substances will have a higher

partition coefficient and thus will more readily diffuse through hydrophobic tissues such

32 as lipid-bilayers of cells and nerve sheaths.” (2) “Casanovas et al. (91) evaluated the

partition coefficient of four dental local anesthetics. Articaine was shown to possess a

superior partition coefficient (123.0) compared to lidocaine (10.0), prilocaine (6.9), and

bupivacaine (83.2).” (1)

“Dudkiewicz et al. (90) evaluated the effectiveness of articaine for mandibular

infiltrations in children. The study included 50 children ranging from 4 to 10 years of

age (mean age of 7 years). Two clinicians performed 84 treatments overall. Articaine

(4%) with 1:200,000 epinephrine was injected into the muco-buccal fold corresponding

to the teeth being treated. One point two milliliters of solution was administered for teeth with a single root, while 2.7 mL was administered for teeth with multiple roots.

Anesthesia was successful in all cases and no reinjection was performed. There were, however, a few instances where a child complained of pain at the beginning of the operative procedure. In such cases an additional 5-minute waiting period was allowed to elapse, after which anesthesia was found to be successful. Because clamp placement and stainless steel crown preparations were performed on the lingual surface without any problems, the authors claimed that articaine was able to diffuse through the bone to the lingual side of the tooth (90). Without lingual perfusion of the anesthetic, these procedures would have been painful and impossible for the children (90). The authors attributed the ability of articaine to diffuse to the lingual tissue to its molecular configuration (the lipophilic thiophene ring) and to the high partition coefficient of articaine found during Casanovas’ study above (91).” (1) “The authors concluded that for successful anesthesia of posterior primary teeth in children, mandibular infiltration using articaine is the technique of choice.” (1)

33 “Donaldson et al. (94) conducted a double-blind crossover study to compare 4%

articaine with 1:200,000 epinephrine to 4% prilocaine with 1:200,000 epinephrine in mandibular block and maxillary infiltration during restorative dentistry. Eighty-one patients (41 adults and 40 children) requiring restorative dental treatment on either both mandibular or both maxillary quadrants of the mouth were randomized into two groups, those receiving prilocaine first and those receiving articaine first. Each patient received the alternate drug on the contralateral quadrant at the second appointment. Two dosages were administered: those patients requiring maxillary infiltration were injected with 0.6 mL of either articaine or prilocaine and those requiring mandibular blocks were injected with 1.8 mL of either anesthetic. An electric pulp tester was used throughout the study period. Articaine had a faster onset for mandibular block anesthesia but not for maxillary infiltration and there was a longer duration for articaine in adults, but again the differences were not significant. The authors concluded that there were no differences between the articaine and prilocaine solutions with respect to onset time and duration.”

(1)

“Ruprecht et al. (96) studied the anesthetic effect of injection with equimolar concentrations of lidocaine and articaine with 1:100,000 and 1:200,000 epinephrine in a randomized, double-blind crossover design. Maxillary central incisors were tested with an electric pulp tester before and after infiltration of the anesthetic. The authors observed that in solutions containing equal concentrations of epinephrine, articaine was found to produce faster and more prolonged anesthesia than the lidocaine solution tested.” (1)

“Vahatalo et al. (95) compared 4% articaine with 1:200,000 epinephrine to 2% lidocaine with 1:80,000 epinephrine for maxillary infiltration anesthesia. Twenty healthy

34 dental student volunteers were included in this double-blind study. Each subject received

0.6 mL of each test solution at different times. Infiltration anesthesia was tested on the

maxillary lateral incisors. The onset and duration of pulpal anesthesia were monitored by

an electric pulp tester. Although not statistically significant, onset was slightly faster for

articaine (187 sec) than for lidocaine (201 sec), and articaine had a slightly longer

duration of action (24.5 min) than lidocaine (23.8 min). The authors were surprised at this finding because the lidocaine solution contained a much higher concentration of vasoconstrictor than the articaine solution. They concluded that there were no statistically significant differences seen in the onset and duration of anesthesia between

the articaine and lidocaine solutions.” (2)

“Qiunn et al. (98) conducted clinical research comparing various formulations of

articaine and lidocaine with and without a vasoconstrictor, using an electric pulp tester to

determine the level of pulpal anesthesia. Their data demonstrated that articaine is an

effective local anesthetic, but none of the formulations were statistically superior to 2%

lidocaine with 1:100,000 epinephrine (98).” (1)

“Malamed et al. (56) studied the efficacy of articaine when comparing 4%

articaine with 1:100,000 epinephrine to 2% lidocaine with 1:100,000 epinephrine in three

identical randomized, double-blind multicenter clinical trials. Subjects ranged from ages

4 to 80 years and were injected with either 4% articaine with 1:100,000 epinephrine or

2% lidocaine with 1:100,000 epinephrine during both simple and complex dental

procedures. A total of 1325 subjects were randomized in a 2:1 articaine:lidocaine ratio to

maximize information gathered about articaine. Subjects received comparable volumes

of articaine and lidocaine for both simple and complex procedures, but higher mg/kg

35 doses of articaine in both types of procedures due to the higher concentration of articaine.

Time of onset and duration of anesthesia for articaine were considered comparable to lidocaine. Efficacy was evaluated on a gross scale immediately following the procedure by having both the subject and the investigator rate the pain experienced by the subject during the procedure using a visual analog scale (VAS). All VAS scores were considered very low, with mean pain scores less than 1.0 cm. In all cases, the mean score for articaine was lower (less pain) than for the lidocaine group (56). However, Malamed et al. found no statistical differences between the two anesthetic solutions tested. They concluded that 4% articaine with 1:100,000 epinephrine was effective and well-tolerated in all 882 subjects (56).” (1) Irrespective of these findings, Malamed finds that ‘dentists love articaine’. The two benefits dentists report are that it works faster and they miss

(block injections) less frequently (56).

“Malamed and Gagnon (77) compared the success of articaine and lidocaine when

administered to pediatric dental patients. Subjects aged 4 to 13 years undergoing general

dental procedures were evaluated for onset time and efficacy of the injected anesthetic

solutions. Fifty subjects were randomized in a 2.5:1 ratio to maximize information

gathered about articaine. Subjects received comparable volumes of articaine and lidocaine for both simple and complex procedures, but higher mg/kg doses of articaine in both types of procedures due to the higher concentration of articaine at 4% versus lidocaine at 2%. Efficacy was evaluated on a gross scale immediately following the procedure by having both the subject and the investigator rate the pain experienced by the

subject during the procedure using a 10 cm VAS. The VAS scores were slightly higher

for both articaine and lidocaine compared to scores for adult groups in similar studies.

36 Time to onset and duration of anesthesia were considered comparable to other

commercially available local anesthetics. All VAS scores were considered very low and

no statistically significant differences were noted between articaine and lidocaine.

Malamed et al. (77) concluded that 4% articaine with 1:100,000 epinephrine is effective

when administered by injection to children at least 4 years of age.” (1)

“In a prospective, randomized, double-blind, repeated-measures study comparing

the efficacy of intraligamentary injections of 1.4 mL of 4% articaine with 1:100,000

epinephrine and 1.4 mL of 2% lidocaine with 1:100,000 epinephrine using the Wand

Plus® Local Anesthetic Delivery System to anesthetize mandibular first molars, Berlin

(69) found no statistical difference in anesthetic success rates between the two solutions

(articaine - 86.3%, vs. lidocaine - 74.5%).” (1)

“Mikesell et al. (79) investigated 4% articaine with 1:100,000 epinephrine and

2% lidocaine with 1:100,000 epinephrine in inferior alveolar nerve (IAN) block. Fifty-

seven subjects randomly received one anesthetic at the first appointment and the other at

the second in a crossover design. Anesthesia was considered successful if the subject

achieved an 80/80 reading within fifteen minutes of the injection and continuously

sustained this reading until the end of the testing period (60 minutes). Using articaine,

successful pulpal anesthesia from the central incisor to the second molar ranged from 4 -

54%. Using lidocaine, success ranged from 2 - 48%. There was no significant difference

between the two anesthetics. The investigators concluded that 4% articaine with

1:100,000 epinephrine is similar to 2% lidocaine with 1:100,000 epinephrine for IAN

block.

Hintze et al. (93) compared 2% and 4% solutions of articaine both with 1:200,000

37 epinephrine. Local infiltration injections were administered for tooth extractions. The

duration of anesthesia was significantly longer for the 4% solution, but the 4% solution

was not considered superior in local anesthetic effect. Therefore a 2% solution can be

considered for tooth extractions.” (2)

“Kanaa et al. (28) also found mandibular buccal infiltrations to be more effective

with 4% articaine with 1:100,000 epinephrine compared to 2% lidocaine with 1:100,000 epinephrine. Injections were given at least 1 week apart in 31 healthy adult volunteers and tested with an electric pulp tester at two-minute intervals. Anesthetic success for the first molar, defined as two consecutive 80/80 readings, was found to be 64.5% with articaine and 38.7% with lidocaine infiltrations (p=0.008).” (1)

“Robertson et al. (29) found articaine to be superior to lidocaine in a mandibular infiltration for pulpal anesthesia. Anesthetic success was defined as achieving the first of two consecutive 80/80 readings with the electric pulp tester within 7 minutes of the injection for the molars, or within 8 minutes of the injection for the premolars, and sustaining this reading for the entire testing time (approximately 60 min). Anesthetic success for articaine and lidocaine were, respectively, as follows: 10.0% and 1.7% of the second molars; 10.0% and 1.7% of the first molars; 31.7% and 10.0% of the second premolars; and 31.6% and 5.3% of the first premolars. Analysis with Multiple-Exact

McNemar test showed a significant difference (p<0.05) between the solutions with each tooth type for success. When anesthetic success was defined as two consecutive 80/80 readings at any time during post-injection testing, the anesthetic success for articaine and lidocaine were, respectively, as follows: 75% and 45% for the second molars; 87% and

57% for the first molars; 92% and 67% for the second premolars; and 86% and 61% for

38 the first premolars. There was a significant difference (p<0.05) between the solutions with each tooth type for success.” (1)

“Sierra-Rebolledo et al. (92) found no statistically significant differences in anesthetic efficacy between 4% articaine with 1:100,000 epinephrine and 2% lidocaine with 1:100,000 epinephrine when given as an IAN block prior to the removal of bilateral mandibular 3rd molars. Each of 30 patients received both solutions in separate appointments at least one month apart. Pain was measured with a visual analog scale and a clinical evaluation of the efficacy of the two anesthetic solutions was made by comparing the need for anesthesia during dental surgery. Clinical performance favored articaine, but no statistically significant differences could be recorded. Pain scores also showed similar efficacy with both solutions.” (1)

“Rosenberg et al. (101) compared the efficacy of 4% articaine with 1:100,000 epinephrine and 2% lidocaine with 1:100,000 epinephrine when used as a supplemental buccal anesthetic in 48 patients with irreversible pulpitis. A standard VAS was used to evaluate the patient’s response to pain after the supplemental injection. The mean percentage change in VAS score after administration of the supplemental anesthetic was

70.5% for articaine and 62.2% for lidocaine. There was no significant difference in pain scores for articaine compared to lidocaine when given as a supplemental buccal infiltration injection in either the maxilla or mandible.” (2)

“Haase et al. (30) found articaine to be significantly superior to lidocaine for pulpal anesthesia of the mandibular first molar when a buccal infiltration injection was administered with each solution. Seventy-three subjects were given an inferior alveolar nerve block with 4% articaine with 1:100,000 epinephrine. Fifteen minutes later, after

39 confirming a successful IAN block, a supplemental buccal infiltration was given with

either 4% articaine with 1:100,000 epinephrine or 2% lidocaine with 1:100,000 epinephrine. Pulpal anesthesia was measured using an electric pulp tester on the first and

second premolars and the first and second molars. Success was defined as obtaining two

consecutive 80 readings within 10 minutes of the IAN block plus buccal infiltration and

continuously sustaining the 80 reading for 60 minutes. Only the first molar showed a

significant difference between the two solutions (p=0.0075) with articaine being

superior.” (1)

“Evans et al. (97) found significantly (p<0.05) greater pulpal anesthesia of the

maxillary central incisor and second premolar with 4% articaine with 1:100,000

epinephrine when compared with 2% lidocaine with 1:100,000 epinephrine. Maxillary

infiltration injections were given apical to the maxillary lateral incisor and the maxillary

first molar. The lateral and central incisors and canine or the first and second molars and

second premolar were tested with an electric pulp tester every 3 minutes for a total of 60

minutes in order to assess pulpal anesthesia. Anesthetic success was defined as an 80/80

reading within the first seven-eight minutes with continuous 80 readings for 60 minutes.

For all six test teeth, articaine had a higher frequency of pulpal anesthesia than lidocaine,

but the difference was only statistically significant for the central incisor and second

premolar. However, when success was defined only as the occurrence of two

consecutive 80 readings with the pulp tester, a significant difference (p<0.05) was found

between the solutions for each tooth type except for the first and second molars.” (2)

“Jung et al. (99) compared the efficacy of an inferior alveolar nerve block with

that of a buccal infiltration using 4% articaine with 1:100,000 epinephrine in mandibular

40 molars. Thirty subjects were randomly given each of the injection types in separate appointments at least one week apart. An electric pulp tester was used to determine pulpal anesthesia, and two consecutive readings of 80/80 was considered a success. After a test period of 30 minutes, 54% of buccal infiltrations and 43% of IAN blocks were successful. This difference was not significant (p=0.34). The authors concluded that articaine provided a similar success rate whether given as an IAN block or a buccal infiltration.” (2)

“In a prospective, randomized, double-blind study, Sherman et al. (104) compared the anesthetic efficacy of 2% lidocaine with 1:100,000 epinephrine to 4% articaine with

1:100,000 epinephrine in maxillary and mandibular posterior teeth with symptoms of irreversible pulpitis. Each patient received either 1.7 mL of 4% articaine with 1:100,000 epinephrine or 1.8 mL of 2% lidocaine by using either a gow-gates inferior alveolar nerve block or maxillary infiltration. If negative pulpal signs with cold stimuli were achieved, the experimental tooth was accessed. After access was completed, patients rated their discomfort on a modified VAS. Anesthesia was considered successful if the subject’s tooth was accessed with a pain rating no greater than that considered mild pain.

Anesthetic success was achieved in 87.5% of all the patients who qualified for the study.

Four anesthetic failures were observed in the mandibular arch and one in the maxillary arch and there was no correlation observed between the anesthetic solutions and failure

(104).” (1)

Corbett et al. (174) evaluated the anesthetic efficacy of a buccal infiltration of 1.8 mL of 4% articaine with 1:100,000 epinephrine and a buccal infiltration of 0.9 mL of 4% articaine with 1:100,000 epinephrine plus a lingual infiltration of 0.9 mL of 4% articaine

41 with 1:100,000 epinephrine. Thirty-one subjects randomly received a buccal infiltration

of 1.8 mL of 4% articaine with 1:100,000 epinephrine in the mucobuccal fold adjacent to

the first molar or a buccal infiltration of 0.9 mL of 4% articaine with 1:100,000

epinephrine plus a lingual infiltration of 0.9 mL of 4% articaine with 1:100,000

epinephrine in two separate appointments spaced at least 1 week apart. Pulpal anesthesia

was measured with the electric pulp tester on the first molar. Two consecutive 80/80

readings on the electric pulp tester were considered a success. The buccal infiltration

alone resulted in a success rate for the mandibular first molar of 64.5% while the success

rate for buccal plus lingual infiltration of the mandibular first molar was 67.7%. The

difference in the anesthetic success was not statistically significant (p = 1.0).

“Kanaa et al. (100) investigated the effectiveness of a supplementary buccal infiltration of 4% articaine as a means of increasing the effectiveness of the IAN block.

In the randomized, controlled, double-blind, crossover study, all 36 subjects received 2.0

mL of 2% lidocaine with 1:80,000 epinephrine in an IAN block at each visit. The

subjects randomly received a dummy injection without drug administration in the

mucobuccal fold adjacent to the first molar or a supplementary buccal infiltration of 2.0 mL of 4% articaine with 1:100,000 epinephrine in two separate appointments spaced at least 1 week apart. Pulpal anesthesia was measured with the electric pulp tester on the first molar, the first and second premolar, and the lateral incisor. Two consecutive 80/80 readings on the electric pulp tester were considered a success. The supplementary buccal infiltration increased the incidence of successful anesthesia from 55.6% to 91.7% in the first molar, from 66.7% to 88.9% in the premolars, and from 19.4% to 77.8% in the lateral incisor (100).” (1)

42 “Tortamano et al. (103) compared the anesthetic efficacy of 4% articaine with

1:100,000 epinephrine with 2% lidocaine with 1:100,000 epinephrine for IAN blocks in patients with mandibular posterior teeth experiencing pulpitis. Forty subjects were divided into 2 groups of 20 patients. Each subject received IAN blocks with 3.6 mL of either 2% lidocaine with 1:100,000 epinephrine or 4% articaine with 1:100,000 epinephrine. Anesthesia was defined as successful when the pulp chamber was accessed without pain being reported by the patient. During the pulpectomy procedures, 7 patients

(35%) of the articaine group and 11 patients (55%) of the lidocaine group reported pain.

There was no statistically significant difference (p=0.20) in success between the two solutions (103).” (1)

“Matthews et al. (102) investigated the anesthetic efficacy of a supplemental infiltration injection of 4% articaine with 1:100,000 epinephrine in mandibular posterior teeth diagnosed with irreversible pulpitis when the conventional IAN block failed.

Eighty-two patients presenting for emergency endodontic treatment with a symptomatic mandibular posterior tooth diagnosed with irreversible pulpitis participated in the study.

All 82 subjects received a standard IAN block with 2% lidocaine with 1:100,000 epinephrine. Subjects were asked to rate any pain experienced during injections and during endodontic treatment on a 170 mm visual analogue scale. If moderate-to-severe pain was felt during treatment, the operator stopped and administered a supplemental buccal infiltration injection of 1.8 mL of 4% articaine with 1:100,000 epinephrine.

Fifty-five out of eighty-two (67%) patients in the study required a supplemental infiltration injection. Thirty-two out of fifty-five (58%) patients had anesthetic success with the supplemental articaine infiltration (102).” (1)

43 “Aggarwal et al. (105) investigated the anesthetic efficacy of supplemental buccal and lingual infiltrations with 4% articaine with 1:200,000 epinephrine and 2% lidocaine with 1:200,000 epinephrine after an IAN block. Eighty-seven patients with a mandibular first or second molar diagnosed with irreversible pulpitis were included in the study. All patients received an IAN block with 2% lidocaine with 1:200,000 epinephrine. Twenty- five patients served as a control and did not receive supplemental anesthesia. Thirty-one patients received buccal and lingual infiltrations with 3.6 mL of 4% articaine with

1:200,000 epinephrine, and 31 patients received buccal and lingual infiltrations with 3.6 mL 2% lidocaine with 1:200,000 epinephrine at 2 minutes after the IAN block.

Endodontic access was initiated 15 minutes after the IAN block was administered. Pain during treatment was recorded on a 170 mm visual analogue scale. Success was defined as “no pain” or “weak/mild” pain during access preparation and instrumentation. The supplemental buccal and lingual infiltration with 2% lidocaine with 1:200,000 epinephrine and 4% articaine with 1:200,000 epinephrine improved the success rate from

33% to 47% and 67%, respectively. The success rate with the articaine solution was significantly higher than with the lidocaine solution (p<0.05).” (1)

“Pabst et al. (204) studied the anesthetic efficacy of a repeated mandibular buccal infiltration injection of articaine given 25 minutes following a primary articaine infiltration injection in mandibular posterior teeth. Using a cross-over design, 86 adult subjects randomly received two sets of injections consisting of a primary infiltration injection of 1.8 mL of 4% articaine with 1:100,000 epinephrine plus a repeated infiltration injection 25 minutes later using either 1.8 mL of 4% articaine with 1:100,000 epinephrine or a mock buccal infiltration injection, in two separate appointments spaced

44 at least one week apart. The second molar through the first premolar were tested with an

electric pulp tester every 3 minutes for a total of 120 minutes. Anesthetic success (two

consecutive 80/80 readings on the electric pulp tester) for Group 1 (initial and repeated infiltration injections both with articaine) and Group 2 (initial articaine infiltration and mock repeated infiltration) were, respectively, as follows: 84.9% and 69.8% of the second molars; 83.7% and 66.3% of the first molars; 97.7% and 78.8% of the second premolars; and 92.8% and 80.7% of the first premolars (204).” (1)

Srinivasan et al. (203) evaluated the anesthetic efficacy of 4% articaine with

1:100,000 epinephrine and 2% lidocaine with 1:100,000 epinephrine for maxillary buccal infiltration in patients with irreversible pulpitis. Twenty adult patients who were experiencing irreversible pulpitis in the maxillary first premolar and 20 patients who were experiencing irreversible pulpitis in the maxillary first molar were included in the study.

The study patients were divided into 4 groups of ten patients: Group 1 – irreversible

pulpitis of the first premolar and received 1.7 mL of 4% articaine with 1:100,000

epinephrine; Group 2 – irreversible pulpitis of the first molar and received 1.7 mL of 4%

articaine with 1:100,000 epinephrine; Group 3 - irreversible pulpitis of the first premolar

and received 1.7 mL of 2% lidocaine with 1:100,000 epinephrine; and Group 4 -

irreversible pulpitis of the first molar and received 1.7 mL of 2% lidocaine with

1:100,000 epinephrine. Five minutes after injection the tooth was accessed and

instrumented. Pain during treatment was recorded on a 10 cm visual analogue scale.

Success was defined as the ability to access and instrument the tooth without pain or mild

discomfort (VAS score of 0 or 1). Both groups 1 and 2 (articaine groups) had an anesthetic success rate of 100%. Groups 3 and 4 (lidocaine groups) had success rates of

45 80% and 30%, respectively. There was a statistically significant difference between

anesthetic success rates of articaine vs. lidocaine in the maxillary first molar (p<0.001).

No statistically significant difference was found between articaine and lidocaine for the

maxillary first premolar (p>0.05).

Fan et al. (202) evaluated the effect of a supplemental buccal infiltration or

periodontal ligament injection with articaine following administration of an IAN block in

patients with irreversible pulpitis in the mandibular first molar. Fifty-nine patients

experiencing symptoms of irreversible pulpitis in their mandibular first molar were

included in the study. All patients received an IAN block with 1.7 mL 4% articaine with

1:100,000 epinephrine. Five minutes after initial IAN block injection the patients were

questioned regarding lip numbness and were excluded from the study if they were not

experiencing profound lip numbness. Two subjects were excluded from the study due to

the lack of profound lip numbness at five minutes. The subjects then received either a

buccal infiltration (BI) of 0.4 mL of 4% articaine with 1:100,000 epinephrine or mesial

and distal periodontal ligament injections (PDL) of 0.2 mL of 4% articaine with

1:100,000 epinephrine per injection site. Endodontic access was performed five minutes after the supplemental injection was performed. Pain during treatment was recorded on a

170 mm visual analogue scale. Success was defined as the ability to complete endodontic access without pain or with mild pain. Twenty-two of twenty-seven patients

(81.48%) were judged to have successful anesthesia in the IAN block /BI group while twenty-five of thirty patients (83.33%) in the IAN block /PDL group had successful pulpal anesthesia. There was no statistically significant difference between anesthetic success rate or subjective injection pain ratings between the IAN block/BI group and the

46 IAN block/PDL group.

Nuzum (207) studied the anesthetic efficacy of a combination labial plus lingual infiltration compared to a labial infiltration using 4% articaine with 1:100,000 epinephrine in mandibular anterior teeth. This prospective, randomized, single-blinded study included eighty-two subjects that received mandibular lateral incisor infiltrations, either a combination of labial and lingual (totaling 3.6 mL) or labial and mock (totaling

1.8 mL) injections, at two separate appointments spaced at least 1 week apart. Anesthetic success was defined as an 80/80 reading within the first ten-eleven minutes with continuous 80 readings for 60 minutes. In mandibular lateral incisors, the labial and lingual combination exhibited a significantly higher anesthetic success rate of 60% success when compared with a 7% success rate with the single labial infiltration. In mandibular central incisors, the labial and lingual combination exhibited a significantly higher anesthetic success rate of 56% success when compared with a 6% success rate with the single labial infiltration. In mandibular canines, the labial and lingual combination exhibited a significantly higher anesthetic success rate of 43% success when compared with a 10% success rate with the single labial infiltration. Successful anesthesia was secondarily defined as the occurrence of two consecutive 80 readings with the pulp tester within the first 60 minutes of testing. Under this definition, the labial plus lingual infiltration of articaine increased the anesthetic success from 76% to 98% in the mandibular lateral incisor, from 82% to 99% in the mandibular central incisor and from

74% to 93% for the mandibular canine. A labial plus lingual infiltration injection of articaine significantly (p<0.05) increased the anesthetic success for all teeth when compared to a labial plus mock infiltration injection.

47 McEntire (1) compared the anesthetic efficacy of 1.8 mL of 4% articaine with

1:100,000 epinephrine to 1.8 mL 4% articaine with 1:200,000 epinephrine in mandibular buccal infiltration injections given next to the first molar. In this prospective, randomized, double-blind study using a cross-over design, 86 adult subjects received two primary buccal mandibular infiltration injections given next to the first molar of 1.8 mL of 4% articaine with 1:100,000 epinephrine and 1.8 mL of 4% articaine with 1:200,000 epinephrine, in two separate appointments, spaced at least one week apart. The second molar through the first premolar were tested with an electric pulp tester every 3 minutes for a total of 60 minutes. No statistically significant differences were found between the test solutions in frequency of pulpal anesthesia (80/80 readings) for any of the teeth tested. Anesthetic success was determined using three definitions. Success #1 was defined as achieving the first of two consecutive 80/80 readings by the third testing cycle

(7 – 8 minutes) and maintaining the 80/80 readings throughout the testing period (60 minutes). Success #2 was defined as achieving the first of two consecutive 80/80 readings by the third testing cycle and sustaining this reading continuously for 60 minutes. Success #3 was defined as the occurrence of two consecutive 80/80 readings at any time during the testing period. According to the definition of success #3 (two consecutive 80/80 readings), anesthesia in Group 1 was achieved in 59.3% of second molars, 67.4% of first molars, 84.9% of second premolars, and 73.8% of first premolars and anesthesia for Group 2 was 59.3% of second molars, 59.3% of first molars, 79.1% of second premolars, and 75.0% of first premolars. There were no statistically significant differences between the two solutions using Success #1, Success #2 or Success #3 for any of the teeth tested. The two solutions showed no statistically significant differences for

48 any tooth when comparing onset of pulpal anesthesia, anesthetic failure, short duration of

anesthesia, slow onset of anesthesia and non-continuous anesthesia.

Onset and Duration of Articaine

“Studies have demonstrated a significantly shorter onset time for 4% articaine

with 1:200,000 epinephrine compared to 2% articaine with 1:200,000 epinephrine (56).

There appears to be a higher variability among patients in the onset time and duration of anesthesia when using the 2% solution (56).

Rahn et al. (74) evaluated 2% articaine without epinephrine and 4% articaine with

1:200,000 epinephrine in a prospective, randomized study to evaluate whether the solution without epinephrine is suitable for dental surgery. The local anesthetic effect of the 2% solution without epinephrine was less effective in obtaining profound local anesthesia for surgical dental procedures than the 4% solution with 1:200,000 epinephrine. Despite the overall differences in anesthetic efficacy, in many cases, the 2%

solution was sufficient for dental treatment, including surgery. The duration of the 2%

solution without epinephrine (33 minutes) was, however, shorter than that of the 4%

solution with 1:200,000 epinephrine (43 minutes).” (1)

“Ram et al. (107) assessed time of onset, efficacy, duration of soft tissue

numbness, and childrens’ sensation after treatment with 4% articaine with 1:200,000

epinephrine and 2% lidocaine with 1:100,000 epinephrine. There was no difference

found in onset or efficacy. There was, however, a significant difference found in

duration of anesthesia. Soft tissue anesthesia was significantly longer with the articaine

solution (3.43+/-0.7h) compared to the lidocaine solution (3.0+/-0.8h) (p=.003).” (2)

49 “Lemay et al. (108) evaluated the anesthetic properties of 1.8 mL Ultracaine DS

(4% articaine with 1:200,000 epinephrine) and 1.8 mL Ultracaine DS forte (4% articaine with 1:100,000 epinephrine) during operative dentistry procedures in a multicenter study of both adults and children. The onset time and duration of anesthetic effect were evaluated using an electric pulp tester. The study found an average onset time of 121 seconds for both epinephrine concentrations. For mandibular nerve block anesthesia, a more rapid onset was obtained with the 1:100,000 concentration of epinephrine (120 seconds) versus the 1:200,000 concentration (170 seconds). This difference, however, was not apparent with maxillary infiltrations. The onset time for the 1:100,000 concentration solution was 105 seconds, and for the 1:200,000 concentration solution it was 119 seconds. The duration of anesthesia had a range of 2.6-4.5 hours for maxillary infiltration and 4.3-5.3 hours for mandibular nerve block anesthesia (108).

In a prospective, randomized, double-blind, repeated-measures study comparing

4% articaine with 1:100,000 epinephrine and 2% lidocaine with 1:100,000 epinephrine in

intraligamentary injections, Berlin et al. (69) found that articaine acted significantly faster

than lidocaine (1.3 min vs. 2.2 min). There was no significant difference in duration

between the two solutions (articaine – 34.2 min vs. lidocaine – 30.6 min). They concluded that there is no significant clinical benefit to be gained by switching from lidocaine to articaine for periodontal ligament injections.” (1)

“Costa and co-authors (109) found that onset and duration of anesthesia with both

4% articaine with 1:100,000 epinephrine and 4% articaine with 1:200,000 epinephrine were superior to 2% lidocaine with 1:100,000 epinephrine with maxillary infiltrations.

The mean onset times for anesthesia were 2.8, 1.6, and 1.4 minutes and duration was

50 39.2, 56.7, and 66.3 minutes, respectively, for 2% lidocaine with 1:100,000 epinephrine,

4% articaine with 1:200,000 epinephrine, and 4% articaine with 1:100,000 epinephrine.

Statistical analysis showed significant differences with better results (shorter onset and longer duration periods) for both articaine solutions compared with the lidocaine solution.

Although 4% articaine with 1:100,000 epinephrine clinically presented the shortest onset and the longest duration periods, there was no statistically significant difference between the articaine solutions (109).

Kanaa et al. (28) found that articaine provided longer lasting pulpal anesthesia compared to lidocaine in a mandibular buccal infiltration. The study was conducted for

30 minutes, and an electric pulp tester was used to test anesthetic success after a buccal infiltration injection with either 4% articaine with 1:100,000 epinephrine or 2% lidocaine with 1:100,000 epinephrine. The maximum duration of anesthesia possible in this study was 28 minutes. Six subjects achieved continuous anesthesia for the entire testing period with articaine compared to only two subjects with lidocaine. The percentage of patients achieving 80/80 readings decreased at all testing points after 22 minutes when lidocaine was used. However, the greatest percentage of nonresponders (teeth) was reported at the end of the study with articaine.” (2)

“Robertson et al. (29) found the onset time of articaine to be superior to lidocaine with a mandibular buccal infiltration injection. Onset was defined as the time of the first of two consecutive 80 readings. The onset of pulpal anesthesia was approximately 4 to 5 minutes for articaine and 6 to 11 minutes for lidocaine, depending upon the tooth tested.

Analysis showed a significant difference (p<0.05) between the solutions for each tooth type. Pulpal anesthesia slowly declined over the 60 minutes.

51 Colombini and co-authors (110) compared 4% articaine with 1:100,000 epinephrine to 2% mepivacaine with 1:100,000 epinephrine in postoperative analgesia for lower third molar removal. Duration of analgesia provided by articaine and mepivacaine was 198.0 +/- 25.8, and 125.4 +/- 13.9 min, respectively (p=0.02); whereas the duration of anesthesia was 273.8 +/- 15.94 and 216.8 +/- 20.1 min, respectively (p=0.06). Both solutions exerted no important effects upon arterial pressure, heart rate, or oxygen saturation (p>0.05) (110).” (2)

“Haase et al. (30) found the duration of pulpal anesthesia of the mandibular first molar using an IAN block and buccal infiltration injection with 4% articaine with

1:100,000 epinephrine to be around 37 minutes. When the buccal infiltration injection was administered with 2% lidocaine with 1:100,000 epinephrine instead, the duration decreased to 28 minutes. Onset time for both solutions was a gradual increase in pulpal anesthesia most likely related to the effect of the infiltrations overcoming IAN block failure, or slow onset of anesthesia with the initial inferior alveolar nerve block.

Jung et al. (99) found the onset of pulpal anesthesia was significantly faster with a mandibular buccal infiltration injection of 4% articaine with 1:100,000 epinephrine compared with that of an inferior alveolar nerve block (p=0.03). Thirty subjects received each of the injection types which were given at two separate appointments, and pulpal anesthesia was evaluated with an electric pulp tester. Onset time for the buccal infiltration injection was most frequently seen at 5 minutes, but it was not seen until 8 minutes with the IAN block.” (2)

Corbett et al. (174) found that there was not a significant difference in onset of pulpal anesthesia between a mandibular buccal infiltration injection of 1.8 mL 4%

52 articaine with 1:100,000 epinephrine compared with that of a mandibular buccal

infiltration injection of 0.9 mL 4% articaine with 1:100,000 epinephrine plus a

mandibular lingual infiltration injection of 0.9 mL 4% articaine with 1:100,000

epinephrine (6.5 mins vs. 7.5 mins, respectively). Thirty-one subjects received each of

the injection types which were given at two separate appointments, and pulpal anesthesia

was evaluated with an electric pulp tester. The maximum duration of anesthesia possible

in this study was 28 minutes. Six subjects achieved continuous anesthesia for the entire

testing period with the buccal infiltration compared to four subjects with the buccal plus

lingual infiltration. The mean duration of successful pulpal anesthesia was reported as

21.6 minutes after buccal infiltration and 20.5 minutes after buccal plus lingual

infiltration. However, duration can not be accurately assessed as ten participants were

still anesthetized at the conclusion of the study.

VASOCONSTRICTORS

“All local anesthetic agents intrinsically produce some vasodilation. Therefore,

vasoconstrictors are often added to local anesthetics to counteract this effect.

Vasoconstrictors are drugs capable of constricting blood vessels. They are classified as sympathomimetics or adrenergic agents because their mode of action resembles the response elicited when a sympathetic nerve is stimulated. Adding vasoconstrictors to

local anesthetics results in prolonged action, improved depth of anesthesia, reduced peak

plasma concentrations of the anesthetic agent, and reduced hemorrhage in the injected

area (31-38).

The vasoconstrictors limit blood flow to the injection site by causing constriction

53 of the lumens of blood vessels. This enables a higher concentration of local anesthetic to

remain at the injection site longer, acting to increase the quality and duration of

anesthesia. In addition, the ability of the vasoconstrictor to produce hemostasis at the site

of administration makes them an adjunct in dental surgical procedures (31,32,36-38).” (1)

“The most commonly used vasoconstrictors in dental local anesthetics are epinephrine and levonordefrin (36). Alpha and beta receptors are directly affected by epinephrine, although the beta effects predominate. On the other hand, levonordefrin predominantly affects alpha receptors, with a lesser effect on beta activity.

Levonordefrin is only 15% as effective as epinephrine as a vasopressor (32,36,37). The local and systemic effects of the vasoconstrictors are a result of their alpha and beta stimulating properties. Stimulation of alpha receptors results in smooth muscle contraction of peripheral blood vessels (vasoconstriction). Beta-1 stimulation increases systolic and diastolic blood pressure, heart rate, strength of contraction, stroke volume, cardiac output, and myocardium oxygen consumption. Beta-2 stimulation causes bronchodilation and vasodilation in skeletal muscle (32,37,38).

When local anesthetics containing epinephrine are injected intraorally, vasoconstriction occurs because the alpha effect predominates. This vasoconstriction response causes decreased regional blood flow. The duration and efficacy of the local anesthetic are thus enhanced. As the local epinephrine concentration diminishes, the alpha-adrenergic effects subside and the beta effects begin to predominate. This results in increased local blood flow and the hemostatic effect caused by epinephrine is lost

(36).” (1)

“Normal dental doses of epinephrine are from 18 to 72 μg. This amount of

54 epinephrine is found in one to four cartridges (1.8 mL in a cartridge) of 2% lidocaine

with 1:100,000 epinephrine. The maximum recommended dose of epinephrine (32) for

the healthy adult per office visit is 200 μg (20 mL of a 1:100,000 concentration, or 11

dental cartridges of 1.8 mL each). Forty micrograms (4 mL of a 1:100,000 concentration

solution, or 2.2 cartridges) is the recommended maximum dose of epinephrine for those

with "clinically significant cardiac impairment" (32). A 1:100,000 solution of

epinephrine contains 10 μg of epinephrine per mL of solution or 0.01 mg/mL. A

1:50,000 solution of epinephrine contains 20 μg/mL of solution and a 1:200,000 solution

contains 5 μg/mL.

An overdose of epinephrine results in CNS symptoms of fear and anxiety, tension, restlessness, throbbing headache, tremor, weakness, dizziness, pallor, respiratory

difficulty, and heart palpitations (32). Signs of overdose include sharp elevation in blood pressure (primarily systolic), elevated heart rate, and possible cardiac arrhythmias, including premature ventricular contractions, ventricular tachycardia and ventricular fibrillation. With an increase in the blood level of the drug, the incidence and severity of

cardiac arrhythmias increase (32). Systolic blood pressure in excess of 300 mm Hg and diastolic pressures in excess of 200 mm Hg may lead to cerebral hemorrhage. In patients with coronary insufficiency, an overdose results in anginal episodes (32).” (1)

“Contraindications to vasoconstrictors in the concentrations found in dental local

anesthetics are few in number. Vasoconstrictors should be used with caution in patients

with hypertension, cardiovascular disease, and hyperthyroidism. These patients may be

particularly sensitive to the pressor effects of the vasoconstrictors (32,34,37). Drug

interactions between vasoconstrictors and monoamine oxidase inhibitors (MAOIs),

55 tricyclic antidepressants, phenothiazines, and beta-blockers have been reported

(33,36,111-113). However, it has been shown that the concomitant use of epinephrine,

levonordefrin, and norepinephrine with MAOIs or phenothiazines was not

contraindicated (112). Vasoconstrictors may also be used in patients taking tricyclic

antidepressants but the dosage should be kept to a minimum (0.05 mg). Medical

conditions such as thyrotoxicosis and pheochromocytoma are absolute contraindications

to the use of epinephrine (36,114).” (1)

“Hersh et al. (43) recently studied the pharmacokinetics and cardiovascular

effects of high-dose articaine with 1:100,000 epinephrine versus 1:200,000 epinephrine.

In the randomized, double-blind, two-way crossover clinical trial, fourteen healthy

subjects randomly received 11.9 mL of 4% articaine with 1:100,000 epinephrine or 11.9

mL of 4% articaine with 1:200,000 epinephrine in two appointments separated by one to

three weeks. An acoustic tonometer was used to gather cardiovascular measurements.

Heart rate, systolic blood pressure, diastolic blood pressure, stroke volume, cardiac output, small and large artery elasticity and systemic vascular resistance were measured

every 10 minutes following the first injection through 120 minutes. Venous blood

samples were also collected at 8, 10, 15, 20, 25, 30, 40, 50, 60, 90 and 120 minutes.

Plasma concentration curves of articaine were similar for both groups over time. Heart

rate was elevated significantly (p=0.047) at 10 minutes after the initiation of the injection

procedures when subjects received the 1:100,000 epinephrine solution compared with the

1:200,000 epinephrine solution (78.2 beats/minute + 3.6 and 69.6 + 3.4, respectively).

Systolic blood pressure at 10 minutes was also significantly greater (p=0.046) when subjects were treated with the 1:100,000 epinephrine solution (130.6 + 2.4 mm Hg) than

56 when they were treated with the 1:200,000 epinephrine solution (124.8 + 2.3 mm Hg).

The authors concluded that 4% articaine with 1:200,000 epinephrine may be a preferable alternative to 4% articaine with 1:100,000 epinephrine when it would be desirable to limit cardiovascular stimulation in certain patient populations (43).” (1)

“Moore et al. (45) conducted two double-blinded, randomized, multicenter clinical trials to determine the efficacy and clinical anesthetic characteristics of 4% articaine with 1:200,000 epinephrine with those of 4% articaine with 1:100,000 epinephrine and 4% articaine without epinephrine. Trial 1 assessed the efficacy and anesthetic characteristics of the three anesthetic solutions in the inferior alveolar nerve block. Trial 2 assessed the efficacy and anesthetic characteristics of the three anesthetic solutions in an infiltration of the maxillary first premolar. In both the inferior alveolar nerve block and the maxillary infiltration, the success rates, the mean onset times and the mean duration of anesthesia for both epinephrine containing-formulations were similar.

The success rate with plain 4% articaine was significantly less than the 1:200,000 and

1:100,000 epinephrine solutions in both trials. The authors concluded that 4% articaine with 1:200,000 epinephrine provides a comparable level of pulpal anesthesia and that it could serve as a useful alternative anesthetic to 4% articaine with 1:100,000 epinephrine

(45).” (1)

MANDIBULAR BUCCAL INFILTRATION INJECTION

“Although the inferior alveolar nerve block is the standard technique for treating mandibular posterior teeth, this method does not always result in successful pulpal anesthesia. Mandibular buccal infiltration injections have been generally avoided

57 because the thick cortical bone associated with the posterior mandible does not allow

adequate diffusion of the anesthetic solution to reach the teeth. However, recent claims

that articaine has properties that allow it to diffuse through bone more efficiently has

instigated investigations using mandibular buccal infiltration injections to achieve more

profound pulpal anesthesia. These injections have been given alone or as a supplement to

the inferior alveolar nerve block to improve success rates. With this technique, the

anesthetic is injected in the buccal vestibule directly adjacent to the mandibular first

molar at the level of the apex.” (2)

“Wright et al. (115) investigated the effectiveness of infiltration anesthesia in

mandibular primary molars. Sixty-six subjects requiring restorative treatment on

mandibular molars, ranging from 42 months to 6 years old, were anesthetized by buccal

infiltration. Three anesthetics were evaluated: 4% articaine, 4% prilocaine, and 2% mepivacaine, all with 1:200,000 epinephrine. Ten minutes after infiltration, the gingiva

was probed to check for anesthesia, a rubber dam was placed, and treatment was initiated.

Success rates for the anesthetic efficacy were based on patient reports of pain during each

step. Prilocaine success rates were 70% during probing, 84% during rubber dam

placement, and 58% during drilling. Mepivacaine success rates were 82% during

probing, 91% during rubber dam placement, and 68% during drilling. Articaine success

rates were 88% during probing, 68% during rubber dam placement, and 68% during

drilling. There were no significant differences between the solutions for any of the three steps. The authors concluded that articaine was as effective as prilocaine and mepivacaine for infiltration anesthesia of primary mandibular molars.” (2)

“Haas et al. (116) investigated the claim that anesthesia of mandibular pulpal and

58 lingual soft tissue, as well as maxillary palatal soft tissue, results following buccal

infiltration of articaine. Using a double-blind, randomized clinical trial model, the

authors compared 1.5 mL 4% articaine with 1:200,000 epinephrine to 1.5 mL 4%

prilocaine with 1:200,000 epinephrine. Nineteen adult volunteers had the two anesthetic

solutions deposited by infiltration next to the second molar and next to the contralateral

second molar. Pulpal anesthesia was assessed by electric pulp tester readings for a period

of 25 minutes. Differences related to soft tissue anesthesia were also analyzed. Lingual

and palatal tissues were not expected to be anesthetized with a buccal infiltration alone.

Haas et al. found that articaine was able to penetrate deep into the tissue resulting in

lingual soft tissue anesthesia in 50% of the subjects. When second molars were

anesthetized by buccal infiltrations, articaine was superior to prilocaine at producing

more clinically profound pulpal anesthesia (63% versus 53%), mandibular lingual tissue

anesthesia (50% versus 37%), and palatal tissue anesthesia (40% versus 30%). Articaine

was also more effective than prilocaine for pulpal anesthesia in the canine region (50%

versus 37%) and for mandibular lingual soft tissue anesthesia. For palatal soft tissue

anesthesia in the region of the maxillary canines, prilocaine was the more effective of the

two anesthetics. These differences between articaine and prilocaine were not statistically

significant as determined by chi-square analysis.” (1)

“Haas et al. (27) followed the same methods used in their previously described

double-blind, randomized trial (116) to test local anesthetic infiltration for mandibular canines. Again, differences between 1.5 mL 4% articaine with 1:200,000 epinephrine and 1.5 mL 4% prilocaine with 1:200,000 epinephrine were compared. Twenty healthy adult volunteers had the anesthetic solutions infiltrated next to the mandibular canine and

59 contralateral canine. Efficacy was again evaluated by electric pulp tester readings for 25

minutes. Differences related to soft tissue anesthesia were also analyzed. Lingual tissues

were not expected to be anesthetized with buccal infiltration alone. Articaine produced

successful pulpal anesthesia in 65% of the subjects compared to 50% for prilocaine.

Lingual tissues achieved anesthesia 10% of the time with articaine compared to 5% with

prilocaine. These differences were not statistically significant as determined by chi-

square analysis.” (1)

“Kanaa et al. (28) compared the anesthesia produced by one cartridge of 2%

lidocaine with 1:100,000 epinephrine to 4% articaine with 1:100,000 epinephrine for mandibular infiltration injections. Success was defined as having two consecutive negative readings with the electric pulp tester at any time during the 30-minute testing period. Articaine had 64.5% success while lidocaine had only 38.7% success in producing mandibular first molar anesthesia.

Meechan and Kanaa et al. (117) compared the results from the mandibular buccal

infiltration using lidocaine to a combined mandibular and lingual infiltration of the mandibular first molar using lidocaine. One cartridge was administered, half at the

buccal site and half at the lingual site. Success was lower with the combined infiltration

(32.3% vs. 38.7%), but this difference was not significant.” (1)

“Robertson et al. (29) conducted a prospective, randomized, double-blind study

comparing the anesthetic efficacy of an infiltration injection of a 4% articaine solution

1:100,000 epinephrine to a 2% lidocaine solution 1:100,000 epinephrine in mandibular

posterior teeth. One cartridge of either solution was given near the apex of the first

molar, and then all four posterior teeth were pulp tested for a one hour period. The

60 articaine solution was found to be superior to the lidocaine solution for all teeth tested.

Haase et al. (30) found a supplemental buccal infiltration injection using 4% articaine with 1:100,000 epinephrine to be superior to the same injection using 2% lidocaine with 1:100,000 epinephrine in the mandibular first molar. Following a standard inferior alveolar nerve block with 4% articaine with 1:100,000 epinephrine, one cartridge of either articaine or lidocaine was deposited at the apex of the mandibular first molar, and all four posterior teeth were analyzed for pulpal anesthesia with the electric pulp tester. The first molar showed a significant improvement with articaine (p=0.0075).

Articaine did not show a significant improvement with the second molar or first and second premolars probably because success was already so high from the IAN block injection alone.” (2)

“Rosenberg et al. (101) found no difference between 4% articaine with 1:100,000 epinephrine and 2% lidocaine with 1:100,000 epinephrine when given as a supplemental mandibular or maxillary buccal injection to patients with irreversible pulpitis. A double- blind injection with one carpule of either articaine or lidocaine was given following either

an infiltration injection in the maxilla with 1.8 mL 2% lidocaine with 1:100,000 or an

IAN block injection in the mandible with 3.6 mL 2% lidocaine with 1:100,000

epinephrine. A VAS was used to rate the pain experienced throughout the procedure.

There were no significant differences in the percentage change in VAS score following

supplemental anesthesia with either articaine or lidocaine.” (2)

“Jung et al. (99) looked at the effects of articaine when given as an inferior

alveolar nerve block injection compared with a buccal infiltration injection. Success was

defined as having two consecutive 80/80 readings at some point throughout the 30-

61 minute testing period. No significant differences were found between the two injection types (p=0.34).

Ram et al. (107) assessed the reaction of children and anesthetic efficacy when using 4% articaine with 1:200,000 epinephrine compared with 2% lidocaine with

1:100,000 epinephrine. Sixty-two pediatric patients who needed similar operative procedures were randomly assigned to receive either articaine or lidocaine at their first or second visit. Twenty-two of the patients were given IAN blocks at both appointments, and 40 were given maxillary infiltration injections at both appointments. Modified

Taddio's behavioral pain scale was used to evaluate pain reaction during injection and treatment and the sensation after injection and treatment was evaluated using the Wong-

Baker FACES pain rating scale. No difference regarding the efficacy of the anesthesia or reaction to pain was observed.” (2)

Corbett (174) studied the anesthetic efficacy of a 1.8 mL buccal infiltration injection of 4% articaine with 1:100,000 epinephrine and a 0.9 mL buccal infiltration injection plus a 0.9 mL lingual infiltration injection of 4% articaine with 1:100,000 epinephrine. There was no significant difference in the anesthetic success (two consecutive 80 readings) between the buccal infiltration and the buccal plus lingual infiltration (64.5% vs. 67.7%, respectively).

Kanaa et al. (100) investigated the effectiveness of a supplementary buccal infiltration of 4% articaine as a means of increasing the effectiveness of the IAN block.

The supplementary buccal infiltration increased the incidence of successful anesthesia

(two consecutive 80 readings) from 55.6% to 91.7% in the first molar, from 66.7% to

88.9% in the premolars, and from 19.4% to 77.8% in the lateral incisor (100).

62 Matthews et al. (102) investigated the anesthetic efficacy of a supplemental

infiltration injection of 4% articaine with 1:100,000 epinephrine in mandibular posterior teeth diagnosed with irreversible pulpitis when the conventional IAN block failed. Thirty- two out of fifty-five (58%) patients had anesthetic success with the supplemental articaine infiltration (102).

Aggarwal et al. (105) investigated the anesthetic efficacy of supplemental buccal and lingual infiltrations with 4% articaine with 1:200,000 epinephrine and 2% lidocaine with 1:200,000 epinephrine after an IAN block. The supplemental buccal and lingual infiltration with 2% lidocaine with 1:200,000 epinephrine and 4% articaine with

1:200,000 epinephrine improved the success rate (“no pain” or “weak/mild” pain during access preparation and instrumentation) from 33% to 47% and 67%, respectively. The success rate with the articaine solution was significantly higher than with the lidocaine solution (p<0.05).

“Pabst et al. (204) studied the anesthetic efficacy of a repeated infiltration injection of articaine given 25 minutes following a primary articaine infiltration injection in mandibular posterior teeth. The repeated infiltration of articaine increased the anesthetic success (two consecutive 80 readings) from 69.8% to 84.9% in the second

molar, from 66.3% to 83.7% in the first molar, from 78.8% to 97.7% in the second

premolar and from 80.7% to 92.8% in the first premolar. A repeated injection of

articaine significantly (p<0.05) increased the anesthetic success for all teeth when

compared to a repeated mock injection.” (1)

Fan et al. (202) evaluated the effect of a supplemental buccal infiltration (BI) or

periodontal ligament (PDL) injection with articaine following administration of an IAN

63 block in patients with irreversible pulpitis in the mandibular first molar. Twenty-two of

twenty-seven patients (81.48%) were judged to have successful anesthesia (the ability to

complete endodontic access without pain or with mild pain) in the IAN block/BI group

while twenty-five of thirty patients (83.33%) in the IAN block/PDL group had successful

pulpal anesthesia. There was no statistically significant difference between anesthetic

success rate or subjective injection pain ratings between the IAN block/BI group and the

IAN block/PDL group.

Nuzum (207) studied the anesthetic efficacy of a combination labial plus lingual

infiltration compared to a labial infiltration using 4% articaine with 1:100,000

epinephrine in mandibular anterior teeth. The labial plus lingual infiltration of articaine

increased the anesthetic success (two consecutive 80 readings) from 76% to 98% in the

mandibular lateral incisor, from 82% to 99% in the mandibular central incisor and from

74% to 93% for the mandibular canine. A labial plus lingual infiltration injection of

articaine significantly (p<0.05) increased the anesthetic success for all teeth when

compared to a labial plus mock infiltration injection.

McEntire (1) compared the anesthetic efficacy of 1.8 mL of 4% articaine with

1:100,000 epinephrine to 1.8 mL 4% articaine with 1:200,000 epinephrine in mandibular buccal infiltration injections given next to the first molar. No statistically significant differences were found between the test solutions in frequency of pulpal anesthesia

(80/80 readings) for any of the teeth tested. The two solutions showed no statistically

significant differences for any tooth when comparing onset of pulpal anesthesia,

anesthetic failure, short duration of anesthesia, slow onset of anesthesia and non-

continuous anesthesia.

64 EFFECT OF VOLUME ON ANESTHESIA

Vreeland et al. (14) studied the anesthetic efficacy of 1.8 mL of 2% lidocaine with

1:100,000 epinephrine, 3.6 mL of 2% lidocaine with 1:200,000 epinephrine, and 1.8 mL of 4% lidocaine with 1:100,000 epinephrine in human inferior alveolar nerve block.

Thirty subjects randomly received each of the solutions at three successive appointments.

The first molar, canine, lateral incisor, and contralateral canine were tested with the pulp tester at various time intervals up to 55 min. Successful anesthesia was defined as an

80/80 reading with the electric pulp tester within 16 minutes and the 80/80 reading was continuously sustained for 55 minutes. Anesthetic success, for all three solutions, occurred in 53-63% of the molars, in 47-63% of the canines, and in 33-43% of the lateral incisors. No significant differences in anesthetic success or failure were found among the three solutions. Potential anesthetic problems (failure, noncontinuous anesthesia, slow onset, and short duration) occurred in 43-57% of the molars, in 43-60% of the canines, and in 57-80% of the lateral incisors.

Nusstein et al. (163) evaluated the anesthetic efficacy of volumes of 1.8 mL and

3.6 mL of 2% lidocaine with 1:100,000 epinephrine for inferior alveolar nerve blocks. In this retrospective review of 13 studies from the section of endodontics at the Ohio State

University, the first molars, first premolars, and lateral incisors of 462 subjects were pulp tested for 55-60 minutes following administration of inferior alveolar nerve blocks. The anesthetic volumes evaluated were 1.8 and 3.6 mL of 2% lidocaine with 1:100,000 epinephrine. Anesthesia was considered successful when two consecutive 80 readings were obtained within 15 to 16 minutes and the 80 reading was sustained continuously for

55 to 60 minutes. The average success for the 1.8 mL volume was 53% of first molars,

65 61% of first premolars, and 35% of lateral incisors. The average success for the 3.6 mL

volume was 44% of first molars, 67% of first premolars, and 32% of lateral incisors.

Results showed no significant difference between the two volumes of anesthetic in

achieving successful pulpal anesthesia.

Nuzum (207) studied the anesthetic efficacy of a combination labial plus lingual

infiltration compared to a labial infiltration using 4% articaine with 1:100,000

epinephrine in mandibular anterior teeth. In mandibular lateral incisors, the labial and

lingual combination exhibited a significantly higher anesthetic success rate (two

consecutive 80/80 readings with the EPT) of 98% success when compared with a 76%

success rate with the single labial infiltration. Similarly, the central incisor and canine

adjacent to the infiltrations exhibited significantly higher anesthetic success rates when

compared with the single infiltration.

Pabst et al. (204) studied the anesthetic efficacy of a repeated infiltration injection

of articaine given 25 minutes following a primary articaine infiltration injection in

mandibular posterior teeth. The repeated infiltration of articaine increased the anesthetic

success (two consecutive 80 readings) from 69.8% to 84.9% in the second molar, from

66.3% to 83.7% in the first molar, from 78.8% to 97.7% in the second premolar and from

80.7% to 92.8% in the first premolar. A repeated injection of articaine significantly

(p<0.05) increased the anesthetic success for all teeth when compared to a repeated mock injection.

Scott et al. (205) studied the anesthetic efficacy of a repeated infiltration injection in maxillary lateral incisors. This prospective, randomized, single-blind, crossover study compared the degree of pulpal anesthesia obtained in 40 adult subjects with two sets of

66 maxillary lateral incisor infiltrations, given in two separate appointments: an initial infiltration of 1.8 mL of 2% lidocaine with 1:100,000 epinephrine plus a repeated infiltration of the same anesthetic and dose given 30 minutes after the initial infiltration, and an initial infiltration of 1.8 mL of 2% lidocaine with 1:100,000 epinephrine plus a mock repeated infiltration given 30 minutes after the initial infiltration. An electric pulp tester was used to test the lateral incisor for anesthesia in two-minute cycles for 90 minutes after the injection. The repeated infiltration improved pulpal anesthesia significantly in the maxillary lateral incisor in the period from 37 through 90 minutes postinjection. A repeated infiltration of 1.8 mL of 2 % lidocaine with 1:100,000 epinephrine given 30 minutes after the initial infiltration significantly improved the duration of pulpal anesthesia in the maxillary lateral incisor.

Mikesell et al. (164) compared the anesthetic efficacy of 1.8 mL and 3.6 mL of

2% lidocaine with 1:100,000 epinephrine for maxillary infiltrations. Ninety-six adult subjects randomly received infiltrations of 1.8 mL and 3.6 mL of the lidocaine solution at two separate appointments, in a crossover design. Thirty-two lateral incisors, 32 first premolars and 32 first molars were studied in this investigation. Anesthetic success

(obtaining two consecutive 80 readings with the electric pulp tester) for the two volumes ranged from 97% to 100%. The onset of pulpal anesthesia was not statistically different between the two volumes. For both volumes, the lateral incisors had a higher percentage of anesthesia of short duration than the first premolar and first molar. The 3.6 mL volume provided a statistically longer duration of pulpal anesthesia for the lateral incisor, first premolar, and first molar. There was no statistically significant difference in discomfort ratings for solution deposition between the two anesthetic volumes.

67 Brunetto et al. (206) evaluated the anesthetic efficacy of 3 volumes of lidocaine with epinephrine in maxillary infiltration anesthesia. A total of 25 subjects received 0.6,

0.9, and 1.2 mL of the anesthetic buccal to an upper canine. Test teeth were assessed with electrical stimulation to determine onset and duration of pulpal anesthesia. The 1.2 mL dose induced faster onset of pulpal anesthesia, a higher success rate, and a longer duration of soft tissue/pulpal anesthesia than were achieved with the other doses

(p<0.05).

THE ELECTRIC PULP TESTER

“The Analytic Technology Vitality Scanner model 2001 (Analytic Technology

Corp., Redmond, WA) is a clinical device used in dentistry to determine the vitality or nonvitality of teeth (49). It is currently marketed as the Kerr Electric Pulp Tester. The unit is powered by five 1.5-volt (AA size) batteries. The output stimulus is generated by a voltage source of 150 kilo-ohms internal impedance generating an output voltage that ranges from 15 to 300 volts. The amperage output ranges from 0 to 50 micro amps. The unit has a digital readout indicating stimulus level on a scale of 0 to 80, with 0 signifying no electrical output and 80 signifying maximum output. One count corresponds to one burst of ten pulses of negative polarity followed by a space ten pulses long. The device is one of constant current, meaning the current will remain stable, due to an increase in voltage, if variable resistances are encountered. The intensity of the stimulus increases at a rate preset on the control unit (118).

Once the probe contacts the tooth, the instrument turns on automatically. This automatic turn-on feature prevents any testing unless a good electrical circuit is

68 established. After electrical contact has been made with the tooth, the intensity of the stimulus increases slowly until a maximum output of 80 is reached or until the patient indicates a sensation, at which time the probe is removed. The tester automatically resets itself to zero output power once the probe is moved to another tooth. This feature prevents the possibility of placing a probe that is delivering an electrical stimulus of maximum intensity on an unanesthetized tooth. An indicator light on the probe signifies

when the unit is activated and the indicator lights on the display readout signify when the

batteries need to be recharged (118,119).” (1)

“Kitamura et al. (120) reported the Analytic Technology Pulp Tester to be 100%

accurate when testing teeth previously determined to be nonvital, and 99% accurate when

testing teeth previously determined to be vital (1% false negative, no response). Cooley

et al. (119) reported two of thirty teeth having endodontic treatment gave false positives.

Dreven et al. (13) evaluated the electric pulp tester as a measure of analgesia in vital

teeth. They tested 34 “normal” teeth, 33 asymptomatic teeth with restorations, caries, or

crown fracture, and 30 teeth with the clinical diagnosis of irreversible pulpitis.

Anesthesia was then administered by block or by infiltration, and the teeth were then

pulp-tested for up to 10 minutes to determine if they responded to the maximum output.

Endodontic therapy was then performed on the teeth and pain, if any, was recorded.

Dreven et al. (13) found that 100% of the normal teeth, 100% of the asymptomatic

carious or restored teeth, and 73% of the teeth with irreversible pulpitis could be

instrumented painlessly after an “80” reading with the electric pulp tester was achieved

prior to the operative procedure.

Certosimo and Archer (121) evaluated the ability of the Analytic Technology

69 electric pulp tester to measure the level of local anesthesia prior to operative procedures.

Pre-operative baseline vitality measures were performed on the teeth to be tested. Only vital teeth were included in this study. Anesthesia was then administered and 5 and 15

minutes were allowed for onset in the maxilla and mandible, respectively. Subjective

signs of anesthesia were confirmed and the teeth were again tested for analgesia using the

electric pulp tester. Operative procedures were started and patients were asked to rate

any sensation felt. If pain was felt during the procedure, supplemental injections were

given. Pain ratings were compared to the pulp test readings after the initial local

anesthetic was given. They found that the electric pulp tester was able to predict

difficulties in anesthesia with a 99% probability. The authors concluded that normal and

asymptomatic carious and restored teeth that obtained an “80” reading with the Analytic

Technology electric pulp tester are considered to have achieved profound pulpal

anesthesia. Teeth that respond at less than “80” have the potential for pain during

operative procedures. Both Dreven et al. (13) and Certosimo and Archer's (121) studies

showed that an “80” reading correlated with clinical anesthesia in normal, asymptomatic

teeth and that the electric pulp tester was an accurate means by which to evaluate local

anesthetic solutions and techniques in normal teeth.” (1)

“Mickel et al. (122) studied various interface media when using an electric pulp

tester. Of the liquids tested, Listerine® conducted the most voltage whereas, of

nonliquids, K-Y® Brand UltraGel and Crest® Baking Soda & Peroxide Whitening Tartar

Control toothpaste conducted significantly higher voltages. These results suggest that

different interface media conduct differently, and that the interface medium should be

water-based and not petroleum-based. These results support a previous study by Martin

70 et al. (123) which found that the medium used in electric pulp testing is not significant but should have a water base. Six electrode media were tested: Two types of toothpaste, prophylactic paste, colloidal graphite, saline pad, and inert oil. The authors found no significant difference between these media (121). It is unknown at this time why certain media conduct better than others.” (1)

THE VISUAL ANALOGUE SCALE

“Since patients’ pain complaints are subjective reports of an otherwise immeasurable stimulus, the sensitivity of the pain measures are constrained by the pain rating scale employed (124). One common type of rating scale used is the verbal rating scale (VRS), which is comprised of 5-7 word categories, such as “none”, “mild”,

“moderate”, and “severe” (125). Although it is the more traditional method for assessing pain, it is insensitive in that it does not measure small changes (126). Furthermore, the patient is forced to translate their feeling and perception into definitive words, and one word may mean different things to different people (125).

The visual analogue scale (VAS) represents another method of assessing pain perceptions. It is a line, the length of which is taken to represent the continuum of pain gradations. It is a simple, sensitive, and reproducible instrument that enables a patient to express the severity of his pain in such a way that it can be given a quantitative value.

The extremes of the line are taken to represent the limits of the pain experience; one end is defined as “no pain” and the other as “severe pain”. Huskisson (126) stated that the

VAS is ideal for crossover experiments, enabling one patient to express an opinion about the relative value of different treatments.” (1)

71 “Since the VAS is difficult to use with no guides other than the endpoints, and since the VRS only offers the patient 3 or 4 words to describe a full range of pain, a compromise between the two instruments was developed in 1983 by Heft and Parker

(124). The resulting graphic rating scale is a horizontal line with categorical descriptors designated on the line. This scale offers more sensitivity than a category rating scale, and is easier to use than a visual analogue scale. However, patients tend to cluster their responses around the descriptors. For this reason, Heft and Parker (124) spaced the words on the graphic rating scale reflecting the spacing between these descriptors as the patient perceived them. Good correlation has been found between pain measurements using visual analogue and simple descriptive pain scales (127).” (1)

72

CHAPTER 3

MATERIALS AND METHODS

Eighty-six adult subjects participated in this study. All subjects were in good

health as determined by a written health history and oral questioning. Subjects taking medications that could alter pain perception and/or alter articaine metabolism were excluded. All female subjects were questioned regarding pregnancy or suspected

pregnancy and were not allowed to participate if pregnant, suspected a pregnancy, were

nursing, or were trying to become pregnant. Females were required to take a urine pregnancy test (Osom®, Genzyme Diagnostics Corp, San Diego, CA) before

participation, at the start of each appointment. Also excluded were subjects who had

contraindications to the injection technique or to the anesthetic solution (4% articaine

with 1:100,000 epinephrine) or were under the age of 18 years or over the age of 65

years. Approval for this study was obtained from The Ohio State University Human

Subjects Review Committee and written consent was obtained from each participant.

Patients were also asked to sign a Health Insurance Portability and Accountability Act

(HIPAA) release form.

All 86 blinded subjects randomly received two injections consisting of a primary

mandibular buccal infiltration injection of 3.6 mL of 4% articaine with 1:100,000 epinephrine (Septocaine, Septodont, New Castle, DE) and 1.8 mL of 4% articaine with

73 1:100,000 epinephrine, in two separate appointments, spaced at least one week apart, in a crossover design. With the crossover design, there were 172 total infiltration injections administered and each subject served as his/her own control. Eighty-six infiltration injections were administered on the left side and 86 infiltration injections were administered on the right side. The same side randomly chosen for the first infiltration injection was used again for the second infiltration injection. The test teeth chosen for the experiment were the first and second molars and first and second premolars. The contralateral canine was used as the unanesthetized control to ensure that the electric pulp tester was operating properly and that the subject was responding appropriately during each experimental portion of the study.

All test teeth were clinically examined with a mirror and explorer prior to patient inclusion in the study. Teeth with previous endodontic therapy, large restorations, caries, full crowns, obvious periodontal disease, or restorations with poor margins were eliminated from the study. If, however, the subject’s contralateral side did qualify for inclusion in the study, the subject remained in the study and the R/L designation was adjusted as needed on the subject envelope and master list. The next opposite designation on the master list was then switched so that an even distribution between the two sides remained.

The master list was generated prior to the beginning of testing with the numbers

one through eighty-six used to identify the subjects corresponding to the order in

which they entered the study. Each patient number had a corresponding set of two

randomly-generated six-digit numbers, one representing 3.6 mL of 4% articaine with

1:100,000 epinephrine and one representing 1.8 mL of 4% articaine with 1:100,000

74 epinephrine. The master list also noted the order of use of the two anesthetics and the

side of the mandible that would be tested, both of which were randomly generated.

Only the random numbers were recorded on the data collection sheets in order to blind

the experiment from the subject, and only the principal investigator had access to the

master list.

Under sterile conditions, the articaine solution was drawn from standard

anesthetic cartridges into 5 mL Luer-Lok syringes to make up a volume of either 1.8

mL or 3.6 mL. The syringes were labeled with the appropriate six digit random

number assigned to the subject. Before drawing up the syringes, all anesthetic

cartridges were checked to ensure their expiration dates were after the projected end of

the study. The syringes were then placed inside a large envelope containing all of the

subject's paperwork. The syringes were not covered during the injection to ensure the

proper rate of solution deposition.

The infiltration injections were administered using the 5 mL Luer-Lok syringe

equipped with a 27-gauge 1¼” needle (Monoject, St. Louis, MO). Before the injection,

each subject was given a hybrid Visual Analog Scale (VAS) (see Appendix H). This

scale consisted of a 170 mm horizontal line with various demarcations which had

descriptive pain terms. These included; “none” (0 mm), “faint” (22 mm), “weak” (37

mm), “mild” (54 mm), “moderate” (83 mm), “strong” (112 mm), “intense” (142 mm), or

“maximum possible” pain (170 mm), placed along the VAS from left to right (Appendix

H). The subject was informed of the rating scales to be utilized and given a clipboard with three VAS lines (representing the three phases of the injection) and a pen. The subject was asked to mark a separate VAS to rate the pain they experienced at each stage

75 of the infiltration injection. The subject was told the stage of the injection at the beginning of each stage. The categories were “insertion” (insertion of the needle under the alveolar mucosa), “placement” (placement of the needle to the target site), and

“deposition” (deposition of the anesthetic solution at the target site.) Once the injection was complete, the patient marked the pain experienced for each injection stage with an

“X” on each corresponding VAS.

The primary mandibular buccal infiltration was administered buccal to the

mandibular first molar bisecting the approximate location of the mesial and distal

roots. Following drying of the alveolar mucosa with sterile 2”x 2” gauze, 0.2 mL of a

topical anesthetic agent (20% benzocaine gel, Patterson Dental Supply, Inc., St. Paul,

MN) covering the tip of a cotton tip applicator was placed for one minute at the

injection site. Next, with the subject’s mouth open, the operator’s free hand retracted

the corner of the mouth and the buccal mucosa adjacent to the posterior teeth. The

direction of the needle insertion was from a superior, anterior and lateral direction into

the buccal vestibule. The needle was gently placed into the alveolar mucosa (needle

insertion) and was advanced, within two to three seconds, until the needle was

estimated to be at or just above the apices of the roots of the first molar (needle

placement). No effort was made to align the bevel of the needle in any particular

direction. As the needle was advanced, no anesthetic solution was deposited. After

reaching the target site, aspiration was performed, and the full volume of the syringe

containing the articaine anesthetic solution was deposited over a period of two minutes

(solution deposition) at a rate of 1.8 mL per minute. The anesthetic solution for the

1.8 mL volume injection was deposited over the first minute and the syringe was then

76 held in place for one additional minute to help blind the subject to the volume of anesthetic delivered. To also help blind the injection, all subjects were blindfolded when they received the injection. All infiltrations were given by the senior author

(MM).

At the beginning of each appointment and before any injections were given, the experimental teeth and control contralateral canine were tested two times with an electric pulp tester (Kerr, Analytic Technology Corp., Redmond, WA) to ensure vitality of the test teeth and to obtain baseline pulp testing readings. These recordings and all future pulp test recordings were done in the following manner. The tooth being tested was isolated with cotton rolls and dried with gauze. Crest Gel® toothpaste (Procter & Gamble Co., Cincinnati, OH) was applied to the probe tip, which was then placed midway between the gingival margin and the occlusal edge of the tooth. The current rate was set at 25 seconds to increase from no output (0) to the maximum output (80). Alkaline batteries (Energizer, St. Louis, MO) were used and changed as needed. The patient was instructed to raise their hand when the initial sensation was felt. The tester probe was then removed from the tooth and the number appearing on the pulp tester at this time was recorded. If the subject did not feel a sensation and the maximum value of 80 was reached, the testing was stopped and a value of 80 was recorded. Trained research personnel performed all pre-injection and post-injection pulp tests. The tester wore non-latex gloves.

One minute after completion of the infiltration injection, the first and second molars were pulp tested with the Kerr EPT to determine clinical, pulpal anesthesia. At

2 minutes, the first and second premolars were tested. At 3 minutes, the contralateral,

77 control canine was tested. At every 6 minutes, the contralateral canine was tested with

a pulp tester with an incomplete circuit to test the reliability of the subject. This cycle

of testing was repeated every 3 minutes for 90 minutes.

Following the completion of pulp testing, subjects received a post-injection

survey with four VAS descriptor lines (see Appendix H) to rate the discomfort, soreness, or pain at the site of injection immediately after the numbness wore off, and in the mornings of the first, second, and third days following the day of injection (172 total surveys). The hybrid VAS descriptor lines used were the same as described previously for the injection survey. Subjects were also asked to note any additional side effects not

relating to pain or discomfort (e.g., numbness, swelling, bruising, etc.). The forms were

returned to the clinic by the subjects after the three days had passed since the

appointment. Surveys were collected after both injections/testing appointments. Subjects

were paid $30 for each of the two appointments and $7.50 for returning the VAS forms,

for a total of $75. If they desired, the subjects were paid as soon as each part of the study

was completed, but most were paid $75 at the completion of their participation.

No response from the subject at the maximum output (80/80 reading) of the pulp

tester was used as the criterion for pulpal anesthesia. Three definitions of success were

used in this study. In the first definition, anesthesia was considered successful if the

subject achieved the first of two consecutive 80/80 readings within the first 7 minutes of testing for the molars or the first 8 minutes of testing for the premolars and recorded the last of two consecutive 80/80 readings at minute 58 for the molars and minute 59 for the premolars. In the second definition, anesthesia was considered successful if the subject achieved the first of two consecutive 80/80 readings within the first 7 minutes of testing

78 for the molars or the first 8 minutes of testing for the premolars and maintained the

80/80 readings continuously through minute 58 for the molars and minute 59 for the

premolars. This more stringent definition excluded subjects who achieved pulpal

anesthesia, lost it, and then regained it before the end of the testing period (non-

continuous anesthesia). In the third definition, anesthesia was considered successful

when two consecutive 80/80 readings were obtained with the electric pulp tester at any time during the test period.

With a non-directional alpha risk of 0.05 and a power of 85% a sample size of

86 subjects was required to demonstrate a difference in anesthetic success of ± 20%.

The data from this study were collected and statistically analyzed. Between

group comparisons between the anesthetic solutions for anesthetic success and

incidence of anesthesia (80/80 readings) was analyzed using Multiple Exact McNemar

and was adjusted using the Step-down Bonferroni method of Holm. Between group

comparisons for onset time were made using using Multiple Wilcoxon, matched-pairs,

signed-ranks test and were adjusted using the Step-down Bonferroni method of Holm.

Between group comparisons of needle insertion, needle placement and solution

deposition pain and postoperative pain were made using Wilcoxon matched pairs signed-ranks test and was adjusted using the Step-down Bonferroni method of Holm.

Comparisons were considered significant at p<0.05.

79

CHAPTER 4

RESULTS

The data from this study can be found in Appendices A through J. The results are

summarized in Tables 1 through 25 and in Figures 1 through 6. The medical history

form, medical consent form, and master list are listed in Appendix D, E, and G,

respectively.

Forty-three females and 43 males, ranging in age from 20 to 45 years, completed

the study. The average age of all participants was 25.6 years (Table 1). The raw

biographical data for all subjects can be found in Appendix C. All subjects were healthy

and did not have any conditions that would interfere with the study.

During the injection procedure, subjects rated pain for needle insertion, needle

placement, and solution deposition. A hybrid Visual Analog Scale (VAS) with

descriptors was used for this study (Appendix H). Mean pain ratings for needle insertion,

needle placement, and solution deposition during the buccal infiltration injections are

presented in Table 2 and Figure 1. Frequency of pain ratings by category (none, mild,

moderate, and severe) are summarized in Tables 4 through 6.

The mean needle insertion pain rating for Group 1 was 25.4 + 21.6 mm and for

Group 2 was 26.8 + 21.9 mm (Table 2). Mean insertion values for both groups fell in the

“mild” pain category and there was no statistical difference between the groups

(p=1.0000) (Table 2). The frequency of needle insertion pain ratings, using the

80 descriptive scale, for each solution can be found in Table 4. For group 1, 16 subjects

(18.6%) reported no pain, 67 subjects (77.9%) reported “mild” pain, 2 subjects (2.3%) reported “moderate” pain, and 1 subject (1.2%) reported “severe” pain for. For group 2,

14 subjects (16.3%) reported no pain, 65 subjects (75.6%) reported “mild” pain, 7

subjects (8.1%) reported “moderate” pain, and no subjects reported “severe” pain (Table

4).

The mean needle placement pain rating for Group 1 was 36.2 + 23.3 mm and for

Group 2 was 39.1 + 27.1 mm (Table 2). Mean placement values for both groups fell in

the “mild” pain category and there was no statistical difference between the groups

(p=1.0000). The frequency of needle placement pain ratings, using the descriptive scale, for each solution can be found in Table 5. For Group 1, 4 subjects (4.7%) reported no pain, 72 subjects (83.7%) reported “mild” pain, 10 subjects (11.8%) reported “moderate”

pain, and no subjects reported “severe” pain. For group 2, 8 subjects (9.3%) reported no

pain, 62 subjects (72.1%) reported “mild” pain, 16 subjects (18.6%) reported “moderate”

pain, and no subjects reported “severe” pain (Table 5).

The mean solution deposition pain rating for Group 1 was 36.8 + 28.6 mm and for

Group 2 was 36.8 + 27.2 mm (Table 2). Mean deposition values for both groups fell in

the “mild” pain category and there was no statistical difference between the groups

(p=1.0000). The frequency of solution deposition pain ratings, using the descriptive

scale, for each solution can be found in Table 6. For Group 1, 12 subjects (14.0%)

reported no pain, 59 subjects (68.6%) reported “mild” pain, 15 subjects (17.4%) reported

“moderate” pain, and no subjects reported “severe” pain. For Group 2, 10 subjects

(11.6%) reported no pain, 61 subjects (70.9%) reported “mild” pain, 15 subjects (17.4%)

81 reported “moderate” pain, and no subjects reported “severe” pain (Table 6).

No statistically significant differences in pain ratings were found between males and females at any stage of the injection regardless of which volume of anesthetic solution was used (Table 3). In general, males reported more discomfort than females for each stage of the injection for both groups except for needle placement in Group 1 where females reported higher mean pain ratings. The mean VAS values for males and females were in the “mild” category for insertion, placement and solution deposition. The highest mean pain ratings were with males for solution deposition in Group 1. One female subject reported “severe” pain during needle insertion in Group 1. No statistically

significant differences were found in males or females between or within Groups 1 and 2.

The volume of anesthetic deposited had no significant effect on discomfort during the 3

stages of the injection.

The electric pulp testing data for each of the experimental teeth in Groups 1 and 2

can be found in Appendix I. The percentage of 80/80 readings for each tooth at each

post-injection time interval in the two groups is reported in Tables 7 through 10

(Appendix A). Figures 2-5 illustrate the percentage of experimental teeth with readings of 80/80 for each test tooth at each postinjection time. All time intervals listed include every third minute between the interval endpoints because each tooth was pulp-tested every three minutes.

The Group 1 second molar, first molar, second premolar and first premolar had a higher percentage of 80/80 readings for each test time. The Group 1 second molars

(Table 7) had significantly more 80/80 readings at 10 minutes and again at 19 minutes and continuously up to 52 minutes, when compared to Group 2. The Group 1 first molars

82 (Table 8) had significantly more 80/80 readings by 7 minutes and continuously up to 49

minutes and at 64 minutes, when compared to Group 2. The Group 1 second premolars

(Table 9) had significantly more 80/80 readings by 35 minutes and continuously up to 89

minutes, when compared to Group 2. The Group 1 first premolars (Table 10) had

significantly more 80/80 readings by 23 minutes and continuously up to 77 minutes,

when compared to Group 2.

For the second premolar (N=85), the number of teeth tested was less than the total

number of subjects (N=86) because one subject had their second premolars previously extracted for orthodontic reasons.

The adjusted odds ratios for pulpal anesthesia are reported in Table 11. The gender of the subjects did not have a significant effect on the chance of any of the teeth gaining pulpal anesthesia. However, the volume of anesthetic used for the infiltration injection was found to have a significant effect on the chance of all four teeth gaining pulpal anesthesia. For the second molar, pulpal anesthesia was 3.12 times more likely when using 3.6 mL of 4% articaine with 1:100,000 epinephrine (Group 1) and the odds ratio was statistically significant (p<0.0001). For the first molar, pulpal anesthesia was

2.34 times more likely when using 3.6 mL of 4% articaine with 1:100,000 epinephrine

(Group 1) and the odds ratio was statistically significant (p<0.0001). For the second premolar, pulpal anesthesia was 3.05 times more likely when using 3.6 mL of 4% articaine with 1:100,000 epinephrine (Group 1) and the odds ratio was statistically significant (p<0.0001). For the first premolar, pulpal anesthesia was 3.75 times more likely when using 3.6 mL of 4% articaine with 1:100,000 epinephrine (Group 1) and the odds ratio was statistically significant (p<0.0001).

83 Three definitions of success were used in this study. In the first definition

(Success #1), anesthesia was considered successful if the subject achieved the first of two

consecutive 80/80 readings within the first 7 minutes of testing for the molars or the first

8 minutes of testing for the premolars and recorded the last of two consecutive 80/80

readings at or after minute 58 for the molars and minute 59 for the premolars. For the

3.6 mL volume of 4% articaine with 1:100,000 epinephrine solution (Group 1), success

by definition #1 was achieved in 14.0% of second molars, 22.1% of first molars, 54.1%

of the second premolars, and 37.2% of first premolars (Table 12). Success with the 1.8

mL volume of 4% articaine with 1:100,000 epinephrine (Group 2) was achieved in 7.0%

of second molars, 11.6% of first molars, 25.9% of second premolars, and 14.0% of first

premolars (Table 12). Success rates were higher with Group 1 for all four teeth. There

were no statistically significant differences between Groups 1 and 2 for the second molar

(p=0.0703), but the first molar, second premolar, and first premolar were significantly

different (p=0.0450, <0.0001, and =0.0001, respectively). Statistical analysis was done

using the Multiple Exact McNemar test and adjusted with the Step-down Bonferroni

method of Holm.

In the second definition (Success #2), anesthesia was considered successful if the

subject achieved the first of two consecutive 80/80 readings within the first 7 minutes of testing for the molars or the first 8 minutes of testing for the premolars and maintaining the 80/80 readings continuously through the minute 58 for the molars and minute 59 for the premolars. This more stringent definition excluded subjects who achieved pulpal anesthesia, lost it, and then regained it before the end of the testing period (non- continuous anesthesia). For Group 1, success by definition #2 was achieved in 12.8% of

84 second molars, 20.9% of first molars, 51.8% of second premolars, and 33.7% of first

premolars (Table 12). Success with Group 2 was achieved in 7.0% of second molars,

11.6% of first molars, 23.5% of second premolars, and 14.0% of first premolars (Table

12). Success rates were higher with Group 1 for all four teeth. There were no statistically significant differences between Groups 1 and 2 for the second molar

(p=0.1250) and first molar (p=0.0772), but the second premolar and first premolar were significantly different (p<0.0001, =0.0007, respectively). Statistical analysis was done using the Multiple Exact McNemar test and adjusted with the Step-down Bonferroni method of Holm.

Previously published studies (1,20,27-29,45,116,117,204,207) have also defined anesthetic success as two consecutive 80/80 reading at any point during the testing time.

Using this definition (Success #3), anesthesia in Group 1 was achieved in 65.1% of second molars, 75.6% of first molars, 92.9% of second premolars, and 91.9% of first premolars (Table 12). The incidence of definition #3 anesthetic success for Group 2 was

48.8% of second molars, 52.3% of first molars, 87.1% of second premolars, and 81.4% of first premolars (Table 12). There was no statistically significant difference between

Groups 1 and 2 for the second premolar (p=0.1797), but the second molar, first molar, and first premolar were significantly different (p=0.0129, <0.0001, and =0.0234, respectively). Statistical analysis was done using the Multiple Exact McNemar test and adjusted with the Step-down Bonferroni method of Holm.

Anesthetic failure was considered to have occurred if the subject never achieved two consecutive 80/80 readings within the testing period. The incidence of anesthetic failure with Group 1 was 34.9% in the second molars, 24.4% in the first molars, 7.1% in

85 the second premolars, and 8.1% in the first premolars (Table 13). The incidence of

anesthetic failure for Group 2 was 51.2% in the second molars, 47.7% in the first molars,

12.9% in the second premolars, and 18.6% in the first premolars (Table 13). There was

no statistically significant difference between Groups 1 and 2 for the second premolar

(p=0.1797), but the second molar, first molar, and first premolar were significantly

different (p=0.0129, <0.0001, and =0.0234, respectively).

The raw data for the onset of pulpal anesthesia for each experimental tooth can be

found in Appendix J. Onset of anesthesia was defined for each tooth as the time when

the first of two consecutive 80/80 readings were recorded. Only matched-pairs could be

statistically analyzed, meaning only those subjects who had onset times for each group per tooth were analyzed. For this reason, the number of subjects analyzed per tooth group differed from the total number of subjects tested (N=86). Anesthetic failures were

not included in this data because, by definition, there can be no onset of anesthesia when

anesthetic failure occurs. A summary of the times necessary for the attainment of pulpal

anesthesia for each experimental tooth can be found in Table 14. The mean onset time

(minutes) for the second molar was 4.6 + 5.0 in Group 1 and 4.9 + 3.8 in Group 2. The

mean onset time (minutes) for the first molar was 4.4 + 3.4 in Group 1 and 5.4 + 4.2 in

Group 2. The mean onset time (minutes) for the second premolar was 4.7 + 4.2 in Group

1 and 5.5 + 3.5 in Group2. The mean onset time (minutes) for the first premolar was 4.3

+ 3.2 in Group 1 and 5.6 + 4.0 in Group 2. For the first and second molars, there were no

statistically significant differences in mean onset times between Groups 1 and 2

(p=0.6318 and 0.6318, respectively). There was a statistically significant difference in

mean onset times for the first and second premolars between Groups 1 and 2 (p=0.0012

86 and 0.0141, respectively), however, while these values are statistically significant, they

are smaller than the pulp test intervals and therefore cannot be clinically significant.

(Table 14).

The mean duration of pulpal anesthesia was calculated for each experimental

tooth in Group 1 and 2. This was defined as the time period (minutes) between the first

of two consecutive 80/80 readings to the last of two consecutive 80/80 readings. The

measurement of anesthetic duration in this study was not a completely accurate indication

of the actual duration of anesthesia because the testing time was not open-ended. The

pulp testing period lasted 90 minutes for all teeth and did not continue until each tooth

lost pulpal anesthesia. Statistical analysis on the mean duration of anesthesia was not

performed due to these limitations in this study. The collected data can only give a

general idea of the expected duration of pulpal anesthesia. The mean duration of

anesthesia (minutes) for Group 1 was 47.0 + 20.8 for the second molar, 49.3 + 22.8 for

the first molar, 62.8 + 21.2 for the second premolar, and 55.0 +18.4 for the first premolar.

The mean duration of anesthesia (minutes) for Group 2 was 27.9 + 18.3 for the second

molar, 32.9 + 20.6 for the first molar, 42.3 + 21.4 for the second premolar, and 36.2 +

18.1 for the first premolar.

The raw data for slow onset of anesthesia for each experimental tooth can be found in Appendix J. Slow onset of anesthesia represents a longer-than-usual amount of

time necessary for the anesthetic to diffuse through tissues into the nerve bundle to effect its action. In the current study, teeth were considered to have a slow onset of anesthesia if the first of two consecutive 80/80 readings was recorded after minute 7 for molars and minute 8 for premolars. Data for slow onset could only be statistically analyzed with

87 matched-pairs, meaning only those subjects who had onset times for each group per tooth

were analyzed. For this reason, the number of subjects analyzed per tooth group differed

from the total number of subjects tested (N=86) and any anesthetic failures would not be

included in the data. Slow onset in Group 1 was seen in 10.5% of second molars, 8.9%

of first molars, 5.6% of second premolars, and 4.3% of first premolars. Slow onset in

Group 2 was seen in 15.8% of second molars, 11.1% of first molars, 12.5% of second premolars, and 13.0% of first premolars. There were no significant differences between

Groups 1 and 2 for any of the four teeth tested (Table 15).

The raw data for anesthesia of short duration for each experimental tooth can be found in Appendix J. Short duration is defined as achieving two consecutive 80/80 readings within 7 minutes for the molars and 8 minutes for the premolars, losing the

80/80 reading before the 60-minute test period, and not regaining it during the remainder of the testing period. Data for short duration could only be statistically analyzed with matched-pairs, meaning only those subjects who had onset times for each group per tooth were analyzed. For this reason, the number of subjects analyzed per tooth group differed from the total number of subjects tested (N=86) and any anesthetic failures would not be included in the data. Short duration in Group 1 was seen in 63.2% of second molars,

53.3% of first molars, 37.5% of second premolars, and 53.3% of first premolars. Short duration in Group 2 was seen in 84.2% of second molars, 77.8% of first molars, 69.4% of

second premolars, and 82.6% of first premolars. Each tooth in the 1.8 mL volume group

was significantly more likely to have anesthesia of short duration than the teeth in the 3.6

mL volume group. The percentages of short duration of anesthesia was significantly

higher for second molar, first molar, second premolar, and first premolar in group 2

88 compared to group 1 (p=0.0215, 0.0068, <0.0001, and =0.0001, respectively) (Table 16).

The raw data for non-continuous pulpal anesthesia for each experimental tooth

can be found in Appendix J. Non-continuous anesthesia was defined as obtaining two

consecutive 80/80 readings, losing the 80 readings, and then regaining them before 90

minutes of the testing period had passed. Non-continuous anesthesia for Group 1 occurred in 10.5% of second molars, 6.7% of first molars, 13.9% of second premolars,

and 10.1% of first premolars. Non-continuous anesthesia for Group 2 occurred in 7.9%

of second molars, 6.7% of first molars, 6.9% of second premolars, and 10.1% of first

premolars. There were no significant differences between Groups 1 and 2 for any of the

four teeth tested (Table 17).

Subjects rated pain for days 0 (day of appointment, after subjective anesthesia

wore off) to postoperative day 3 using a hybrid VAS with descriptors (Appendix H). The

subject rated the level of pain in the area of his/her mouth where the infiltration injections

were given. Subject post-operative pain rating responses were measured in millimeters

and were then placed into one of four different categories, as previously described.

The comparison of the mean postoperative pain rating values between Groups 1

and 2 is found in Table 18 and Figure 6. The mean values for each postoperative day and

for both solutions were in the “mild” pain range. Mean pain ratings decreased throughout

the postoperative period, from the day of the injection (when subjective numbness

ceased) to the third postoperative day. One subject (1.2%) reported “severe” pain ratings

for the first postoperative period (when subjective numbness ceased) for Group 1. The

mean pain ratings for Group 1 were higher for each post-operative period.

The comparison of the mean postoperative pain rating values between genders is

89 found in Table 19. Statistical analysis was performed using the Wilcoxon matched pairs

signed-ranks test and was adjusted using the Step-down Bonferroni method of Holm.

Females reported higher mean pain ratings for all postoperative time periods in both groups. All mean pain ratings were in the “mild” range for both genders. There was a statistically significant difference between Groups 1 and 2 for men and women at post-op day 0 and 1, and for men at post-op day 2. No statistically significant differences were seen for women at post-op day 2 or for either gender at post-op day 3. Between gender analysis showed a statistically significant difference (p=0.0240) for post-op day 2 for the

1.8 mL volume of 4% articaine with 1:100,000 epinephrine. No other statistically significant differences were seen between genders.

Data for the frequency of post-operative pain ratings (none, mild, moderate, severe) after the numbness wore off (Day 0) can be found in Table 20. For Group 1, 10 subjects (11.6%) reported no pain, 57 subjects (66.3%) reported “mild” pain, 18 subjects

(20.9%) reported “moderate” pain, and 1 subject (1.2%) reported “severe” pain. For

Group 2, 21 subjects (24.4%) reported no pain, 60 subjects (69.8%) reported “mild” pain,

5 subjects (5.8%) reported “moderate” pain, and no subjects reported “severe” (Table

20).

Data concerning post-operative pain for the first post-injection morning (Day 1) can be found in Table 21. For Group 1, 18 subjects (20.9%) reported no pain, 53 subjects

(61.6%) reported “mild” pain, and 15 subjects (17.4%) reported “moderate” pain. For

Group 2, 30 subjects (34.9%) reported no pain, 53 subjects (61.6%) reported “mild” pain, and 3 subjects (3.5%) reported “moderate” pain. No subjects reported “severe” pain in either group (Table 21).

90 Data concerning post-operative pain for the second post-injection morning (Day

2) can be found in Table 22. For Group 1, 32 subjects (37.2%) reported no pain, 44

subjects (51.2%) reported “mild” pain, and 10 subject (11.6%) reported “moderate” pain.

For Group 2, 45 subjects (52.3%) reported no pain, 38 subjects (44.2%) reported “mild”

pain, and 3 subjects (3.5%) reported “moderate” pain. No subjects in either group

reported “severe” pain (Table 22).

Data concerning post-operative pain for the third post-injection morning (Day 3) can be found in Table 23. For Group 1, 44 subjects (51.2%) reported no pain, 35 subjects

(40.7%) reported “mild” pain, and 7 subject (8.1%) reported “moderate” pain. For Group

2, 57 subjects (66.3%) reported no pain, 27 subjects (31.4%) reported “mild” pain, and 2

subjects (2.3%) reported “moderate” pain. No subjects in either group reported “severe”

pain (Table 23).

The frequency of postoperative complications, as reported by the subjects on the

returned questionnaires, is summarized in Tables 24 and 25. The majority of subjects did

not report any complications. There were no reports of any incidence of permanent

anesthesia or paresthesia, or any reports of hematoma or bruising following any of the

injections. The most frequent complication was a tenderness to touch at the site of

injection (18.6% in Group 1 and 8.1% in Group 2). Swelling was reported by 10.5% of

subjects in Group 1 and 4.7% in Group 2. One female subject in Group 1 reported 4-5

hours of paresthesia as numbness initially wore off. One female subject in Group 2

reported tingling in the premolar region on post-op days 2 and 3. Statistical analysis of

postoperative complications was not performed due to the low number of incidences for

each category.

91

CHAPTER 5

DISCUSSION OF MATERIALS AND METHODS

Selected portions of the following have been adapted from previous theses by

McEntire (1) and Pabst (2) from the Division of Endodontics at The Ohio State

University College of Dentistry.

Eighty-six adult subjects participated in this study of which 43 were males and 43

were females. “Reviews by Unruh (128) and Miaslowski (129) have indicated that there

are differences between males and females regarding clinical pain experiences. Unruh

(115) reported that females have higher levels of pain, have pain more frequently, and

have a longer duration of pain than do males. An equal number of males and females

were tested in the current study to attempt to eliminate gender as a variable.” (1)

“The population of subjects came entirely from The Ohio State University. Most

subjects were educated and tended to be dental students, dental hygiene students, and

college students. For this reason, it could be that this group may not have been

representative of that portion of the population who is fearful of dental procedures or

those who have difficulty in obtaining profound anesthesia. All subjects were in good

health as determined by a written health history and oral questioning. Good health was a prerequisite to be in this study to help avoid possible contraindications to the use of local

anesthetic with epinephrine, and to ensure the absence of systemic problems that could

negatively affect anesthetic efficacy. People who are in poor health may take

92 medications such as tricyclic antidepressants, nonselective β-adrenergic blockers, or adrenergic neuron blockers, including guanethidine, which relatively contraindicates the use of local anesthetic solutions containing epinephrine (34). In addition, systemic health problems can reduce the effectiveness and duration of local anesthetics.” (1) The age range for the subjects in this study was from 20 to 45 years, with a mean of 25.6 years.

“Nordenram and Danielsson (130) found that local infiltration injections were more effective in elderly patients than a younger age group. The authors speculated that this effect might be due to a higher pain threshold in the elderly.” (1) Since we studied a relatively young adult population, the results of this study may not apply to children younger than 18 or the elderly. The subjects had no contraindications to the injection techniques, nor the solution tested.

“The maximum recommended dose of anesthetic solution that should be given as a dental injection is dependent on the subject’s weight. The maximum recommended dose for 4% articaine regardless of epinephrine concentration is 7 mg/kg (32). In 1954, the New York Heart Association recommended that the maximum epinephrine dose be limited to 0.2 mg per appointment (131). This dose is usually reduced if the patient is a child or the patient has a medical condition that limits the use of a vasoconstrictor.

Bennett (132) recommended that the maximum dose of epinephrine in a cardiac risk patient should be no more than 0.04 mg. This equates to approximately two 1.8 mL cartridges with a 1:100,000 epinephrine concentration.” (1) In this study, the maximum amount of anesthetic solution injected during a single appointment was 144 mg (3.6 mL) of articaine and the maximum amount of epinephrine injected during a single appointment was 0.036 mg. These values were all well below the maximum allowable

93 dosages for the normal, healthy, adult subjects used in this study.

An over-the-counter pregnancy test, Osom® hCG-Urine Test, was utilized to rule

out pregnancy before females participated in the study. “The Osom® pregnancy test

detects human Chorionic Gonadotropin (hCG), which is present in urine only during

pregnancy. The Genzyme Diagnostics Corporation claims that urine specimens containing as low as 25 mIU/mL hCG will yield positive results when tested with the

Osom® hCG-Urine Test (133). In normal pregnancy, hCG levels in urine can reach 25

mIU/mL as early as 7 to 10 days post conception, and continue rising to reach a

maximum concentration in excess of 200,000 mIU/mL at the end of the first trimester

(134). McCready et al. (135) claimed that 25 mIU/mL can be detected as early as two to three days before expected menses. In one clinical study, 40 urine specimens were tested with the Osom® hCG-Urine Test and the results were compared to results obtained from other commercially available visual tests for hCG. The Osom® hCG-Urine Test, when

compared to other tests, resulted in a sensitivity of 100% and a specificity of 100%

(133).” (1)

“Several investigators have disputed the accuracy and reliability of home

pregnancy test manufacturer claims (136-140). These studies have reported accuracy

values from 46% - 89% (136-140), which are very different from the >99% detection

quoted by most manufacturers. Butler et al. (141), in researching manufacturer claims of

early detection pregnancy tests, questioned manufacturer claims and concluded that the

true accuracy of home pregnancy tests for detecting pregnancy on the day of and/or in the

week following the missed menstrual period is uncertain.” (1)

In our study, females who thought there might be any chance they were pregnant

94 were given the Osom® urine pregnancy test prior to both appointments. “The reason for

excluding pregnant or potentially pregnant women was due to the potential unknown risks of articaine to the fetus. To determine the risks associated with the use of drugs in

pregnancy, the FDA classifies prescription drugs based on fetal injury risk. The

Categories range from A to X. Drugs in Categories A and B are considered safe for use,

as no adverse effects have been demonstrated in humans. Drugs in Category C may be

used based on animal studies, but no controlled human studies are available. Category D

and X drugs have been associated with adverse effects in humans and should be

avoided.” (1)

“Articaine is classified in Category C by the Food and Drug Administration.

There have been no adequate or well-controlled studies in human pregnant women.

Leuschner et al. (81), however, studied the toxicologic profile of 4% articaine with

1:100,000 epinephrine in vitro and in vivo for repeated dose toxicity, reproduction toxicity, mutagenic potential, and local tolerance in animals. In their study, rats and dogs were subjected to repeated subcutaneous administration of 4% articaine. Reproduction studies were evaluated at doses ten times the maximum recommended human dose of 7 mg/kg/day and showed no evidence of harm to the fetus or to other related aspects of reproduction. This was true even when the doses were toxic to the parental animals. The mutagenicity studies also showed no mutagenic potential up to cytotoxic concentrations or up to the maximum tolerated dose levels. The authors concluded that the local tolerance of articaine was very good. The data indicated that articaine did not possess

any relevant side effects or toxicity and could be considered a safe local anesthetic.

However, animal reproduction studies are not always predictive of human responses (68)

95 and, therefore, articaine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.” (1)

The subjects’ motivation to participate in this study may have been for financial gain, a desire to learn more about anesthesia and the different injection techniques, or an interest in endodontics. All subjects were financially compensated for their participation at a rate of $35.00 per visit. Upon completion of all post-injection questionnaires, the subject was paid an additional $5.00 as an incentive to return the forms. A total of

$75.00 was paid to each subject who completed the study and returned both post- injection questionnaires. Participation in this study was voluntary in accordance with

The Ohio State University Human Subjects Committee.

This study involved a human test model that simulated a clinical setting. Animal studies can demonstrate the relative potency of various local anesthetics; however, animal studies cannot be used to directly correlate anesthetic effect in humans. For this reason, the use of a human test model allowed direct correlation between different anesthetic volumes.

The experimental teeth selected for this study were the mandibular first and second molars, and mandibular first and second premolars. Clinically normal pulps were evaluated in this study. Only virgin or minimally restored teeth were used. Teeth exhibiting active caries, periodontal disease, extensive restorations or a previous history of sensitivity disqualified that particular quadrant of teeth from participation in the study.

The pulpal anesthesia produced by the anesthetic solution was evaluated by the use of the electric pulp tester. “Bjorn (7) recommended the use of the electric pulp tester to evaluate the effects of local anesthetic solutions. McDaniel et al. (12) reported that the

96 electric pulp tester was safe to pulpal tissue. The use of the electric pulp tester did not produce histological changes, such as necrosis or inflammation. Bjorn (9) demonstrated that repeatable and reliable threshold values were attainable with the electric pulp tester on clinically normal teeth. Brynolf (142) demonstrated that repeated applications of a

local anesthetic followed by electric pulp testing did not alter the initial threshold

response values in a given subject. These findings enabled the subjects, who participated

in this study, to be given injections and to be pulp-tested in two successive appointments.

The repeated measures technique used in this study controlled the variable of sex, age,

anatomic variations and individual responses (142) to the electric pulp tester (10,119).”

(1)

This study utilized the Kerr (Vitality Scanner 2006) electric pulp tester to test the

anesthetic effectiveness of two different anesthetic volumes: 1.8 and 3.6 mL of 4%

articaine with 1:100,000 epinephrine. “Myers (143) reported telephone conversations

with SybronEndo which revealed that the Analytic Technology (Vitality Scanner 2005)

and the Kerr (Vitality Scanner 2006) electric pulp testers were identical in form and

function, with the only difference being the labeling on their display faces. Since they

are constructed and function identically, data collected with the Analytic Technology and

Kerr electric pulp testers can be compared without the type of pulp tester being a factor.

The Analytic Technology electric pulp tester has been shown by Cooley et al. (119) and

Kitamura et al. (120) to be extremely accurate (97-99%). This instrument has an internal

resistance of 150 k/ohms in order to negate the effects of high resistance in teeth as

recommended by Bjorn (7) and Mumford and Bjorn (144). The maximum voltage of this

instrument is 300 volts. One hundred and forty volts was found, by Matthews (145,146)

97 to be sufficient to stimulate all vital pulps in normal, asymptomatic teeth. Fifty

microamperes is the maximum amperage of the Kerr electric pulp tester. The current

output must be sufficient to stimulate the pulpal tissue but not to stimulate tissues beyond

the confines of the tooth. A current of 50 microamperes was found to be sufficient by

Pepper and Smith (147) and Matthews (146), to stimulate healthy pulps and a current of

200 microamperes was necessary to stimulate the surrounding periodontal tissues.

Researchers have recommended the use of an electric pulp tester, which stimulates with

cathode polarity, since tissues have a lower threshold for stimulation using cathode polarity, rather than anode polarity (144,145,147). Matthews (145,146) also suggested

that a constant current stimulation system be used. This results in a more valid vitality

reading in comparison to an impulse current stimulation system. A constant current

system allows the current output to remain stable even if variable resistances are

encountered in tooth structures (118).” (1)

The Kerr electric pulp tester was utilized in this study because it functions by the

aforementioned criteria. “The unit delivers a cathodal polarity current output from 0 to

50 microamperes and generates an output voltage that ranges from 15 to 300 volts. It

possesses an internal resistance of 150 k/ohms and is a constant current stimulation

system (118). During the study, the rate of voltage increase was calibrated so that the

elapsed time to obtain an 80 reading starting from a 0 reading was approximately 25

seconds. This rate of voltage increase was chosen because Kleier et al. (148) found that a

slow rise in voltage output (25 seconds to go from 0/80 to 80/80) resulted in a

significantly less painful response to the patient when compared to a more rapid rise (5

seconds to go from 0/80 to 80/80). Alkaline batteries were used and changed as needed

98 to ensure adequate power supply.” (1)

“Dreven et al. (13) used the Analytic Technology pulp tester to measure clinical

analgesia in normal teeth, asymptomatic carious or restored teeth with a clinical diagnosis of irreversible pulpitis. In their study, the teeth were tested with the electric pulp tester ten minutes after anesthetic solution administration. If a reading of 80/80 was obtained, a pulpectomy was performed on the tooth to test clinical analgesia. If a reading of 80/80 was not obtained after ten minutes, then supplemental injections were administered until a reading of 80/80 could be obtained. Once a reading of 80/80 was obtained, a pulpectomy was performed to test clinical analgesia. Profound pulpal anesthesia was obtained 100% of the time in normal and in asymptomatic carious or restored teeth.

Profound pulpal anesthesia was obtained in only 73% of the teeth with a diagnosis of irreversible pulpitis. They concluded that normal, asymptomatic carious and restored teeth that obtained an 80/80 reading with the Analytic Technology electric pulp tester were considered to have achieved profound pulpal anesthesia.” (1)

“Furthermore, Certosimo and Archer (121) concluded from their study that the

Analytic Technology electric pulp tester was an accurate predictor of the level of clinical pulpal analgesia in asymptomatic carious teeth. Their results showed that a reading of

80/80 with the Analytic Technology electric pulp tester predictably indicated that the patient would experience no pain during cavity preparation procedure. In addition, they found that soft tissue signs of anesthesia were not reliable indicators of local anesthesia.

All subjects had soft tissue signs of anesthesia; however, 21% of the subjects experienced pain during tooth preparation. All of these subjects had readings less than 80. It is on these findings that we base the interpretation of our data in this study.” (1)

99 Prior to pulp testing, all teeth were dried with a 2x2 inch cotton gauze and isolated

with cotton rolls. “Stephan (149) and Narhi et al. (150) showed that if the experimental

teeth were not dried adequately, there could be a response to electrical stimulation of the

periodontal tissues resulting in a false positive response. Cooley et al. (119) and Cooley

and Robinson (151) showed that wet teeth may allow shunting of the electrical stimulus

resulting in false negative responses.” (1) The electrode medium chosen for this study

was Crest® gel toothpaste. “Martin et al. (123) compared various brands of toothpaste,

as well as other water-based media, as an electrolyte for electric pulp testing. They found

no differences among the media tested in terms of conductance ability from the pulp

tester to the tooth. Crest® gel was preferred over non-gel toothpastes because it did not

dry out as quickly, it had a thicker viscosity which minimized flow, and its water

solubility allowed easy removal from the tooth with a wet gauze.” (1)

The principal investigator and trained assistants performed the electric pulp testing. Both the assistants and the subjects were blinded to the solutions being used at each appointment. The experimental teeth and control tooth were tested two times prior to the injection with the Kerr electric pulp tester. The readings were recorded and served as baseline information. The baseline information was used to determine if all the test teeth were vital. If any teeth registered 80/80 two straight times, they were determined to

be non-vital which disqualified that side of the subject’s mandible from the study. If this

occurred, the testing was done on the patient’s contralateral side and the next applicable

master list L/R designation was reversed so that left and right sides were equally

represented overall.

All testers wore non-latex or vinyl gloves to conform to infection control

100 guidelines. The Kerr electric pulp tester was supplied with an electrical lead that attached

to both the electrode and a lip clip. The lip clip could be held by hand or placed on the

lip to establish the necessary contact to complete the electrical circuit required by the electrical pulp tester. The probe was placed flat against the buccal or facial enamel in the middle third of the clinical crown. “Jacobson (152) evaluated probe placement sites on anterior and premolar teeth using an oscilloscope, an Analytic Technology pulp tester and

extracted teeth. He found placing the probe on the incisal edge or the occlusal two-thirds

of facial enamel of the tooth was the best location for the placement of the probe. This

placement used the minimal voltage necessary to stimulate the pulpal fibers. It also reduced the likelihood of stimulation of the nerve fibers in the gingiva. Bender et al.

(153) showed that the condition of the tooth enamel affected the threshold response.

They felt that optimal probe placement location in non-anesthetized anterior teeth was on the incisal edge. Recently, Lin et al. (154) aimed to determine the best location for probe placement on first molars. They found the lowest threshold for electric pulp test response to be on the mesiobuccal cusp tip. A progressive increase in readings from the mesiobuccal cusp tip to the middle third of buccal surface was found; however, these differences were not significant. There were no significant differences between maxillary and mandibular molars or between male and female subjects. ” (1) In this study we used the middle third of the clinical crown to remain consistent with previous studies conducted by the Division of Endodontics at The Ohio State University.

This study used a repeated-measures design in which each subject was seen at two appointments scheduled at least one week apart. “Brynolf (142) observed that the initial

threshold values of the experimental teeth were unaffected by the repeated administration

101 of local anesthetics and electrical pulp testing. McDaniel et al. (12) found that an electric

pulp tester at maximum current strength did not histologically affect the pulp or cause inflammation or necrosis.” (1) The one-week minimum period between appointments was selected to allow time for healing of possible post-injection sequelae, similar to the studies of Robertson et al. (29), Haase et al. (30), Pabst et al.(204), McEntire (1), and

Nuzum (207).

A master list (Appendix G) was generated prior to the beginning of testing, with

172 random six-digit numbers. Two of these numbers were assigned to each patient number (1 through 86) to identify the anesthetic solution given at each appointment. The order of use of the two anesthetic volumes was randomly generated. Therefore, half of the subjects received 1.8 mL 4% articaine with 1:100,000 epinephrine at the first appointment and 3.6 mL of 4% articaine with 1:100,000 epinephrine at the second

appointment. The other half of the subjects received the injections in the reverse order.

Randomizing the sequence helped prevent subject bias in terms of injection pain and

anesthetic efficacy. A letter code, R or L, was assigned to denote whether the buccal

infiltration injection was to be given on the subject’s right or left side. Both solutions

were given on the same side in each subject. This was done to remove the side of

injection as a variable, and to establish reproducibility for each injection so the subjects

could accurately compare the effects of each solution on the same teeth and same tissues.

The principal investigator performed all mandibular buccal infiltration injections. An

equal number of mandibular left and right sides were tested to attempt to eliminate right

versus left side as a variable: 43 subjects received left-sided injections and 43 received

right-sided injections. It is unknown if anesthetic success varies on the right or left side,

102 or what influence a right or left handed operator has on the anesthetic success of the side injected.

Under sterile conditions, the anesthetic cartridges were drawn up into 5 mL Luer-

Lok syringes and the corresponding six-digit codes were written on each syringe. No attempt to opaque the syringe was made so the principal investigator could accurately assess the rate at which the solution was deposited. Before drawing up the syringes, all anesthetic cartridges were checked to ensure their expiration dates were after the projected end of the study. The syringes were then placed inside an envelope containing all of the subject's paperwork.

The clinical assistants and subjects were unaware of the solution volume being delivered since they were not shown the syringe prior to and during injection. This avoided any bias or preconceived ideas concerning discomfort or their ability to get numb

with any particular anesthetic solution.

“Berlin (69) reported that although the 4% articaine with 1:100,000 epinephrine

solution is supplied in a cartridge labeled 1.7 mL, the volume delivered was equal to 1.8

mL of anesthetic in other dental cartridges (i.e. 1.8 mL of 2% lidocaine with

epinephrine). Weaver (67) acknowledged that articaine anesthetic cartridges actually

contain 1.8 mL of solution. The FDA requires the manufacturer to indicate the solution

as a 1.7 mL cartridge because some anesthetic cartridges were found to occasionally

contain slightly less than 1.8 mL of solution (67).” (2)

The buccal infiltration injection was administered using the 5 mL Luer-Lok

syringe and a 27-gauge 1¼ -inch needle. “This gauge needle was chosen since it is the

most commonly used in dentistry (155). The 27-gauge needles used in this study were

103 consistent with those used in previous studies conducted by the Division of Endodontics allowing comparisons to be made and additional data to be collected to corroborate the results of past studies.” (2)

Twenty percent benzocaine gel was utilized as topical anesthetic in this study.

The use of topical anesthetic has been advocated as an aid in reducing the pain of needle

insertion. “While Rosivack et al. (156) demonstrated the effectiveness of topical

anesthetic, Gill and Orr (157) and Kincheloe et al. (158) showed no significant pain

reduction with the use of topical anesthetic. Nusstein et al. (159) conducted a study to

compare the effectiveness of 20% benzocaine in reducing the pain of needle insertion

during maxillary posterior and anterior infiltration and inferior alveolar nerve block

injections. Logistic regression analysis showed no differences in pain ratings between

topical and no topical groups for the inferior alveolar nerve block and posterior maxillary infiltration injections. The use of topical anesthetic did reduce the pain of needle insertion with the maxillary anterior injections. For the inferior alveolar nerve block injection,

Yonchak et al. (22) and Nist et al. (20) concluded that there was not a significant difference in patient discomfort following application of topical anesthetic, Vaseline, or nothing to the site of injection. Martin et al. (160) found that if the patient thought they were receiving topical, whether they did or not, pain ratings were lower. Therefore, the most important aspect of using topical anesthetic may not be its clinical effectiveness, but rather the psychological effect on the patient who feels the practitioner is doing everything possible to prevent pain (160).” (1) The principal investigator chose to use topical anesthetic due to this psychological effect and the evidence from Nusstein et al.

(159) showing efficacy for use with infiltration injections.

104 All injections were given by the principal investigator. This was done to ensure uniformity with the injection technique. With the subject’s mouth open, the operator’s free hand retracted the corner of the mouth and the buccal mucosa adjacent to the posterior teeth. The direction of the needle insertion was from a superior, anterior and lateral direction into the buccal vestibule.

After initial penetration, the needle was advanced to the target site within two to three seconds. The needle was advanced until the tip of the needle was estimated to be at or just above the root apex of the first molar. No effort was made to align the bevel of the needle in any particular direction. “Malamed (32) states that ‘The orientation of the needle bevel is not a significant factor in the success or failure of an injection technique.’

” (1) As the needle was advanced over a period of 2 to 3 seconds, no anesthetic solution was deposited. There are no objective clinical studies that have evaluated injection discomfort using a 2-stage technique or the deposition of anesthetic solution while the needle is being advanced during a mandibular posterior buccal infiltration. Nusstein et al. (177) compared IAN block injection discomfort using a 2-stage and 1-stage injection technique. The authors found that the 2-stage injection technique, giving 0.4 mL of 2% lidocaine with 1:100,000 epinephrine submucosally and waiting 5 minutes before performing the traditional IAN block, provided significantly less discomfort for women during needle placement than a one-stage injection technique where 0.4 mL of 2% lidocaine with 1:100,000 epinephrine was deposited while the needle was advanced, but no significant difference in discomfort was seen for needle placement in men.

McCartney et al. (215) evaluated injection discomfort of IAN blocks in patients experiencing irreversible pulpitis of mandibular posterior teeth. The authors found that

105 there was no significant difference in needle placement discomfort between patients who

received an IAN block with 0.2-0.4 mL of 2% lidocaine with 1:100,000 epinephrine

deposited as the needle was advanced to the target site and patients who received an IAN

block without any solution being deposited during needle advancement. Since no

difference in needle placement discomfort was shown when anesthetic solution is

deposited as the needle is advanced to the target site (215), we decided to advance the

needle to the target site without depositing any anesthetic solution.

After reaching the target site, aspiration was performed, and the anesthetic solution (articaine) was deposited over a period of two minutes for the 3.6 mL volume

and over a one minute period with the syringe being held in place for an additional one

minute for the 1.8 mL volume. The two volumes of anesthetic were given at the same

rate of 1.8 mL per minute to blind the patients to which injection they were receiving. “A

one-minute period for solution deposition is recommended as a means of reducing patient

discomfort during injection. ‘Slow deposition of solution permits its gradual distribution

into the tissues…As a general rule, solution deposition should take approximately 1

minute per cartridge’ (161).” (1) The needle was removed after completing solution

deposition.

“In a clinical situation, many dental procedures require 60 minutes or less to be

completed. The key to providing dental treatment in a timely manner is having fast

anesthesia onset for both soft and pulpal tissues. Delayed onset of anesthesia results in

prolonged treatment times, which can cause the dentist to fall behind with the remainder

of the day’s patient schedule. In addition, the duration of anesthesia seems to be most

important during the first hour while treatment is performed and completed.” (1)

106 Subjects were asked to rate any pain felt during the three stages of the injection

for both anesthetic solutions using a hybrid Visual Analog Scale (VAS) (Appendix H).

This scale consisted of a 170 mm horizontal line with various demarcations which have

descriptive pain terms. These included; none (0 mm), faint (22 mm), weak (37 mm), mild

(54 mm), moderate (83 mm), strong (112 mm), intense (142 mm), and maximum possible

pain (170 mm), placed along the VAS from left to right. The three stages of the injection

surveyed included: needle insertion, needle placement, and solution deposition. Each

stage had its own VAS for recording the pain experienced. During the injection, the

principal investigator would state “insertion”, “placement”, and “deposition” at the time

that each stage of the injection occurred. The subjects were told to make a mental note of

the pain intensity caused at each of the three stages. Once the injection was completed,

the subjects would place a mark on the 3 VAS lines for each stage to describe their level

of pain, but not necessarily at the markings with the descriptive terms.

“The visual analog scale is a line, the length of which is taken to represent the

continuum of some type of experience like pain. It is a simple, sensitive, and

reproducible instrument that enables a patient to express the severity of his/her pain in

such a way that it can be given a numerical value (126). The scale is ideal for crossover

experiments, enabling one patient to express an opinion about the relative value of different treatments. The extremes of the line are taken to represent the limits of the pain experience; one end is therefore defined as ‘no pain’ and the other as ‘severe pain’

(126).” (1)

“The scale may be vertical or horizontal (126). Although 4- and 5-point scales have wide acceptance in literature, they appear to lack sufficient sensitivity to measure

107 the pain experience (124). Since a visual analog scale is difficult to use with no guides, other than the endpoints, a hybrid between the two scales was developed in 1983 by Heft and Parker (124). The resulting graphic rating scale was a horizontal line with category word designations on the line (124). Clusters of results tend to occur around the descriptors when a vertical VAS is used (126). However, when the line is horizontal this grouping is not seen (126). Good correlation has been found between pain measurements using visual analog and simple descriptive pain scales (127).” (1)

“Kreimer (162) investigated the efficacy and pain of injection of 2% lidocaine with 1:100,000 epinephrine versus a solution of 2% lidocaine with 1:100,000 epinephrine and 1.82 mL mannitol. He used both a hybrid visual analog scale and a numerical scale.

The numerical scale consisted of 4 pain ratings: 0 = none; 1 = mild; 2 = moderate; 3 = severe. The hybrid visual analog scale had 8 descriptive words on a 170 mm scale. The mean correlation value for all of the pain ratings was reported as 0.92. These results showed a very high correlation between the visual analog scale and the numerical scale.

Kreimer (162) stated that the results obtained from the visual analog scale were easier to analyze statistically. Therefore, Kreimer (162) felt that the visual analog scale was superior to the numerical pain scale.” (1)

Post-injection evaluation timing began immediately after the needle was withdrawn. Digital timers were used to keep pace with the post-injection time intervals.

The pulp testing began one minute after the injection was completed. The rate of voltage increase on the electric pulp tester was set at 25 seconds for the electric pulp tester to reach an 80 reading. This rate of increase automatically excluded more than two teeth being pulp tested each minute. At 1 minute post-injection, the experimental first and

108 second molars were tested with the electric pulp tester and the results were recorded. At

2 minutes post-injection, the first and second premolars were tested. One subject was missing one of their premolars, and therefore testing for the missing tooth was omitted.

The contralateral canine served as both a positive and a negative control. At 3 minutes post-injection, the positive control canine was tested. As a positive control, testing the non-anesthetized canine assured that the electric pulp tester was operating correctly. On every third cycle for the contralateral canine, the ground wire was removed from the electrical wand to evaluate the reliability of patient responses. This third cycle acted as the negative control. A positive response with the negative control would have disqualified the subject from further participation in this study. This did not occur. The testing cycle was repeated every 3 minutes for the 90-minute duration of the study. This testing cycle was implemented in order to remain consistent with the testing technique used in the studies of Robertson et al. (29), Haase et al. (30), Pabst et al. (204), Nuzum

(207), and McEntire (1).

Three definitions of success were used in our study. Definition #1 was defined as achieving the first of two consecutive 80/80 readings by the third testing cycle (7 minutes for molars and 8 minutes for premolars) and obtaining two consecutive 80/80 readings at or after the twentieth testing cycle (58 minutes for molars and 59 minutes for premolars).

A 60-minute duration of pulpal anesthesia was considered an adequate length of time of anesthesia for most dental procedures. In addition, 7-8 minutes of onset appears to be a reasonable time period to wait for anesthesia without significantly delaying treatment and wasting both the dentist and the patient’s time. This definition reliably showed which patients achieved pulpal anesthesia in a reasonable amount of time and maintained some

109 level of anesthesia for an hour. However, it included subjects that may have lost anesthesia and then regained it before 60 minutes of testing had been completed (non- continuous anesthesia). Clinically, this could result in pain during a dental procedure, even if the pain was temporary and was eventually relieved by the recurrence of anesthesia.

Definition #2 was defined as achieving the first of two consecutive 80/80 readings by the third testing cycle and continuously sustaining this reading through 60 minutes of testing. This was the most stringent definition of success. This definition ensured that, clinically, the subject would be numb for the entire 60-minute dental appointment and would not feel pain at any point during treatment. Other studies have also defined pulpal anesthesia using definitions similar to this (1,29,204,207) and can therefore be compared to our results.

Definition #3 was defined as the occurrence of two consecutive 80/80 readings at any time during the 90 minutes of testing. Using this definition means that the patient may only have a minimum of 3 consecutive minutes of pulpal anesthesia during the testing period and this may occur at any time. If the patient achieved pulpal anesthesia immediately before the tooth was tested and lost anesthesia immediately after it was tested at the next interval 3 minutes later, then the patient would have had anesthesia for only a 3 minute period. Therefore this definition is not as clinically useful as the first two definitions. However, several studies have used this definition when evaluating pulpal anesthesia (1,20,27-29,116,117,204,207), and it was added to our results for the purpose of comparison with these studies.

110 Anesthetic failure was considered to have occurred if the subject never achieved

two consecutive 80/80 readings. Anesthetic failure is the opposite of success #3. Single

80/80 readings would indicate that anesthetic duration only lasted for approximately 3

minutes, which would be clinically unacceptable. Teeth that respond to an electric pulp

tester at values less than 80 are likely to elicit a painful response when pulpal procedures

are performed (13,121).

Onset was evaluated for each of the four teeth tested. It was impossible to

determine exactly when onset of pulpal anesthesia occurred because all of the teeth

would need to have been tested continuously starting immediately after solution

deposition was completed. Due to the three minute testing cycle, we were only able to

determine onset to an accuracy of ± 3 minutes because a tooth could have theoretically

become numb immediately after it was tested and we would not have known it was

anesthetized until the next testing cycle 3 minutes later. We were, however, able to show

whether a tooth was anesthetized within a certain period of time. For this study, an onset

time of 7-8 minutes was considered clinically acceptable. This should allow enough time

for pulpal anesthesia to take place while not delaying the initiation of dental treatment.

Duration of anesthesia was analyzed by calculating the time period between the

first of two consecutive 80/80 readings to the last of two consecutive 80/80 readings.

Since the testing period in this study was not open-ended, the maximum duration was 90 minutes. For practical scheduling purposes, the pulp testing did not continue until each tooth lost anesthesia. Because this study was not open-ended we could not accurately assess the duration of anesthesia for teeth that remained numb at the end of the 90 minute

111 test period. Therefore, the average duration of anesthesia could not be accurately

calculated, but the calculation of duration allowed for the overall trend to be shown.

All subjects were provided a take-home survey to complete after each

appointment. This survey asked the subjects to rate any postoperative pain felt from the

injection site for 3 days using a VAS (Appendix H). The subjects completed the initial

part of the survey once they felt the anesthetic had completely worn off, indicated by

normal sensation in the subjects’ teeth and soft tissues. The subjects continued to rate

any postoperative pain experienced from the injection site upon waking each morning for

the next three days. It was felt that respondents would be more likely to take the time to

record any symptomotology they were experiencing before they became involved with

their daily activities. The frequency of reporting was chosen to be once daily as opposed

to multiple reports to further increase patient compliance. A VAS, similar to that utilized

to report injection pain, was used for this survey (Appendix H). Subjects also recorded any postoperative complications (swelling, tissue damage, etc.). The purpose of this was

to reveal and document any possible sequelae in hopes of understanding the mechanism

of their etiology. These surveys were also provided in order to allow for comparisons

with data from previous studies of Robertson et al. (29), Haase et al. (30), Pabst et al.

(204), Nuzum (207), and McEntire (1) to help build a larger study pool of subjects.

The data from this study were collected and statistically analyzed. Between

group comparisons between the anesthetic solutions for anesthetic success and

incidence of anesthesia (80/80 readings) was analyzed using a Multiple Exact McNemar

test and was adjusted using the Step-down Bonferroni method of Holm. The Multiple

Exact McNemar test was used due to the cross-over design of non-parametric data. The

112 Step-down Bonferroni method of Holm allows for corrections in α in situations where

multiple comparisons are made. This method allowed for a more stringent acceptance

of α making the analysis more powerful. Between group comparisons for onset time

were made using using Multiple Wilcoxon, matched-pairs, signed-ranks test and was

adjusted using the Step-down Bonferroni method of Holm. Between group

comparisons of needle insertion, needle placement and solution deposition pain and

postoperative pain were made using Wilcoxon matched pairs signed-ranks test and was

adjusted using the Step-down Bonferroni method of Holm. The Wilcoxon matched

pairs signed-ranks test was used due to the cross-over design of non-parametric, continuous data. Comparisons were considered significant at p<0.05.

113

CHAPTER 6

DISCUSSION OF RESULTS

Selected portions of the following have been adapted from previous theses by

McEntire (1) and Pabst (2) from the Division of Endodontics at The Ohio State

University College of Dentistry.

All the teeth used in this study were clinically normal, with no history of sensitivity, no active caries, no large restorations, and no periodontal disease. This

ensured that the pulps evaluated in this study were clinically normal. “Inflammatory conditions of the pulp affect clinical anesthesia (165)” (1); therefore, only asymptomatic, clinically normal teeth were used in this study. The experimental model used in this study was a repeated-measures design and therefore the distribution of age, weight, and gender between the two subject groups was identical.

The average age of the participants in this study was 25.6 years (Table 1).

“Nordenram and Danielsson (130) investigated different anesthetic parameters, such as onset time, frequency of anesthesia, duration of tooth anesthesia, and soft tissue numbness of commonly used dental local anesthetics in healthy older subjects. The authors found that the anesthetic solutions tested were more effective in the older group than the younger group. Nordenram and Danielsson (130) speculated that this might be due to a higher pain threshold in the older group due, possibly, to reduced vascularity,

114 fatty degeneration of bone tissue, or secondary dentin formation. Therefore, due to our low mean age, the results of the current study may not be applicable to older subjects.

Additionally, children under the age of 18 were not included in this study and the results of the study may not be applicable to children.” (1)

Forty-three females and 43 males were included in this study (Table 1). “Even with a repeated-measures design, it is important to have an approximately equal number of males and females because it is possible that a particular anesthetic may work differently depending on the subject’s gender. If this were the case, the results would not necessarily be applicable to the gender with low representation in the study.” (1) In our study, both genders were equally represented.

During this study, pain of injection and post-treatment pain were measured. The effect of differences in reporting pain between genders was also controlled by having an equal distribution of subjects. “Many studies have found differences between sexes regarding pain tolerance. Liddel and Locker (166) surveyed 5,061 adults about their thoughts and feelings regarding dental treatment. A five-point rating scale ranging from

1 (relaxed) to 5 (extreme fear) was used to measure dental anxiety and the experience of dental pain. Another four-point scale ranging from 1 (strongly agree) to 4 (strongly disagree) was used to measure pain avoidance, acceptance of pain, and fear of pain. The results showed that women were significantly more anxious about dental treatment than men (p<0.001) and dental anxiety decreased significantly with age (p<0.001). In addition, women said they would try to avoid pain more, accept pain less, and fear pain more than men (p<0.001).” (1)

115 “Fillingim et al. (167) studied clinical pain experiences, thermal pain thresholds, and pain tolerance in 209 (117 female and 92 male) healthy young adults. The subjects underwent thermal pain assessment, including the determination of their warmth detection threshold, their thermal pain threshold, and their thermal pain tolerance. The authors found that women had a significantly lower warmth detection threshold, thermal pain threshold, and thermal pain tolerance than men (p<0.001). Results showed a strong correlation between the thermal warmth detection and the thermal pain threshold. These results imply that the sex difference might be due to a generally enhanced somatosensation rather than a difference in nociceptive processing in women. Therefore the authors re-analyzed the difference in thermal pain threshold and thermal pain tolerance after statistically controlling for warmth detection. Women still showed significantly lower thermal pain threshold and thermal pain tolerance levels compared to males (p<0.001). Fillingim et al. (167) suggested that pain responses may be more clinically relevant for females than males. The authors concluded that the contributing factors may include hormonal alterations (168), resting blood pressure (169), and psychological factors (170). Other investigators have reported that other contributing factors, such as sex role expectancies (171) and anxiety (172) may also moderate differences in pain tolerance seen between sexes.” (1)

“Keogh et al. (173) studied the effects of two different attentional strategies

(focused versus avoidance) on how males and females responded to experimentally induced pain. Subjects attempted to place their non-dominant hand in an ice bath for up to 2 minutes. Pain threshold (the point of just noticeable pain), pain tolerance (the point at which the patient could not tolerate further pain and withdrew their hand from the

116 water), and pain recovery (the time needed for pain to dissipate after the subject withdrew

her/his hand) were measured. The subjects were then divided into 2 groups, the

avoidance group and the focused group. The avoidance group was asked to focus their

thoughts on things other than the cold water and the focused group was asked to concentrate on the sensations that their hand was having when placed into the cold water.

Keogh et al. (173) found that males had a significantly higher tolerance for cold pressor pain than females. The authors also found that males, who were given attentional focus instructions, had lower sensory pain compared to males whom were instructed to avoid pain. This was not true with the female groups.” (1)

In order for the results of this study to be considered valid for both sexes, it was important that both male and female subjects participated in this study. Differences due to gender regarding pain reported during needle insertion, placement, solution deposition, and postoperatively, and differences in anesthetic efficacy were possible in our study.

There were no significant differences between genders at any stage of the injection for either solution in the current study (Table 3). Similarly, all post-operative time periods for both solutions showed no significant difference in male versus female pain ratings

(Table 19). The repeated-measures design of our study helped ensure that differences due to gender would not affect the results when comparing pain levels and anesthetic efficacy of the two test solutions.

Two baseline electric pulp test readings for the experimental and control teeth were recorded prior to the injections at each appointment. “Bjorn (9), using the electric pulp tester on teeth, showed that daily variations in the thresholds of clinically normal teeth were not significantly different. Hinkley et al. (15), McLean et al. (16), and

117 Vreeland et al. (14) statistically compared baseline pulp test readings at three different

appointments spaced approximately one week apart. They showed no significant

differences in baseline electric pulp test readings.” (1) In the current study, baseline

electric pulp test readings were recorded. The values were not statistically analyzed

because they were used only to assure that the experimental teeth were vital.

PAIN OF INJECTION

Pain on Needle Insertion

During the injection procedure, subjects rated pain for needle insertion, needle

placement, and anesthetic solution deposition. Data for the mean insertion pain ratings

for Group 1 and Group 2 are reported in Table 2. Needle insertion pain ratings for the

current study are reported in Appendix H. A summary of the frequency of needle

insertion pain ratings, using a descriptive pain scale, for each solution can be found in

Table 4. Needle insertion for Group 1 resulted in a mean pain rating of 25.4 mm (“mild”

pain). Ninety-seven percent of pain ratings were in the none-to-mild category while 3%

were in the moderate-to-severe category. Needle insertion for Group 2 resulted in a mean

pain rating of 26.8 mm (“mild” pain). Ninety-two percent of pain ratings were in the

none-to-mild category while 8% were in the moderate-to-severe category. Both mean

values were in the “mild” pain category. Statistical analysis of needle insertion pain

ratings found no significant differences between the two solutions (Table 2). These findings were anticipated since the technique of needle insertion was identical regardless of the volume of anesthetic solution used. The same gauge needle (27-gauge) was used for all injections and the same operator performed each injection. One would not expect

118 solution volume to have an effect on the needle insertion pain ratings because no anesthetic solution was deposited during the insertion stage. When evaluating the gender differences in pain ratings during needle insertion, no difference between males and females for either Group 1 or Group 2 was found (Table 3). Because all injections were given by the principal investigator, operator difference was not a confounding factor in the findings of this study.

The pain ratings for needle insertion from our study can be compared with those of Robertson et al. (29), Pabst et al. (204), and McEntire (1) due to the location of the injection site. Robertson et al. (29) utilized an identical mandibular buccal infiltration injection next to the first molar with either 4% articaine with 1:100,000 epinephrine or

2% lidocaine with 1:100,000 epinephrine. Their reported mean needle insertion pain was

23.9 mm with articaine and 27.0 mm with lidocaine (29). Pabst et al. (204) gave an initial mandibular buccal infiltration injection next to the first molar with 4% articaine with 1:100,000 epinephrine followed by a repeated injection of 4% articaine with

1:100,000 epinephrine or a mock injection at 25 minutes. Needle insertion pain was only analyzed for the first injection because all but one of the subjects reported no pain for the repeated injection. The mean pain ratings for needle insertion for the initial injections were 19.6 mm and 21.7 mm. McEntire (1) gave an identical mandibular buccal infiltration injection next to the first molar with either 4% articaine with 1:100,000 epinephrine or 4% articaine with 1:200,000 epinephrine. Their reported mean needle insertion pain was 36.9 mm with 4% articaine with 1:100,000 epinephrine and 37.2 mm with 4% articaine with 1:200,000 epinephrine (1). Similar to the means in our study, these ratings were all in the “mild” pain range.

119 The low ratings could be attributed to the use of topical anesthetic. Topical

anesthetic was utilized in our study, as well as Robertson’s (29), Pabst’s (204), and

McEntire’s (1) studies, at the site of needle penetration prior to administration of the

buccal infiltration injections. “Mikesell et al. (164) evaluated the effect of using topical

anesthetic on maxillary infiltration injection pain ratings. Ninety-six volunteers

participated in the study. Before each injection, approximately 0.2 mL of topical

anesthetic or placebo was passively placed for 60 seconds. For all injections, three

minutes were used to administer the local anesthetic. The results showed that for the

maxillary lateral incisor with topical anesthetic, 81% reported none-mild pain and 19%

reported moderate-severe pain. For the maxillary lateral incisor without topical

anesthetic, 66% reported none-mild pain, and 34% reported moderate-severe pain. There

were no statistically significant differences between the topical anesthetic group and the

placebo group for the maxillary lateral incisor (p=0.129). Nusstein and Beck (159)

evaluated 20% benzocaine as a topical anesthetic for three injection types. They found that it had no effect on injection pain for inferior alveolar nerve block injections or for maxillary posterior infiltrations. The use of topical anesthetic did reduce the amount of pain reported by patients for maxillary anterior infiltrations.” (1)

“In a study similar to ours, Kanaa et al. (28) did not use topical anesthetic prior to a mandibular buccal infiltration using a 30-gauge needle next to the first molar utilizing a

4% articaine with 1:100,000 epinephrine solution. Pain ratings were recorded for the overall injection pain, as opposed to each phase of the injection, as was done in our study.

Because of this difference in pain evaluation, direct comparison of injection pain between the two studies cannot be made. In addition, Kanaa et al. used a 100 mm VAS without

120 descriptors between the endpoints, while the Heft-Parker VAS utilized in our study was

170 mm with descriptors between the endpoints. Still, it can be determined that in both studies, the mean VAS scores for needle penetration were in the ‘mild’ category as defined for each scale.” (1)

Corbett et al. (174) compared the efficacy of a buccal infiltration with a 4% articaine with 1:100,000 epinephrine solution to buccal plus lingual infiltrations with the same articaine solution in mandibular first molars using a 27-gauge needle. They reported the mean overall pain of injection to be 20.9 mm on a 100 mm VAS without the use of topical anesthesia which, using proportional analysis, would correspond to 35.5 mm on a 170 mm VAS. Although it cannot be directly compared to our pain measurement scale for the same reasons stated above, the values found in this study correlate to the “mild” pain levels found in our study. Meechan and Kanaa also compared buccal alone and buccal plus lingual infiltration injections using a 30-gauge needle without the use of topical anesthesia for efficacy of pulpal anesthesia of the mandibular first molar using a lidocaine solution (117). The overall pain of injection was recorded on a 100 mm VAS. The mean pain of injection for a buccal infiltration was

17.8 mm for 1.8 mL of lidocaine solution and 19.6 mm for 0.9 mL of lidocaine solution

(30.3 and 33.3 mm based on a 170 mm VAS, respectively). Both means correlate to a

“mild” pain rating. Nist et al. (20) also used a 100 mm VAS when evaluating an incisive nerve block using a 27-gauge needle with a lidocaine solution and no topical anesthetic.

The mean score for needle insertion was 9.23 mm (15.7 mm based on a 170 mm VAS) and in the ‘mild’ pain category as defined for this scale. Even without the use of topical anesthetic, the pain ratings for these studies are consistent with our results for mandibular

121 buccal infiltration needle penetration. A future study would need to directly compare the

use of topical anesthetic to the use of a placebo or no topical anesthetic to determine if

topical anesthetic has any effect on needle insertion pain for mandibular buccal

infiltrations.

“Since the pain experienced during an injection is more than a simple nociceptive

sensation, psychological factors may also influence the efficacy of topical anesthetics.

While the research indicates that the use of topical anesthetic would not significantly decrease the discomfort associated with an injection (157,158), Martin et al. (160) found that if the patient thought they were receiving topical anesthetic, pain ratings for an injection were lower than for those patients not believing they received a topical anesthetic. If there is truly a physiologic or psychologic effect produced by the use of topical anesthetic, it follows that the pain ratings for needle insertion and placement could have been higher had topical anesthetic not been used.” (1)

Pain on Needle Placement

Data for the mean placement pain ratings for Group 1 and Group 2 are reported in

Table 2. Needle placement pain ratings for the current study are reported in Appendix H.

A summary of the frequency of needle placement pain ratings, using a descriptive pain scale, can be found in Table 5. Needle placement for Group 1 resulted in a mean pain rating of 36.2 mm (Table 2). Eighty-eight percent of pain ratings were in the none-to- mild category while 12% were in the moderate-to-severe category (Table 5). Needle placement for Group 2 resulted in a mean pain rating of 39.1 mm. Eighty-one percent of

122 pain ratings were in the none-to-mild category while 19% were in the moderate-to-severe

category. Both mean values were in the “mild” pain category. There was no statistically

significant difference between the two groups for needle placement (Table 2). These

findings were anticipated since the technique of needle placement was identical

regardless of the anesthetic volume. Because no anesthetic was administered during

needle placement, one would not expect the anesthetic solution to have an effect on the

needle placement. In addition, no differences were seen between males and females for

pain ratings in either group during needle placement (Table 3).

Robertson et al. (29), Pabst et al. (204), and McEntire (1) reported on needle

placement pain for mandibular buccal infiltration injections given next to the first molar.

Robertson et al. (29) reported pain ratings of 33 mm for an articaine solution and 32 mm

for a lidocaine solution. Pabst et al. (204) reported pain ratings of 41.7 mm and 34.3 mm

for needle placement with the initial mandibular buccal infiltration with 4% articaine with

1:100,000 epinephrine. McEntire (1) reported needle placement pain ratings of 37.3 mm with 4% articaine with 1:100,000 epinephrine and 40.1 mm with articaine with 1:200,000 epinephrine (1). The mean pain ratings for these studies were in the “mild” category.

These findings were similar to our study.

“Haase et al. (30) reported pain ratings of 18.0 mm with 4% articaine with

1:100,000 epinephrine and 19.0 mm with 2% lidocaine with 1:100,000 epinephrine for needle placement during mandibular buccal infiltrations given next to the first molar.” (1)

These results cannot be compared to our study because an inferior alveolar nerve block with 4% articaine with 1:100,000 epinephrine was administered prior to the buccal infiltration injections. “The inferior alveolar nerve block has been shown to anesthetize

123 the buccal nerve 63-84% of the time (14,19). This may explain the lower values of

needle placement found in Haase’s study when compared to our study.” (1)

“The studies by Kanaa et al. (28), Corbett et al. (174), and Meechan and Kanaa

(117) evaluated the overall pain of injection, but did not report values for pain upon needle placement. Similarly, Nist et al. (20) using the incisive nerve block, did not distinguish between the phases of needle insertion and needle placement. Subjects in their study rated the entire injection in two phases called ‘needle placement’ and ‘solution

deposition.’ Nist et al. (20) also deposited 0.2 mL of anesthetic solution during ‘needle

placement’ and then 1.6 mL of anesthetic solution after the target site was reached.” (1)

Therefore, pain values for needle placement cannot be compared with these studies.

The mean pain values for needle placement were higher than the mean pain

values for needle insertion (36.2 vs. 25.4 mm for Group 1, and 39.1 vs. 26.8 mm for

Group 2 for needle placement and needle insertion, respectively) (Table 2). However,

both values were in the “mild” category. During needle placement, the needle penetrates

alveolar mucosal tissue and submucosal tissues until the apices are the 1st molar roots are

approximated. The minor trauma to mucosal and submucosal tissues can result in pain.

“The severity of the pain reported can be dependent on the subject’s pain tolerance, the

subject’s expectations of pain, the manner in which the practitioner executes the

injection, and possibly the design of the needle bevel used for the injection (175).” (2)

Pain on Solution Deposition

Data for the mean solution deposition pain ratings for Group 1 and Group 2 are

reported in Table 2. Solution deposition pain ratings for the current study are reported in

124 Appendix H. A summary of the frequency of solution deposition pain ratings, using a

descriptive pain scale, can be found in Table 6. Solution deposition for Group 1 (3.6 mL

of 4% articaine with 1:100,000 epinephrine) resulted in a mean pain rating of 36.8 mm.

Eighty-three percent of the pain ratings were in the none-to-mild category while 17%

were in the moderate-to-severe category. Solution deposition for Group 2 (1.8 mL of 4%

articaine with 1:100,000 epinephrine) resulted in a mean pain rating of 36.8 mm. Eighty-

three percent of pain ratings were in the none-to-mild category while 17% were in the

moderate-to-severe category. Both mean values were in the “mild” pain category, and there were no significant differences between the two groups (Table 2). The current study used a 27-gauge needle and deposited the 3.6 mL volume of anesthetic solution over a period of approximately 120 seconds and the 1.8 mL volume over a period of approximately 60 seconds and the needle was held in place for an additional 60 seconds.

This technique allowed for a solution deposition rate of 1.8 mL per minute and aided in the blinding of the subjects to which injection they were receiving.

The mean pain ratings for solution deposition in this study were consistent with studies by Robertson et al. (29), Pabst et al. (204), and McEntire (1) all of which used the same injection technique. The mean pain ratings for solution deposition for Robertson et al. (29), Pabst et al. (204), and McEntire (1) were 36 mm, 34.3-35.5 mm, and 30.0-30.1 mm, respectively. The mean values for those studies were in the “mild” category.

“Kanaa et al. (28) and Corbett et al. (174) also reported “mild” discomfort during solution deposition of 4% articaine with 1:100,000 epinephrine using a 30-gauge needle and depositing the 1.8 mL of anesthetic solution over a period of approximately 30 seconds next to the mandibular first molar. In trying to compare the studies by Kanaa et al. (28)

125 and Corbett et al. (174) to the current study, it appears that the needle gauge (30- vs. 27-

gauge) and speed of injection (30- vs. 60-second) may not play a role in solution

deposition pain in mandibular buccal infiltrations. However, a direct comparison is

difficult due to differences between the studies in pain measurement techniques.” (1)

Haase et al. (30) reported “mild” pain ratings for a buccal infiltration injection with 4%

articaine with 1:100,000 epinephrine, however their results cannot be directly compared

to the current study because an inferior alveolar nerve block was administered prior to the

buccal infiltration next to the first molar.

“Nist et al. (20) used a 27-gauge needle to deposit 1.6 mL of lidocaine with

1:100,000 epinephrine within the mental foramen over a period of two minutes following

the initial deposition of 0.2 mL of solution during needle insertion. A mean pain value of

11.1 mm on a 100-mm VAS for solution deposition was reported, which is consistent

with “mild” pain. Because a 170-mm VAS was used in our study, it is difficult to

compare the results. However, using proportional analysis, this score would represent a

rating of 18.9 mm (‘mild’ pain) on our scale.” (2) This pain value is lower than seen for

both groups in our study. The use of articaine in our study compared to the use of

lidocaine by Nist et al. is not likely the difference in pain ratings with solution deposition.

Robertson et al. (29) showed that there was no significant difference in solution

deposition pain between articaine and lidocaine when used in a buccal infiltration of the

mandibular 1st molar. The deposition of 0.2 mL of anesthetic solution during needle

insertion by Nist et al. may have helped reduce the overall pain of solution deposition as the anesthetic deposited during needle insertion may have begun anesthetizing the soft tissue in the area prior to the deposition of the larger bolus of anesthetic at the target site.

126 No other study has directly compared the pain of injection of 3.6 mL and 1.8 mL volumes of 4% articaine with 1:100,000 epinephrine for primary mandibular buccal infiltration injections over the first molar. Pabst et al. (204) added a supplemental injection of 1.8 mL of articaine with 1:100,000 epinephrine or a mock injection 25 minutes after a primary injection of 1.8 mL of articaine with 1:100,000 epinephrine. As such, Pabst et al. (204) also looked at 3.6 mL vs. 1.8 mL volumes of articaine for mandibular buccal infiltrations over the first molar. The values seen with Pabst et al.

(204) for each of the three stages of the injection were very similar to those seen in our study.

Unlike the first two stages of the injection, needle insertion and placement, one might expect to see a difference in pain during the third stage, solution deposition,

dependent on the volume of solution used. Since the rate of injection was held constant

in our study, the only explanation for any differences seen in solution deposition pain in

this study would be attributed to the volume of anesthetic deposited. Pabst et al. (204)

showed no significant differences in solution deposition pain between a repeated buccal

infiltration of articaine following a primary infiltration injection of 1.8 mL of 4%

articaine with 1:100,000 epinephrine (3.6 mL volume total) over the mandibular 1st molar and a mock injection following the same primary injection (1.8 mL volume total).

Vreeland et al. (14) studied the anesthetic efficacy of 1.8 mL of 2% lidocaine with

1:100,000 epinephrine, 3.6 mL of 2% lidocaine with 1:200,000 epinephrine, and 1.8 mL of 4% lidocaine with 1:100,000 epinephrine in human inferior alveolar nerve block. They found no significant differences in solution deposition pain between the different volumes or concentrations of anesthetic for an IAN block. Mikesell et al. (164)

127 compared 1.8 mL and 3.6 mL volumes of 2% lidocaine with 1:100,000 epinephrine for maxillary infiltration injections. They reported no significant difference in solution deposition discomfort between the two anesthetic volumes. Like the above studies, the current study found no significant differences between the 3.6 mL and 1.8 mL volumes of

4% articaine with 1:100,000 epinephrine with regard to solution deposition. This may be due to the rapid nature of soft tissue anesthesia seen in mandibular buccal infiltrations which provides complete soft tissue anesthesia prior to the completion of the deposition of 1.8 mL of anesthetic. The rapid soft tissue anesthesia allows additional volumes of anesthetic (3.6 mL in this study) to be deposited without additional discomfort. Since the rate of injection was held constant in our study and the rapidity of soft tissue anesthesia produced by articaine in mandibular buccal infiltrations, no significant difference in pain of solution deposition was seen for this stage of the injection.

“Subjects were instructed to rate pain after all three phases of the injection were completed. Comparative analysis by the subject may have been prevented if we had measured pain immediately after each phase of the injection. Additionally, some subjects may have been experiencing significant lingering discomfort from the needle placement phase of the injection and were unable to distinguish the solution deposition phase from the needle placement phase because of this lingering needle placement pain. Pain resulting from trauma to a structure may not generally disappear entirely the moment the trauma has ended.” (30)

It is apparent from the previously mentioned studies that moderate-to-severe pain is possible during a mandibular buccal infiltration injection using articaine with epinephrine (1,28,29,174,204). Thirty subjects (15 subjects in Group 1 and 15 subjects in

128 Group 2) in our study reported moderate-to-severe pain during solution deposition.

Variations in the rate of injection, differences in subjects’ pain thresholds, injection

location (in this study a mandibular buccal infiltration), and differences in solution

composition could all account for differences in pain ratings during solution deposition.

The current study and others (1,29,30,204) performed in the Division of Endodontics at

The Ohio State University have used a rate of injection of approximately 1 mL every 30

seconds, or 1.8 mL every minute. “Malamed (32) suggests slowing the rate of anesthetic

deposition to 1 mL in not less than 60 seconds, or 1.8 mL in about 2 minutes.” (1) The

previous statement by Malamed is not supported by any research and is simply his

opinion on the proper rate of anesthetic deposition. “Steinkruger et al. (178)

hypothesized that using a two-stage injection technique could minimize the severity of

the pain experienced during an inferior alveolar nerve block injection. Using the two-

stage injection, 0.4 mL of the anesthetic solution was deposited just beneath the mucosa

and the needle was withdrawn. After 5 minutes, the needle was re-inserted until the

target site was reached and the remaining anesthetic was deposited. It was thought that the initial injection would adequately anesthetize the soft tissue, thereby reducing the pain during needle placement and deposition of the solution at the target site. However, they reported no significant difference during solution deposition (2% lidocaine with

1:100,000 epinephrine) between the one and two-stage injection techniques (178).” (1)

These results may hold true for other injection techniques, but more research would be needed to properly ascertain the effect of a two stage injection on a mandibular buccal infiltration injection.

“It has been suggested that buffering anesthetic solution to make the pH similar to

129 that of the tissue may help to reduce solution deposition pain, but attempts to buffer an

anesthetic solution to reduce deposition pain has not produced significantly better results.” (1) Primosch and Robinson (179) and Whitcomb (180) attempted to reduce pain of different injection techniques, but the buffering of the anesthetic solutions failed to significantly reduce solution deposition pain in IAN blocks. Buffering of the anesthetic solution may or may not impact solution deposition for the mandibular buccal infiltration injections. Further research is needed to determine the effect of buffering the anesthetic solution on solution deposition pain in mandibular buccal infiltration injections.

In summary, the two volumes tested in the current study did not show a statistically significant difference in pain intensity during any of the three stages of the mandibular buccal infiltration injection (Table 2). Needle placement was the most painful stage for the 1.8 mL volume. Solution deposition was the most painful stage for the 3.6 mL volume. Needle insertion was the least painful stage for both volumes. All stages of the injection were in the mild pain category. Moderate-to-severe pain was experienced during needle insertion, needle placement, and solution deposition, however it occurred rarely for both groups. Gender did not affect pain ratings as there were no significant differences between males or females for any stage of the injection (Table 3).

ANESTHETIC EFFICACY

Several factors, such as frequency of pulpal anesthesia, anesthetic success, anesthetic failure, and the onset of pulpal anesthesia were considered when evaluating anesthetic efficacy. The following subsections evaluate the results of this study in those terms.

130 Frequency of Pulpal Anesthesia

Figure 2 and Table 7 illustrate pulpal anesthesia (% 80/80) of the mandibular second molar throughout the 90 minute testing period. The second molar had a higher percentage of 80/80 readings with Group 1 (3.6 mL of 4% articaine with 1:100,000 epinephrine) for each test time. Figure 3 and Table 8 illustrate pulpal anesthesia of the mandibular first molar throughout the 90 minute testing period. The first molar had a higher percentage of 80/80 readings with Group 1 (3.6 mL of 4% articaine with

1:100,000 epinephrine) for each test time. Figure 4 and Table 9 illustrate pulpal anesthesia of the mandibular second premolar throughout the 90 minute testing period.

The second premolar had a higher percentage of 80/80 readings with Group 1 (3.6 mL of

4% articaine with 1:100,000 epinephrine) for each test time. Figure 5 and Table 10 illustrate pulpal anesthesia of the mandibular first premolar throughout the 90 minute testing period. The first premolar had a higher percentage of 80/80 readings with Group

1 (3.6 mL of 4% articaine with 1:100,000 epinephrine) for each test time. Please refer to

Figures 2-5, Tables 7-10, and the results chapter for more detailed information on the frequency of pulpal anesthesia for Groups 1 and 2.

There were statistically significant differences between 3.6 and 1.8 mL of 4% articaine with 1:100,000 epinephrine regarding the incidence of pulpal anesthesia (80/80 readings) for each of the test teeth. When looking at Figures 2 through 5, the 3.6 mL volume of 4% articaine with 1:100,000 epinephrine solution demonstrated the ability to produce a higher incidence of pulpal anesthesia for all of the test teeth at each time period. The 3.6 mL volume of 4% articaine with 1:100,000 epinephrine had a higher percentage of 80/80 readings for each of the thirty test periods for the each tooth tested.

131 Pabst et al. (204) also showed significant differences regarding the incidence of

pulpal anesthesia (80/80 readings) for each of the test teeth when a repeated infiltration was administered 25 minutes after a primary buccal infiltration with 4% articaine with

1:100,000 epinephrine. When comparing to the incidence of pulpal anesthesia in this

study, we found higher incidence of pulpal anesthesia for the 3.6 mL group compared to

Pabst over the first 5 time periods, but then saw a steady decline in pulpal anesthesia over

the remainder of the test period. Pabst (2) showed an increase in the incidence of pulpal

anesthesia for all test teeth beyond what was obtained from the initial injection once the

repeated injection was administered. That is an example of augmentation, or enhanced

effectiveness of a drug when given repeatedly. The increased frequency of pulpal

anesthesia obtained after the repeated injection exceeded the percentages of pulpal

anesthesia seen in this study for all test teeth. The repeated injection 25 minutes after the

primary mandibular buccal infiltration injection resulted in a higher frequency of pulpal anesthesia than that obtained from a single primary infiltration of a 3.6 mL volume.

McEntire (1) had a higher frequency of pulpal anesthesia than seen in this study for

Group 2 (1.8 mL volume of 4% articaine with 1:100,000 epinephrine) for nearly all time points for the first and second molar, but a similar frequency of pulpal anesthesia for the first and second premolars. The incidence of pulpal anesthesia for Group 1 of this study were generally higher than those shown by McEntire for each tooth tested. Robertson

(189) showed rates of pulpal anesthesia for 1.8 mL of 4% articaine with 1:100,000 epinephrine that were far higher than those seen in this study for Group 2 and were far higher than those shown by Pabst (2) and McEntire (1) for 1.8 mL of 4% articaine with

1:100,000 or 1:200,000 epinephrine. The frequencies of pulpal anesthesia obtained by

132 Robertson for all teeth tested were very similar to the frequencies obtained in Group 1 of this study. The differences in frequency of pulpal anesthesia shown by McEntire (1) and

Robertson (189) are likely the result of differences in patient population or operator technique (i.e. injection location or needle depth).

The maximum percentage of 80/80 readings for each of the four test teeth occurred from 10 to 23 minutes for Group 1 and from 10 to 17 minutes for Group 2.

After these times, fewer teeth were achieving onset of anesthesia, but instead a gradual loss of anesthesia was occurring over time.

It is assumed that most dental appointment procedures will take one hour or less to complete. Therefore, it would be advantageous for the percentage of teeth with profound anesthesia to be as high as possible during this time to avoid pain and complications during treatment. At approximately 30 minutes post-injection, Group 1 had a frequency of pulpal anesthesia of 53.5% for the second molar, 58.1% for the first

molar, 85.9% for the second premolar, and 86.0% for the first premolar. Group 2 had a

frequency of pulpal anesthesia of 25.6% for the second molar, 31.4% for the first molar,

71.8% for the second premolar, and 62.8% for the first premolar. For both solutions, the

second premolar had the highest frequency of pulpal anesthesia, followed by the first

premolar. The second molar had the lowest overall frequency of pulpal anesthesia at 30

minutes. Group 1 had a higher frequency of pulpal anesthesia at 30 minutes for all teeth tested compared to Group 2.

At approximately 45 minutes post-injection, Group 1 had a frequency of pulpal

anesthesia of 34.9% for the second molar, 37.2% for the first molar, 80.0% for the second

premolar, and 73.3% for the first premolar. Group 2 had a frequency of pulpal anesthesia

133 of 10.5% for the second molar, 19.8% for the first molar, 48.2% for the second premolar, and 34.9% for the first premolar. For both solutions, the second premolar had the highest frequency of pulpal anesthesia, followed by the first premolar. The second molar had the lowest overall frequency of pulpal anesthesia at 45 minutes. Group 1 had a higher frequency of pulpal anesthesia at 45 minutes for all teeth tested compared to Group 2.

At approximately 60 minutes post-injection, Group 1 had a frequency of pulpal anesthesia of 17.4% for the second molar, 18.6% for the first molar, 55.3% for the second premolar, and 38.4% for the first premolar. Group 2 had a frequency of pulpal anesthesia of 2.3% for the second molar, 2.3% for the first molar, 27.1% for the second premolar, and 14.0% for the first premolar. For both solutions the second premolar had the highest frequency of pulpal anesthesia followed by the first premolar. The second molar had the lowest overall frequency of pulpal anesthesia at 60 minutes. Group 1 had a higher frequency of pulpal anesthesia at 60 minutes for all teeth tested compared to Group 2.

The results of this study indicate that the different volumes of 4% articaine affected the frequency of pulpal anesthesia for each of the teeth tested. Neither 3.6 nor 1.8 mL of 4% articaine with 1:100,000 epinephrine, used for a primary mandibular buccal infiltration, provided dependable pulpal anesthesia for a dental appointment lasting 60 minutes.

“In the posterior mandibular buccal infiltration, the anesthetic solution may diffuse through the buccal cortical plate and then the cancellous bone, reaching the inferior alveolar nerve within the mandible and/or its branches to the individual teeth. If this scenario is true, the injection would act like a conventional inferior alveolar nerve block, but without the usual accompanying tongue numbness. That is, all the teeth anterior to the site of injection would achieve pulpal anesthesia.” (1) In the current study,

134 the premolars were anesthetized more often than the molars and the second premolar had

a higher frequency of pulpal anesthesia than the first premolar. This was also found to be

true in studies by Robertson et al. (29), Pabst et al. (204), and McEntire (1), utilizing a

mandibular buccal infiltration injection next to the first molar with 4% articaine with

1:100,000 epinephrine or 4% articaine with 1:200,000 epinephrine.

“If the anesthetic solution is able to diffuse through the cortical plate, the

thickness or density of an individual’s buccal cortical plate would likely determine

whether the injection will be successful. This is supported by pediatric studies by

Dudkiewicz et al. (90) and Wright et al. (115) involving mandibular buccal infiltrations

using 4% articaine with 1:200,000 epinephrine. They found that articaine was fairly

successful in producing numbness in primary teeth, presumably due to the relatively thin

and more porous mandibular bone of children. Two percent mepivacaine and 4%

prilocaine were also used in the study by Wright et al. (115). They concluded that ‘the quality of anesthesia was not significantly related to tooth location, age, or type of anesthetic agent.’”(1)

The pattern of pulpal anesthesia observed in this study suggests that the anesthetic solution tended to diffuse more readily anterior to the first molar region. In this case, it may have diffused into the mandible through the relatively thin cortical bone located adjacent to the premolars. “According to Malamed, (32) the bone forming the buccal alveolar processes in the anterior region (incisors) is usually less dense than that over the

posterior teeth, permitting infiltration (supraperiosteal) anesthesia to be employed with

some expectation of success. Perhaps the density or thickness of bone buccal to the

135 premolars is greater than in the anterior region, but less than in the molar region, allowing

some degree of success to be achieved in this area.” (1)

Another explanation for the higher frequency of pulpal anesthesia in the

premolars is that the anesthetic solution may enter the mental foramen after diffusing

anteriorly through the soft tissue. In this case, the premolars would be the most likely to

be anesthetized, as was observed in our study. Adjacent teeth in either direction may also

be anesthetized, depending on how far the anesthetic solution diffuses after entering the

mental foramen. “Tebo and Telford (181) and Mastuda (182), in anatomical studies,

reported the location of the mental foramen to be in the apical area of the second

premolar approximately 50% and 68% of the time, respectively. Phillips et al. (183)

found the foramen in line with the long axis of the second premolar 63% of the time.

When the foramen was mesial or distal to the long axis of the second premolar, it was

within 2 mm of the long axis.” (1) Nist et al. (20), utilizing an incisive nerve block with

2% lidocaine with 1:100,000 epinephrine, reported success rates of 30% for the first premolar, 35% for the second premolar, 10% for first molar, and 8% for the second molar. The results of our study as well as the studies by Nist et al. (20), Robertson et al.

(29), Pabst et al. (204), and McEntire (1) support this mechanism because the second

premolar was the most likely tooth to achieve anesthesia followed by the first premolar.

Frequency of pulpal anesthesia is a useful statistic to predict the probability that a given tooth in a given patient will be profoundly numb at a given time point. For example, one could predict that if a patient received a mandibular buccal infiltration adjacent to the first molar with 3.6 mL of 4% articaine with 1:100,000 epinephrine, 37 minutes later there would be a 54.7% chance that the patient's first molar would be numb.

136 The same tooth, tested at the same time period, would have a 27.9% chance of being numb if 1.8 mL of 4% articaine with 1:100,000 epinephrine were used instead.

Unfortunately, no anesthetic volume tested in this or any other study has been shown to achieve 100% predictable local anesthesia at any time point.

Anesthetic Success

Studies investigating mandibular buccal infiltrations next to the first molar have defined anesthetic success differently. In our study, pulpal anesthesia was analyzed using three definitions of success to determine any differences between 3.6 and 1.8 mL of 4% articaine with 1:100,000 epinephrine in regards to anesthetic efficacy. The definition of

Success #1 was achieving the first of two consecutive 80/80 readings by the third testing cycle (7 minutes for molars and 8 minutes for premolars) and obtaining two consecutive

80/80 readings at or after the twentieth testing cycle (58 minutes for molars and 59 minutes for premolars). This definition included teeth that lost anesthesia and then regained it within the testing period (non-continuous anesthesia). Group 1 (3.6 mL 4% articaine with 1:100,000 epinephrine) and Group 2 (1.8 mL 4% articaine with 1:100,000 epinephrine) produced successful pulpal anesthesia using this definition, respectively, as follows: 14.0% and 7.0% for the second molars; 22.1% and 11.6% for the first molars;

54.1% and 25.9% for the second premolars; and 37.2% and 14.0% for the first premolars.

For each tooth tested, the incidence of success using this definition was higher with the

3.6 mL volume of 4% articaine with 1:100,000 epinephrine. There was no statistically significant differences between Groups 1 and 2 for the second molar, but the first molar,

137 second premolar, and first premolar were significantly different (p=0.0450, <0.0001, and

=0.0001, respectively) (Table 12).

“Pabst (2) studied the anesthetic efficacy of a repeated mandibular buccal infiltration injection of 4% articaine with 1:100,000 epinephrine given 25 minutes

following a primary infiltration injection with 4% articaine with 1:100,000 epinephrine in

mandibular posterior teeth. Using this definition of success (success #1), Pabst (2)

reported that a primary infiltration with 1.8 mL of 4% articaine with 1:100,000

epinephrine produced successful pulpal anesthesia in 11.6% of the second molars, 9.3%

of the first molars, 32.9% of the second premolars, and 24.1% of the first premolars.” (1)

These results are similar to the results we found with 1.8 mL 4% articaine with 1:100,000

epinephrine (Group 2). Pabst (2) reported that a primary infiltration with 1.8 mL of 4%

articaine with 1:100,000 epinephrine followed by a repeated buccal infiltration of 1.8 mL

4% articaine with 1:100,000 epinephrine 25 minutes later produced successful pulpal

anesthesia in 34.9% of the second molars, 48.4% of the first molars, 62.4% of the second

premolars, and 59.0% of the first premolars. The success rates with this definition for the

repeated buccal infiltration injection were higher than seen in this study for each tooth

tested. The higher success rates shown by Pabst (2) are likely the result of the timing of

the second injection of articaine. By providing the repeated infiltration 25 minutes after

the primary injection, the duration of anesthesia was likely increased allowing the pulpal

anesthesia to exceed the 60 minute mark with greater frequency than providing the

additional volume of anesthetic at the time of the primary injection as we did in our

study. One possible explanation for why the repeated infiltration was more successful

than a higher volume in the primary injection may be that there is a critical number or

138 concentration of anesthetic molecules necessary to provide pulpal anesthesia. If the

anesthetic solution dissipates from the injection site at the same rate regardless of the

volume, then providing double the volume initially would result in double the anesthetic

molecules available to provide pulpal anesthesia initially. For example, 1000 molecules may be available initially for a 3.6 mL injection versus 500 molecules for a 1.8 mL injection. This may explain the earlier higher success seen in our study compared to

Pabst et al. (204). As time passes, however, the number of molecules available to

provide pulpal anesthesia decreases as the anesthetic dissipates. In our example after 30

minutes there would be 500 molecules remaining from the 3.6 mL injection and only 250

molecules from the 1.8 mL injection. If you then provide an additional volume of

anesthetic as Pabst did, there is an increase in the number of anesthetic molecules

available to provide anesthesia. You then have a situation where there are more

molecules available to provide anesthesia than if you gave the same volume in the initial

injection as we did in our study. In our example waiting another 30 minutes would result

in only 250 molecules remaining from the initial 3.6 mL injection while there are 375

molecules remaining after the repeated injection. If the critical number of molecules is

250 to maintain pulpal anesthesia, then the 3.6 mL injection would be wearing off while the repeated injection group would continue to maintain pulpal anesthesia. This also

allows you to maintain the critical number of anesthetic molecules to achieve pulpal

anesthesia for a longer period than if all of the anesthetic is given initially. This may explain the increased success and duration of pulpal anesthesia seen by Pabst when compared to our study. The low success rates reported in the current study and by Pabst

(2) using this definition would indicate that a mandibular buccal infiltration given next to

139 the first molar would not provide dependable anesthesia for a dental appointment lasting one hour.

Scott et al. (205) evaluated the efficacy of a repeated infiltration thirty minutes after a primary infiltration injection buccal to the maxillary lateral incisor. Scott demonstrated success at extending duration of anesthesia when a repeated infiltration of

2% lidocaine with 1:100,000 epinephrine was given over the maxillary lateral incisor 30 minutes after the initial injection. The repeated infiltration injection statistically improved pulpal anesthesia in the period from 37 minutes through 90 minutes when compared to a mock injection at 30 minutes. In addition, the incidence of short duration of anesthesia was 70% with the single infiltration and 8% with the repeated infiltration injection (205). While direct comparison to our study cannot be done due to the different site of anesthetic injection, we can see that like our higher initial volume of anesthetic the repeated infiltration allowed for an increase in the success and duration of pulpal anesthesia compared to the mock injection. However, the results of Scott et al. (205) like those of Pabst et al. (204) show an increase of anesthesia success rates beyond those obtained initially and an increase in duration of anesthesia after the administration of the repeated infiltration, as compared to our higher initial volume injection which showed no such augmentation in anesthesia efficacy beyond the initial higher success rate compared to the 1.8 mL volume.

McEntire (1) also reported on success of a primary mandibular buccal infiltration with 4% articaine with 1:100,000 epinephrine using this definition. McEntire (1) found this injection to produce successful pulpal anesthesia in 12.8% of the second molars,

14.0% of the first molars, 32.6% of the second premolars, and 23.8% of the first

140 premolars. These results are similar to our results for 1.8 mL of 4% articaine with

1:100,000 epinephrine (Group 2) using definition #1. Although not significantly

different, McEntire (1) found that a primary buccal infiltration of 4% articaine with

1:200,000 epinephrine provided successful pulpal anesthesia in 8.1% of second molars,

8.1% of first molars, 25.6% of second premolars, and 12.5% of first premolars. These

results are similar but slightly lower than our results for 1.8 mL of 4% articaine with

1:100,000 epinephrine (Group 2) using definition #1.

Success #2 was defined as achieving the first of two consecutive 80/80 readings within the first 7 minutes of testing for the molars or the first 8 minutes of testing for the premolars and maintaining the 80/80 readings continuously through the minute 58 for the molars and minute 59 for the premolars. This definition is most stringent and excludes teeth that experienced non-continuous anesthesia. Using this definition, Group 1 and

Group 2 produced successful pulpal anesthesia, respectively, as follows: 12.8% and 7.0%

of the second molars; 20.9% and 11.6% of the first molars; 51.8% and 23.5% of the second premolars; and 33.7% and 14.0% of the first premolars. For each tooth, the incidence of success using this definition of success was higher with 3.6 mL volume of

4% articaine with 1:100,000 epinephrine. There were no statistically significant differences between Groups 1 and 2 for the second molar and first molar, but the second premolar, and first premolar were significantly different (p<0.0001, =0.0007, respectively) (Table 12).

Robertson (189) also investigated the anesthetic efficacy of 4% articaine with

1:100,000 epinephrine for mandibular buccal infiltrations. Similar to our study (Success

#2), success was defined as achieving the first of two consecutive 80/80 readings with the

141 electric pulp tester within 7 minutes of the injection for the molars, or within 8 minutes of

the injection for the premolars, and sustaining this reading for the entire testing time (60

minutes). Robertson (189) reported success rates of 10.0% for the second molars; 10.0%

for the first molars; 31.7% for the second premolars; and 31.6% for the first premolars.

Our results for the 1.8 mL volume of 4% articaine with 1:100,000 epinephrine using this

definition (Success #2) are similar to Robertson’s (189) results for the second molar and

first molar. However, our percentages for the second premolar and first premolar were

8% and 17% lower than Robertson’s results, respectively. This difference in success

rates for the first and second premolars could be due to differences in patient population

or operator technique (i.e. injection location or depth of needle placement).

Pabst (2) also reported success of a primary mandibular buccal infiltration with

4% articaine with 1:100,000 epinephrine using this definition. Pabst (2) found the

injection to produce successful pulpal anesthesia in 4.7% of the second molars, 10.5% of

the first molars, 23.5% of the second premolars, and 20.5% of the first premolars. These

results are similar to our results for the 1.8 mL volume (Group 2) using definition #2.

Pabst (2) reported that a primary infiltration with 1.8 mL of 4% articaine with 1:100,000

epinephrine followed by a repeated buccal infiltration of 1.8 mL 4% articaine with

1:100,000 epinephrine 25 minutes later produced successful pulpal anesthesia in 31.4%

of the second molars, 43.0% of the first molars, 57.7% of the second premolars, and

49.4% of the first premolars. The success rates using definition #2 for the repeated buccal infiltration injection were higher than seen in this study (Group 1) for each tooth tested. The higher success rates shown by Pabst (2) are likely the result of the timing of the second injection of articaine. As discussed previously, by providing the repeated

142 infiltration 25 minutes after the primary injection the duration of anesthesia was likely

increased allowing the pulpal anesthesia to exceed the 60 minute mark with greater

frequency than providing the additional volume of anesthetic at the time of the primary

injection as we did in our study.

McEntire (1) also reported success of a primary mandibular buccal infiltration

with 4% articaine with 1:100,000 and 1:200,000 epinephrine using this definition.

McEntire (1) found this injection to produce successful pulpal anesthesia in 8.1% of the

second molars, 12.8% of the first molars, 29.1% of the second premolars, and 23.8% of

the first premolars for 4% articaine with 1:100,000 epinephrine and in 3.5% of second

molars, 7.0% of first molars, 20.9% of second premolars, and 10.0% of first premolars

for 4% articaine with 1:200,000 epinephrine. These results are similar to our results

(Group 2 – 1.8 mL volume) using definition #2.

Success #3 was defined as the occurrence of two consecutive 80/80 readings at

any time during the testing period. Utilizing Success #3, Group 1 and Group 2 produced

successful pulpal anesthesia, respectively, as follows: 65.1% and 48.8% for the second

molar; 75.6% and 52.3% for the first molar; 92.9% and 87.1% for the second premolar,

and 91.9% and 81.4% for the first premolar (Table 12). For each tooth tested, the

incidence of successful pulpal anesthesia using definition #3 was higher with the 3.6 mL

volume of 4% articaine with 1:100,000 epinephrine. There was no statistically significant difference between Groups 1 and 2 for the second premolar (p=0.1797), but the second molar, first molar, and first premolar were significantly different (p=0.0129,

<0.0001, and =0.0234, respectively) (Table 12).

Robertson et al. (29), Pabst et al. (204), and McEntire (1) also utilized this

143 definition of success (two consecutive 80/80 readings at any time) when evaluating the

efficacy of a single buccal infiltration injection with articaine. Robertson et al. (29)

reported success rates of 75% for the second molar, 87% for the first molar, 92% for the

second premolar and 86% for the first premolars. These percentages are higher than what was found in our study using the 1.8 mL volume of 4% articaine with 1:100,000 epinephrine but were similar to the percentages found in our study using the 3.6 mL volume of 4% articaine with 1:100,000 epinephrine. Depth of needle penetration, location of the needle (mesial-distally) in relation to roots of the first molar, or proximity to the bone and tooth structure could have been slightly different between operators. In order to control for such differences, either the same operator would need to perform each injection or the fabrication of a template or a guide could help eliminate some of the variations seen between different operators.

Pabst et al. (204) found success rates of 69.8% for the second molar, 66.3% for

the first molar, 78.8% for the second premolar, and 80.7% for the first premolar for a

single buccal infiltration with 4% articaine with 1:100,000 epinephrine. Pabst et al. (204)

had higher success rates for the first and second molars but lower success rates for the

second and first premolars when compared to the success rates seen in Group 2 of our

study. The differences could be related to needle placement, position of the mental

foramen, and thickness of the buccal bone in the subjects. For the repeated injection

group, Pabst et al. (204) found success rates of 84.9% for the second molar, 83.7% for the

first molar, 97.7% for the second premolar, and 92.8% for the first premolar. These

results were higher than ours using 3.6 mL of 4% articaine with 1:100,000 epinephrine

for each tooth. Differences seen between our results and the repeated infiltration

144 injection from Pabst’s study may be attributed to differences in operator technique, as previously discussed, differences in patient population, and most likely the timing and effect of the additional volume of anesthetic. Results from Pabst (2) indicate an increase in anesthesia and a prolonging of anesthesia in all of the teeth tested after the repeated infiltration injection. The results from Pabst (2) are similar to those seen by Scott et al.

(205) where a repeated injection was performed thirty minutes after a primary infiltration injection over the maxillary lateral incisor. Scott et al. (205) showed an increase in anesthetic success rates and a prolonging of anesthesia in all of the teeth tested after the repeated infiltration injection.

McEntire (1) reported success rates of 59.3% for the second molar, 67.4% for the first molar, 84.9% for the second premolar and 73.8% for the first premolars. These results are similar to what was found in our study for the 1.8 mL volume of 4% articaine with 1:100,000 epinephrine.

Our results using Success #3 can also be compared with those of Kanaa et al.

(28). In their study, thirty-one healthy adult volunteers were pulp-tested at 2-minute intervals following a mandibular buccal infiltration with 1.8 mL 4% articaine with

1:100,000 epinephrine. Like our study (Success #3), success was defined as two consecutive 80/80 pulp tester readings at any time during their 30-minute testing period.

They found a 64.5% success rate for first molars, which is higher than our success rate of

52.3% for the first molar with 1.8 mL of 4% articaine with 1:100,000 epinephrine but lower than our success rate of 75.6% for the first molar with 3.6 mL of 4% articaine with

1:100,000 epinephrine (28).

Corbett et al. (174) compared the anesthetic efficacy of a mandibular buccal

145 infiltration with articaine to a buccal plus lingual infiltration with articaine. Thirty-one volunteers with at least one vital first molar tooth were given a buccal infiltration of 1.8 mL 4% articaine with 1:100,000 epinephrine plus a mock lingual injection or a buccal infiltration of 0.9 mL 4% articaine with 1:100,000 epinephrine plus a lingual infiltration of 0.9 mL 4% articaine with 1:100,000 epinephrine. Like our study (Success #3), success was defined as an 80/80 reading on the electric pulp tester on two or more consecutive measurements. The teeth were tested every two minutes for thirty minutes. A single

buccal infiltration injection in their study resulted in a 64.5% success rate and a buccal

plus lingual injection resulted in a 67.7% success rate (184). These success rates are

higher than those seen in Group 2 of our study, but lower than those seen in Group 1 of

our study. The differences may relate to differences in patient population, small size of

the sample population, operator technique, or the two minute time period between pulp

testing which could have allowed more teeth to obtain two consecutive 80/80 readings

than found in our study where there was 3 minutes between pulp testing of the teeth.

“Jung et al. (99) compared the anesthetic efficacy of an inferior alveolar nerve

block with that of a mandibular buccal infiltration given next to the first molar using 1.7

mL of 4% articaine with 1:100,000 epinephrine for both injections. Thirty subjects were

randomly given each of the injection types in separate appointments at least one week

apart. An electric pulp tester was used to determine pulpal anesthesia, and like our study

(Success #3), two consecutive readings of 80/80 was considered a success. Jung et al.

(99) reported a success rate of 54% for the buccal infiltration of the first molar using 4%

articaine with 1:100,000 epinephrine.” (1) Using this definition of success (Success #3),

our success rate for the first molar with the 1.8 mL volume of 4% articaine with

146 1:100,000 epinephrine solution was similar to the success rates reported by Jung et al., and the success rate with the 3.6 mL volume of 4% articaine with 1:100,000 epinephrine

was 22% higher than that reported by Jung et al. (99).

Nuzum (207) studied the anesthetic efficacy of a combination labial plus lingual infiltration compared to a labial infiltration near the mandibular lateral incisor using 4% articaine with 1:100,000 epinephrine in mandibular anterior teeth. In mandibular lateral incisors, the labial and lingual combination (3.6 mL) exhibited a significantly higher anesthetic success rate (two consecutive 80/80 readings with the EPT) of 98% success when compared with a 76% success rate with the single labial infiltration (1.8 mL).

Similarly, the central incisor and canine adjacent to the infiltrations exhibited significantly higher anesthetic success rates when compared with the single infiltration.

While the current study and the study by Nuzum (207) cannot be directly compared due

to differences in the site of anesthetic deposition, both studies as well as Pabst et al. (204)

show that increasing the volume of anesthetic deposited in mandibular infiltration

injections results in significantly greater chances of achieving pulpal anesthesia.

Mikesell et al. (164) compared the anesthetic efficacy of 1.8 mL and 3.6 mL of

2% lidocaine with 1:100,000 epinephrine for maxillary infiltrations. Thirty-two lateral

incisors, 32 first premolars and 32 first molars were studied in this investigation.

Anesthetic success (obtaining two consecutive 80 readings with the electric pulp tester)

for the two volumes ranged from 97% to 100%. No significant difference in anesthetic

success was seen between the two volumes. This is in contrast to what our study showed

about increasing the volume of anesthetic used. However, maxillary infiltrations may not

be as volume dependent as mandibular buccal infiltrations due to the different thickness

147 of buccal bone and the different diffusability of the anesthetic through the bone in the maxilla and mandible. Brunetto et al. (206) evaluated the anesthetic efficacy of 3 volumes of lidocaine with epinephrine in maxillary infiltration anesthesia. A total of 25 subjects received 0.6, 0.9, and 1.2 mL of the anesthetic buccal to an upper canine. Test teeth were assessed with electrical stimulation to determine onset and duration of pulpal anesthesia. The 1.2 mL dose induced faster onset of pulpal anesthesia, a higher success rate, and a longer duration of soft tissue/pulpal anesthesia than were achieved with the other doses (p<0.05). The low volumes of anesthetic used by Brunetto et al. (206) may be more important for showing what the critical volume is for achieving anesthesia in the maxillary canine than for showing that increasing the volume increases the success of pulpal anesthesia.

Using success definitions #1 and #2, Group 1 consistently showed higher percentages of success for all four teeth tested when compared to Group 2, however the percentages were still very low. Success #1 accurately describes pulpal anesthesia that occurs within a reasonable amount of time for dental treatment to start without delay (7 minutes for molars and 8 minutes for premolars) and that lasts throughout a 60-minute treatment period usually required for most dental procedures. However, it also includes those subjects that may lose and regain anesthesia and could therefore experience pain, although temporary, during treatment. Success #2 more strictly defines pulpal anesthesia to exclude these subjects. Hence, it is possible to assume that any subject considered a success under this definition will not experience pain during a 60-minute dental appointment if treatment is started 7-8 minutes after the initial injection. Based on the low success rates found in this study, a primary mandibular buccal infiltration with 1.8 or

148 3.6 mL of 4% articaine with 1:100,000 epinephrine would not provide adequate pulpal anesthesia for a dental appointment lasting 1 hour.

Success #3 only ensures a minimum of three consecutive minutes of anesthesia at any time throughout the 90-minute testing period. This definition is not as clinically relevant as the previous two definitions, but was included in our study for the purpose of comparison with other studies using a similar definition of success.

“Various authors (184-187) have investigated the efficacy of a primary intraosseous injection for the mandibular first molar using 1.8 mL of 2% lidocaine with

1:100,000 epinephrine. Using the definition of success as achieving two consecutive

80/80 EPT readings at any time during a 60-minute test period, first molar anesthesia success ranged from 74% to 100%.” (1) In our study, the mandibular buccal infiltration using 3.6 mL of 4% articaine 1:100,000 epinephrine had a 75.6% success rate for the first molar and 1.8 mL of 4% articaine with 1:100,000 epinephrine had a 52.3% success rate for the first molar. The low success rate for the first molar when using 1.8 mL of 4% articaine with 1:100,000 epinephrine suggests that a mandibular buccal infiltration for the first molar using this volume is not as effective as an intraosseous injection with 2% lidocaine with 1:100,000 epinephrine, but a 3.6 mL volume of 4% articaine with

1:100,000 epinephrine may be nearly as effective as an intraosseous injection with 2% lidocaine with 1:100,000 epinephrine.

Anesthetic Failure

In this study, failure to achieve two consecutive 80/80 readings at any time during the 60-minute testing period was considered an anesthetic failure. Anesthetic

149 failures were reported for Group 1 and Group 2, respectively, as follows: 34.9% and

51.2% of the second molars; 24.4% and 47.7% of the first molars; 7.1% and 12.9% of the

second premolars; and 8.1% and 18.6% of the first premolars (Table 13).

Kanaa et al. (28), using a similar definition for anesthetic failure, found lower

failure rates using 1.8 mL 4% articaine with 1:100,000 epinephrine in a buccal

infiltration. Kanaa’s results showed a 35.5% failure rate of mandibular first molars,

compared to 47.7% in our study. These differences in failure rates are most likely due to

differences in patient population, a smaller population size (31 patients vs. 86 patients in

our study) utilized by Kanaa et al., operator technique, or the two-minute interval

between pulp testing used by Kanaa et al.

Defining failure as the absence of success (failure to achieve two consecutive

80/80 readings during the 30-minute testing period), Corbett et al. (174) found failure

rates for the mandibular first molar to be 34.5% for a buccal infiltration injection with 1.8

mL of 4% articaine with 1:100,000 epinephrine and 32.3% for a buccal plus lingual

infiltration injection with the same articaine solution in the thirty-one subjects that

participated in the study. These failure rates are also lower than the failure rates we

found in our study for the 1.8 mL volume (Table 13).

Robertson (189), Pabst (2), and McEntire (1) also used the same definition for failure to analyze a mandibular buccal infiltration with 1.8 mL 4% articaine with

1:100,000 epinephrine. Robertson (189) reported failure rates of 20% for the second molar, 10% for the first molar, 7% for the second premolar and 12% for the first premolar. The results of his study showed lower failure rates for all teeth as compared to what was found in our study. In fact, Robertson (189) reported lower failure rates than

150 anyone who has investigated mandibular posterior buccal infiltration injections. This difference could be due to differences in operator injection technique. Depth of needle

penetration, location of the needle (mesial-distally) in relation to the roots of the first

molar, or proximity to the bone and tooth structure could have been slightly different

between operators and could have affected the failure rates of the injections. Pabst (2)

also found lower failure rates (30.2% of the second molars, 33.7% of the first molars,

21.2% of the second premolars, 19.3% of the first premolars) to Group 2 of the current

study when using a single buccal infiltration with 4% articaine with 1:100,000 epinephrine. Pabst (2) also found lower failure rates (15.1% vs. 34.9% of the second molars, 16.3% vs. 24.4% of the first molars, 2.3% vs. 7.1% of the second premolars,

7.2% vs. 8.1% of the first premolars) compared to Group 1 of the current study when using a repeated buccal infiltration of 4% articaine with 1:100,000 epinephrine 25 minutes following the initial injection. The addition of a repeated infiltration injection 25 minutes after the primary injection may have reversed previous failures from the primary injection where the use of a larger volume of anesthetic in the primary injection can decrease some failures initially but would not allow for reversal of failures as seen in a repeated injection technique. Adding a repeated buccal infiltration of 4% articaine with

1:100,000 epinephrine 25 minutes following the initial injection significantly reduced the failure rates in all of the test teeth, as did increasing the volume of anesthetic used in the primary buccal infiltration as seen in our study. McEntire (1) found failure rates of

40.7% for the second molar, 32.6% for the first molar, 15.1% for the second premolar and 26.2% for the first premolars when administering 1.8 mL volume of 4% articaine

151 with 1:100,000 epinephrine. These results are similar to what was found in our study for the 1.8 mL volume of 4% articaine with 1:100,000 epinephrine (Group 2).

The current study revealed significantly higher anesthetic failure rates for the

second molar, first molar, and first premolar when using 1.8 mL of 4% articaine with

1:100,000 epinephrine compared to using 3.6 mL of 4% articaine with 1:100,000

epinephrine. The second premolar had a higher anesthetic failure rate for the 1.8 mL

volume compared to the 3.6 mL volume, but the difference was not statistically

significant. Anesthetic failure reveals the inability to produce at least three consistent

minutes of pulpal anesthesia during a ninety-minute testing cycle. The high incidence of

failure with a single mandibular buccal infiltration injection with 3.6 mL of 4% articaine

with 1:100,000 epinephrine (from 7.1% of the second premolars to 34.9% of the second

molars) and 1.8 mL of 4% articaine with 1:100,000 epinephrine (from 12.9% of second

premolars to 51.2% of the second molars) would indicate that a high percentage of

patients would have pain during treatment of a mandibular posterior tooth when this

technique was used alone. These patients would require supplemental anesthesia to be

comfortable during the procedure.

Onset of Pulpal Anesthesia

Onset times for pulpal anesthesia, in minutes, for each tooth with each solution

can be found in Appendix J. Onset of pulpal anesthesia was defined as the time at which

the first of two consecutive 80/80 readings with the electric pulp tester occurred. The

mean onset times for pulpal anesthesia are summarized in Table 14. Only matched-pairs

could be statistically analyzed, meaning only those subjects who had onset times for each

152 group per tooth were analyzed. For this reason, the number of subjects analyzed per

tooth group differed from the total number of subjects tested (N=86). Anesthetic failures

were not included in this data because, by definition, there can be no onset of anesthesia

when anesthetic failure occurs.

We did not expect the different volumes of the articaine solutions to significantly

affect the time of onset of pulpal anesthesia due to the relatively rapid nature of pulpal

anesthesia onset with buccal infiltrations. Statistical analysis of onset times found no statistically significant difference between the two solutions for onset of pulpal anesthesia for the first and second molars, but a statistically significant difference in onset time was seen for the first and second premolars. While these values are statistically significant for the premolars, they are smaller than the pulp test intervals and therefore cannot be clinically significant (Table 14). The second molar had a mean onset of anesthesia in 4.6 minutes with Group 1, compared to 4.9 minutes with Group 2. The first molar had a mean onset of anesthesia in 4.4 minutes with Group 1, compared to 5.4 minutes with

Group 2. The second premolar had a mean onset of anesthesia in 4.7 minutes with

Group 1, compared to 5.5 minutes with Group 2. The first premolar had a mean onset of

4.3 minutes with Group 1, compared to 5.6 minutes with Group 2 (Table 14).

The results of our study can be directly compared to Robertson et al. (29), Pabst et al. (204), and McEntire (1). Robertson et al. (29) reported onset times for a mandibular buccal infiltration using 4% articaine with 1:100,000 epinephrine of 4.6 minutes for the second molar, 4.2 minutes for the first molar, 4.3 minutes for the second premolar, and

4.7 minutes for the first premolar. Pabst et al. (204) reported onset times using a single buccal infiltration with 4% articaine with 1:100,000 epinephrine of 5.4 – 11.1 minutes

153 for the second molar, 4.7 – 9.1 minutes for the first molar, 5.1 – 10.8 minutes for the

second premolar, and 6.6 – 9.5 minutes for the first premolar. McEntire (1) reported

onset times for a mandibular buccal infiltration using 4% articaine with 1:100,000

epinephrine of 4.9 minutes for the second molar, 4.7 minutes for the first molar, 4.7

minutes for the second premolar, and 4.9 minutes for the first premolar. The onset times reported by Robertson et al. (29), Pabst et al. (204), and McEntire (1) are similar to those

reported in our study.

“Between-tooth comparisons were not statistically analyzed since the teeth were

tested at different time intervals throughout the appointment. In order to make a valid set

of between-tooth comparisons for the onset of pulpal anesthesia, all the teeth would have

had to be pulp tested at the same time to determine the exact time of anesthesia onset.

This would require the use of separate electric pulp testers for each tooth. Unfortunately,

the current design of the electric pulp tester made this impossible.” (1)

“In addition, because readings were taken every three minutes, onset that

occurred between tests could not be recognized. Therefore, onset times are exact to

within three minutes of actual onset due to the limited test sensitivity. In order to get an

exact onset time, a continuous testing device would be needed.” (1)

Duration of Pulpal Anesthesia

The mean duration of pulpal anesthesia was calculated for each experimental

tooth in Groups 1 and 2. Duration was defined as the time period (minutes) between the first of two consecutive 80/80 readings to the last of two consecutive 80/80 readings. The

pulp testing period lasted 90 minutes for all teeth and did not continue indefinitely or

154 until each tooth lost anesthesia. Therefore, we could not calculate the exact duration of anesthesia for teeth that were still anesthetized at the end of the 90 minute test period because the testing period was not open-ended. When deciding whether to include analysis of duration of pulpal anesthesia in the current study, the fact that pulp testing lasted for 90 minutes instead of being open-ended was considered. Because of this, statistical analysis on mean duration of anesthesia was not performed. For the same reason, other authors have been unable to report true duration times

(1,28,29,117,174,204). Also, it must be noted that if the subject never achieved two consecutive 80/80 readings on a particular tooth (anesthetic failure), the data for that tooth could not be used to evaluate duration.

Most dental procedures can be completed in an hour or less. Therefore, having a duration of pulpal anesthesia approaching or exceeding an hour is considered to be clinically desirable. The aforementioned success rates (Success #1 and Success #2) give an indication of a clinically acceptable duration in that, by the definition given for success, all of these teeth had pulpal anesthesia at or after the 60-minute time period.

True duration could not be determined because it is not known how much longer the teeth sustained pulpal anesthesia beyond the 90-minute test period in our study. However,

Figures 2 through 5 may give an indication as to the trend of anesthesia for each tooth and may allow a clinician to predict the potential duration of pulpal anesthesia. Looking at the Figures for Group 1, less than 50% of the subjects were numb at 34 minutes for the second molar, 40 minutes for the first molar, 62 minutes for the second premolar and 56 minutes for the first premolar. For Group 2, less than 50% of the subjects were numb at

13 minutes for the second molar, 10 minutes for the first molar, 44 minutes for the second

155 premolar, and 38 minutes for the first premolar. After these time periods pulpal anesthesia for both groups gradually decreased. Based on Figures 2 through 5, a mandibular buccal infiltration given next to the first molar with either 1.8 or 3.6 mL of

4% articaine with 1:100,000 epinephrine will not provide predictable continuous pulpal anesthesia for one hour.

Mikesell et al. (164) compared the anesthetic efficacy of 1.8 mL and 3.6 mL of

2% lidocaine with 1:100,000 epinephrine for maxillary infiltrations. The 3.6 mL volume provided a statistically longer duration of pulpal anesthesia for the lateral incisor, first premolar, and first molar.

Brunetto et al. (206) evaluated the anesthetic efficacy of 3 volumes of lidocaine with epinephrine in maxillary infiltration anesthesia. A total of 25 subjects received 0.6,

0.9, and 1.2 mL of the anesthetic buccal to an upper canine. Test teeth were assessed with electrical stimulation to determine onset and duration of pulpal anesthesia. The 1.2 mL provided longer duration of soft tissue/pulpal anesthesia than were achieved with the other doses (p<0.05).

Scott et al. (205) evaluated the efficacy of a repeated infiltration thirty minutes after a primary infiltration injection buccal to the maxillary lateral incisor. Scott demonstrated success at extending duration of anesthesia when a repeated infiltration of

2% lidocaine with 1:100,000 epinephrine was given over the maxillary lateral incisor 30 minutes after the initial injection. The repeated infiltration injection statistically improved pulpal anesthesia in the period from 37 minutes through 90 minutes when compared to a mock injection at 30 minutes. Scott et al. (205) did not, however, report an average duration of anesthesia as their study was not open ended and some subjects

156 retained pulpal anesthesia at the end of the 90 minute test period. In addition, the

incidence of short duration of anesthesia was 70% with the single infiltration and 8%

with the repeated infiltration injection (205), hence the duration of anesthesia was

prolonged by the repeated infiltration injection.

Slow Onset of Anesthesia, Short Duration of Anesthesia and Non-continuous

Anesthesia

"Slow onset of anesthesia represents a longer-than-usual amount of time

necessary for the anesthetic to diffuse through tissues into the nerve bundle to effect its

action. This may be the result of depositing the anesthetic solution further from the nerve

so that diffusion through more muscle, fat, connective tissue or bone is necessary.

Thicker cortical bone, or more dense bone, would be expected to slow diffusion of

anesthetic, leading to a slower onset or failure of anesthesia. Slow onset may also be due

to a compromised ability of the anesthetic to diffuse through tissues quickly enough.

Clinically, slow onset of anesthesia may result in patient discomfort if the dental

procedure is started too soon.” (1)

Under Success #1 and 2, slow onset would have occurred if the molars had their

first of two consecutive 80/80 readings after minute 7, or if the premolars had their first

of two consecutive 80/80 readings after minute 8 and therefore would not be considered

successful. However, under Success #3, a tooth with slow onset would be considered a

success as long as it achieved two consecutive 80/80 readings at any time during the 90-

minute testing period. As discussed above with mean onset times, slow onset data could

only be statistically analyzed with matched-pairs, meaning only those subjects who had

onset times for each group per tooth were analyzed. For this reason, the number of

157 subjects analyzed per tooth group differed from the total number of subjects tested

(N=86) and any anesthetic failures would not be included in the data.

In our study, slow onset of anesthesia (defined by Success #1 and #2) occurred in

Group 1 and 2, respectively, as follows: 10.5% and 15.8% of the time in second molars,

8.9% and 11.1% of the time in first molars, 5.6% and 12.5% of the time in second

premolars, and 4.3% and 13.0% of the time in first premolars (Table 15). No statistically

significant differences were found for any of the four teeth. Pabst (2) reported slow onset

of pulpal anesthesia in 31 – 36% of second molars, 21 -25% of first molars, 18 – 22% of

second premolars, and 27 – 30% of first premolars. The differences in percentage of

teeth experiencing slow onset between the current study and Pabst’s study may be

attributed to differences in operator technique, as previously discussed, or differences in

patient population. McEntire (1) reported slow onset of pulpal anesthesia in 12.2% of

second molars, 6.7% of first molars, 9.2% of second premolars, and 5.5% of first

premolars for 4% articaine with 1:100,000 epinephrine. Data for slow onset of anesthesia

was not analyzed by Robertson (189), Kanaa et al. (28), Corbett et al. (174) or Moore et

al. (45) and therefore, no comparisons could be made.

Anesthesia of short duration is defined as achieving two consecutive 80/80

readings initially, losing the 80/80 reading before the end of the minute 60 of the test

period, and not regaining it for the remainder of the 90-minute testing period. Like onset,

only matched-pairs could be statistically analyzed for duration. Therefore, anesthetic

failures would not be included in this data because, by definition, there is no duration

when anesthetic failure occurs. For this reason, the number of subjects analyzed per tooth group differed from the total number of subjects tested (N=86).

158 In our study, anesthesia of short duration was reported in Group 1 and Group 2, respectively, as follows: 63.2% and 84.2% of the time in second molars, 53.3% and

77.8% of the time in first molars, 37.5% and 69.4% of the time in second premolars, and

53.6% and 82.6% of the time in first premolars (Table 16). The 3.6 mL volume of 4% articaine with 1:100,000 epinephrine resulted in a significantly lower percentage of short duration for all of the test teeth. Using a single buccal infiltration with 4% articaine with

1:100,000 epinephrine, Pabst (2) found short duration to occur in 80.4% of second molars, 77.2% of first molars, 53.7% of second premolars, and 66.7% of first premolars.

For the repeated injection 25 minutes after the initial buccal infiltration, Pabst (2) found short duration to occur in 16.1% of second molars, 14.0% of first molars, 6.0% of second premolars, and 1.5% of first premolars. Differences seen between our results and the repeated infiltration injection from Pabst’s study may be attributed to differences in operator technique, as previously discussed, differences in patient population, and the timing and effect of the additional volume of anesthetic. Results from Pabst (2) indicate an increase in anesthesia and a prolonging of anesthesia in all of the teeth tested after the repeated infiltration injection. “A study by Scott et al. (205) demonstrated success at extending duration of anesthesia when a repeated infiltration of 2% lidocaine with

1:100,000 epinephrine was given over the maxillary lateral incisor 30 minutes after the

initial injection. The repeated infiltration injection statistically improved pulpal

anesthesia in the period from 37 minutes through 90 minutes when compared to a mock

injection at 30 minutes. In addition, the incidence of short duration of anesthesia was

70% with the single infiltration and 8% with the repeated infiltration injection (205).” (2)

The results of Scott et al. (205) show both an increase in anesthesia success rates and an

159 increase in duration of anesthesia by administration of the repeated infiltration. Mikesell et al. (164) evaluated the anesthetic efficacy of 1.8 mL and 3.6 mL of 2% lidocaine with

1:100,000 epinephrine for maxillary infiltrations. The 3.6 mL volume provided a statistically longer duration of pulpal anesthesia and significantly less incidences of anesthesia of short duration for the maxillary lateral incisor, first premolar, and first molar. McEntire (1) found anesthesia of short duration 71.9% of the time in second molars, 73.7% of the time in first molars, 60.4% of the time in second premolars, and

64.3% of the time in first premolars with a buccal infiltration injection of 1.8 mL of 4% articaine with 1:100,000 epinephrine. These percentages are comparable to the findings in our study for the 1.8 mL volume of 4% articaine with 1:100,000 epinephrine.

“Anesthesia of short duration would result, clinically, in the patient experiencing pain before the end of procedures requiring profound pulpal anesthesia for a full hour.

Like slow onset of anesthesia, anesthesia of short duration may require the reinjection of the patient with more anesthetic, but with short duration anesthesia it would be more likely that the clinician may not believe that the patient is experiencing discomfort, or may rush the procedure in order to finish more quickly than usual. Depending on the level of discomfort being experienced by the patient, some clinicians would accept that the patient was not going to be completely comfortable and proceed as usual.” (2)

Success #1 and 2 of our study excluded patients experiencing short duration of anesthesia, therefore it can be concluded that this scenario would be avoided when anesthesia is considered successful by these definitions. However, Success #3 is not as specific, and subjects who responded successfully under this definition could still undergo the discomfort of short duration anesthesia. As shown in our study and others

160 (1,28,29,117,174,204), a single buccal infiltration injection of articaine does not provide a duration long enough to consistently last for an hour long dental appointment.

Non-continuous anesthesia is defined as achieving an 80/80 reading initially, losing the 80/80 reading, and then regaining an 80/80 reading during the testing period

(90 minutes). According to Success #1, non-continuous anesthesia was included as a

“success.” However, the more strict guidelines for Success #2 excluded subjects experiencing non-continuous anesthesia during the first 60 minutes of testing. Clinically patients with this phenomenon would experience pain at some point throughout a dental procedure and could lead to fear and loss of confidence in the clinician. Furthermore, the clinician would be forced to decide whether or not the anesthesia would return, and waiting for the return of pulpal numbness would create a delay in treatment or re- injecting the area with more anesthetic solution.

In the current study, non-continuous anesthesia was experienced in Group 1 and

Group 2, respectively, in the following percentages: 10.5% and 7.9% of second molars,

6.7% and 6.7% of first molars, 13.9% and 6.9% of second premolars, and 10.1% and

10.1% of first premolars. There were no significant differences in the incidence of non- continuous anesthesia between the two groups for any of the four test teeth (Table 17).

McEntire (1) found that non-continuous anesthesia was experienced in 12.2% of second molars, 2.2% of first molars, 16.9% of second premolars, and 0.0% of first premolars for

1.8 mL of 4% articaine with 1:100,000 epinephrine. Using a single buccal infiltration next to the first molar with 4% articaine with 1:100,000 epinephrine, Pabst (2) reported non-continuous anesthesia in 16.3% of the second molars, 11.6% of the first molars,

15.3% of the second premolars and 9.6% of the first premolars. For the repeated

161 injection 25 minutes after the initial buccal infiltration, Pabst (2) reported non-continuous

anesthesia in 24.4% of second molars, 19.8% of first molars, 16.5% of second premolars,

and 15.7% of first premolars. Robertson (189) did not report results on non-continuous

anesthesia. By the most stringent definition (Success #2), if a tooth was neither a success

nor a failure, it would fall into at least one, and possibly all three, of these categories.

POSTOPERATIVE PAIN

Postoperatively, subjects were asked to report injection site discomfort at four

time periods for both groups. Mean pain ratings for Groups 1 and 2 are shown in Table

18, and the distribution between genders is shown in Table 19. Frequency of pain

categories for each day can be found in Tables 20-23. The same visual analog scale that

was used to record pain experienced during the injection phases was also used for the

postoperative pain ratings occurring at the injection sites (Appendix H). Pain ratings

were recorded following cessation of anesthesia (Day 0) and in the morning of

postoperative days 1, 2 and 3 after waking from sleep.

Following cessation of anesthesia, Group 1 resulted in a mean pain rating of 35.8

mm and Group 2 resulted in a mean pain rating of 24.3 mm. There was a statistically

significant difference (p=0.0004) between groups for mean pain rating, however both

mean pain ratings were in the mild category. The significant difference seen in post- operative pain is likely the result of increased tissue damage from the higher volume.

Gutmann and Harrison (82) stated that “rapid injection produces localized pooling of

solution in the injected tissues, resulting in delayed and limited diffusion into adjacent tissues, minimal surface contact with microvascular and neural channels, and less than

162 optimal hemostasis and anesthesia. Rapid injections may be painful because of

distension and tearing of tissues, and frequently the injection sites remain sore for several

days.” While the authors were specifically talking about tissue damage from a rapid

injection, the increase in initial volume of anesthetic solution deposited can also result in

pooling of solution and distension and tearing of tissues resulting in increased post- operative pain. Pabst (2) reported that “trauma may also be caused when the anesthetic is deposited in the dental tissues, causing them to stretch and expand.” In her study Group

1 received two cartridges of anesthetic, the tissues suffered the damage from expansion twice during the appointment. This may explain why Pabst’s experimental Group 1 experienced more post-operative pain than Group 2, who only received a single cartridge of anesthetic, since both groups received a second needle insertion. For Group 1, males averaged 28.3 mm, while females reported pain levels at 43.3 mm. The pain ratings between gender for Group 1 were not significantly different. Seventy-eight percent of pain ratings were in the none-to-mild category, 20.9% were in the moderate category, and

1.2% of subjects reported severe pain. For Group 2, males averaged 22.1 mm and females average 26.5 mm. The pain ratings between genders for Group 2 were not significantly different. Ninety-four percent of pain ratings were in the none-to-mild category, 5.8% were in the moderate category and no subjects reported severe pain.

Robertson et al. (29) found post-operative results to be comparable to our pain ratings for the 1.8 mL volume. Following a buccal infiltration with 1.8 mL 4% articaine with

1:100,000 epinephrine, the mean pain rating for Day 0 was 20 mm. McEntire (1) found post-operative results to be comparable to our pain ratings for the 1.8 mL volume.

Following a buccal infiltration with 1.8 mL 4% articaine with 1:100,000 epinephrine, the

163 mean pain rating for Day 0 was 19.7 mm. Pabst et al. (204) reported post-operative pain

ratings of 27.7 mm for Day 0 following a single buccal infiltration with articaine. For the

repeated injection group, Pabst et al. (204) reported post-operative pain ratings of 40.1

mm for Day 0. These values were similar to our results for the two different anesthetic

volumes. Jensen et al. (186) studied the intraosseous injection and found it to be more

painful, in comparison to the 1.8 mL volume infiltration injection in our study, but very

similar in postoperative discomfort to our 3.6 mL volume infiltration for all four time

periods. A single perforation and injection resulted in a mean pain rating of 31.8 mm

after subjective anesthesia ceased. Like our study, all mean pain ratings reported by

Robertson et al. (29), McEntire (1), Pabst et al. (204), and Jensen et al. (186) were within

the mild pain category.

For postoperative day 1, Group 1 resulted in a mean pain rating of 30.8 mm and

Group 2 resulted in a mean pain rating of 17.1 mm. There was a statistically significant

difference (p=0.0004) between groups for mean pain rating and is likely the result of

increased trauma from the additional volume as explained above. For Group 1, males

averaged 24.3 mm, while females averaged 37.3 mm. The pain ratings between genders

for Group 1 were not significantly different. Eighty-three percent of pain ratings were in the none-to-mild category, 17.4% were in the moderate category, and no subjects reported severe pain. For Group 2, males averaged 12.1 mm and females average 22.1 mm. The pain ratings between genders for Group 2 were not significantly different.

Ninety-seven percent of pain ratings were in the none-to-mild category, 3.5% were in the moderate category and no subjects reported severe pain. Robertson et al. (29) and

McEntire (1) reported mean pain ratings for Day 1 of 15 mm and 12.6 mm, respectively,

164 following a buccal infiltration with 1.8 mL 4% articaine with 1:100,000 epinephrine.

The results of Robertson et al. (29) and McEntire (1) for post-operative day 1 were similar to those seen in Group 2 of our study, but were lower than the pain ratings reported in Group 1 of our study. Pabst et al. (204) reported post-operative pain ratings of 19.3 mm for Day 1 following a single buccal infiltration with articaine. For the repeated injection group, Pabst et al. (204) reported post-operative pain ratings of 33.4 mm for Day 1. These values were similar to our results for the two different anesthetic volumes. In a study by Berlin (69), the periodontal ligament (PDL) injection resulted in a mean pain rating of 35.0 mm for postoperative day 1. This rating is higher than the ratings in our study for both groups on postoperative day 1. Jensen et al. (186) studied the intraosseous injection. A single perforation and injection resulted in a mean pain rating of 30.6 mm for Day 1. These results are higher than those seen for Day 1 in Group

2, but were very similar to those seen in Group 1 for our study. Like our study, all mean pain ratings reported by Robertson et al. (29), McEntire (1), Pabst et al. (204), Berlin

(69), and Jensen et al. (186) were within the mild pain category.

For postoperative day 2, Group 1 resulted in a mean pain rating of 24.9 mm and

Group 2 resulted in a mean pain rating of 13.4 mm. The pain ratings at day 2 continued to decline for both groups from the pain ratings seen at the initial cessation of anesthesia and at post-operative day 1. There was a statistically significant difference (p=0.0004) between groups for mean pain rating and is likely the result of increased trauma from the additional volume as explained above. For Group 1, males averaged 19.5 mm, while females averaged 30.3 mm. The pain ratings between genders for Group 1 were not significantly different. Eighty-eight percent of pain ratings were in the none-to-mild

165 category, 11.6% were in the moderate category, and no subjects reported severe pain.

For Group 2, males averaged 6.7 mm and females average 20.0 mm. The pain ratings

between genders for Group 2 were significantly different (p=0.0240). Ninety-seven

percent of pain ratings were in the none-to-mild category, 3.5% were in the moderate category and no subjects reported severe pain. Robertson et al. (29) and McEntire (1) reported mean pain ratings for Day 2 of 11 mm and 8.1 mm, respectively, following a buccal infiltration with 1.8 mL 4% articaine with 1:100,000 epinephrine. The results of

Robertson et al. (29) and McEntire (1) for post-operative day 2 were similar to those seen

in Group 2 of our study, but were lower than the pain ratings reported in Group 1 of our

study. Pabst et al. (204) reported post-operative pain ratings of 14.0 mm for Day 2

following a single buccal infiltration with articaine. For the repeated injection group,

Pabst et al. (204) reported post-operative pain ratings of 23.1 mm for Day 2. These

values were similar to our results for the two different anesthetic volumes. Berlin (69)

reported that the periodontal ligament (PDL) injection resulted in a mean pain rating of

14.7 mm for postoperative day 2 when an articaine solution was used. The PDL injection

produced similar ratings to Group 2 (1.8 mL volume) of our study groups on

postoperative day 2, but had lower pain ratings when compared to Group 1 (3.6 mL

volume) in our study. Jensen et al. (186) studied the intraosseous injection and found a

mean pain rating of 25.0 mm for day 2. This was higher than the ratings seen in Group 2

of our study, but very similar to the pain ratings in Group 1. Like our study, all mean

pain ratings reported by Robertson et al. (29), McEntire (1), Pabst et al. (204), Berlin

(69), and Jensen et al. (186) were within the mild pain category.

166 For postoperative day 3 the pain ratings continued to decline for both groups.

Group 1 resulted in a mean pain rating of 17.9 mm and Group 2 resulted in a mean pain

rating of 9.1 mm. There was a statistically significant difference (p=0.0004) between

groups for mean pain rating and is likely the result of increased trauma from the

additional volume as explained above. For Group 1, males averaged 14.8 mm, while

females reported average pain levels of 21.0 mm. The pain ratings between genders for

Group 1 were not significantly different. Ninety-two percent of pain ratings were in the

none-to-mild category, 8.1% were in the moderate category, and no subjects reported severe pain. For Group 2, males averaged 6.3 mm and females average 11.8 mm. The pain ratings between genders for Group 2 were not significantly different. Ninety-eight

percent of pain ratings were in the none-to-mild category, 2.3% were in the moderate

category and no subjects reported severe pain. Robertson et al. (29) and McEntire (1)

reported mean pain ratings for Day 3 of 6 mm and 5.4 mm, respectively, following a

buccal infiltration with 1.8 mL 4% articaine with 1:100,000 epinephrine. The results of

Robertson et al. (29) and McEntire (1) for post-operative day 3 were similar to those seen

in Group 2 of our study, but were lower than the pain ratings reported in Group 1 of our

study. Pabst et al. (204) reported post-operative pain ratings of 7.9 mm for Day 3

following a single buccal infiltration with articaine. For the repeated injection group,

Pabst et al. (204) reported post-operative pain ratings of 13.9 mm for Day 3. These

values were similar to our results for the two different anesthetic volumes. Berlin (69)

reported that the periodontal ligament (PDL) injection resulted in a mean pain rating of

5.5 mm for postoperative day 3 when an articaine solution was used. The PDL injection

produced similar ratings to Group 2 of our study groups on postoperative day 3, but had

167 lower pain ratings for postoperative day 3 when compared to Group 1 in our study.

Jensen et al. (186) studied the intraosseous injection and found a mean pain rating of 20.8 mm for day 3. These pain ratings were higher than both Groups in our study. Like our study, all mean pain ratings reported by Robertson et al. (29), McEntire (1), Pabst et al.

(204), Berlin (69), and Jensen et al. (186) were within the mild pain category.

The current study supports the findings by Robertson et al. (29), Pabst et al. (204), and McEntire (1) that the mandibular buccal infiltration injection results in less postoperative discomfort than the PDL (69) or intraosseous injection techniques (186) when using a 1.8 mL volume of 4% articaine with 1:100,000 epinephrine. The current study supports the findings of Pabst et al. (204) that the mandibular buccal infiltration injection results in similar postoperative discomfort to the PDL (69) or intraosseous injection techniques (186) when using a 3.6 mL volume of 4% articaine with 1:100,000 epinephrine. Similar to Robertson et al. (29), Pabst et al. (204), McEntire (1), Berlin

(69), and Jensen et al. (186) all mean values for both groups for all four time periods were in the “mild” pain range and the pain values decreased for each solution over the three postoperative days.

In general, females had a higher overall mean pain ratings for all 4 post-operative periods in both groups. This is likely the result of gender differences in pain transmission and could be influenced by gender differences in willingness to report pain. Women may be more likely than men to report the pain that they are experiencing. Gender differences in pain ratings have been shown in previous studies (166-173), and the occurrence of higher pain ratings by females is consistent with these findings. “Liddel and Locker

(167) showed that women were significantly more anxious about dental treatment than

168 men (p<0.001) and dental anxiety decreased significantly with age (p<0.001). In addition, women said they would try to avoid pain more, accept pain less, and fear pain more than men (p<0.001). Fillingim et al. (168) studied clinical pain experiences, thermal pain thresholds, and pain tolerance in 209 (117 female and 92 male) healthy young adults. These results imply that the sex difference might be due to a generally enhanced somatosensation rather than a difference in nociceptive processing in women.

Fillingim et al. (168) also suggested that pain responses may be more clinically relevant for females than males. The authors concluded that the contributing factors may include hormonal alterations (169), resting blood pressure (170), and psychological factors (171).

Other investigators have reported that other contributing factors, such as sex role expectancies (172) and anxiety (173) may also moderate differences in pain tolerance seen between sexes. Keogh et al. (174) studied the effects of two different attentional strategies (focused versus avoidance) on how males and females responded to experimentally induced pain. Keogh et al. (174) found that males had a significantly higher tolerance for cold pressor pain than females. The authors also found that males, who were given attentional focus instructions, had lower sensory pain compared to males whom were instructed to avoid pain. This was not true with the female groups.” (1)

There were no significant differences between genders for both groups for any of the post-operative days, except for post-operative day 2 with the 1.8 mL volume (Group

2) (p=0.0240). Women reported moderate pain more frequently than men at each post- operative period for both groups except for post-operative day 0 for Group 2 (1.8 mL volume). Also, there were 4 outliers in the female group that reported moderate or severe pain for all time periods and for both volumes that may have skewed the data enough to

169 create the observed differences between genders in mean post-operative pain. A larger

sample size may have reduced the impact of the outliers, but females may still report higher pain ratings than males for the reasons described previously.

The mean pain ratings associated with Group 1 were statistically higher than the mean pain ratings of Group 2 for all for time periods, but the mean pain ratings were all still within the mild category. There were more subjects reporting more significant discomfort in the moderate range after receiving 3.6 mL of 4% articaine with 1:100,000 epinephrine than 1.8 mL of 4% articaine with 1:100,000 epinephrine. It is possible that patients rated the post-operative pain after the first injection higher than post-operative pain after the second injection. In the current study, the order of use of the two volumes of anesthetic solutions was randomly generated. Therefore, half of the subjects received

1.8 mL 4% articaine with 1:100,000 epinephrine at the first appointment and 3.6 mL of

4% articaine with 1:100,000 epinephrine at the second appointment. The other half of the subjects received the injections in the reverse order. Randomizing the sequence helped prevent subject bias in terms of injection pain and post-operative pain.

“Generally, the postoperative complaints reported by our subjects were likely due to trauma from the injection. Some people are more likely to note discomfort from this trauma than others. When muscle tissue is penetrated by the needle during the injection, it often results in localized tissue damage, which heals within a few days (32). Trauma may also be caused when the anesthetic is deposited in the dental tissues, causing them to stretch and expand.” (2) The results of the current study indicate that the volume of articaine does affect post-operative pain when used for the mandibular buccal infiltration.

“Malamed et al. (70) reported adverse post procedural events in 22% of patients

170 receiving articaine. Nerve blocks and infiltration injections were both included in their

study. The most common complaint of patients receiving articaine was pain, reported by

13%, followed by headache, reported by 4%. The author categorized some adverse events

to be drug-related. The most commonly reported drug-related adverse events were

paresthesia (0.9%), hypoesthesia (0.7%), headache (0.55%), infection (0.45%), rash

(0.3%), and pain (0.3%).” (2) Of these events, the current study found pain, headache,

and infection in common (Table 24 and 25).

One incidence of paresthesia was reported by the subjects in our study. One

female patient reported paresthesia for 4-5 hours on the day of the injection of the 3.6 mL volume. When further questioned about the symptoms experienced, the patient described symptoms similar to those commonly experienced as numbness wears off. Several patients that participated in the study were being anesthetized for the first time and some reported post-op symptoms expected as anesthesia wore off. One other female patient reported an occasional spontaneous tingling sensation in the premolar region on post- operative days 2 and 3 after receiving the 1.8 mL volume. This patient reported that the tingling completely subsided after post-op day 3. Since the patient did not experience a continual paresthesia from the time anesthesia wore off through the completion of the post-operative survey, it is likely that the site of tingling was somehow traumatized after the anesthetic solution had dissipated and was not a direct response to the anesthetic itself. This patient also reported swelling that began on post-op day 2, and may have therefore experienced a minor localized infection in the area of the premolars as a result

of the injection. Localized swelling could have caused some compression of the nerve

bundle exiting the mental foramen resulting in the tingling sensation reported. Cohenca

171 and Rotsein (188) presented a case of mental nerve paresthesia caused by compression of

the mental nerve by an enlarging periapical inflammatory lesion. The authors also discussed other potential causes of temporary nerve paresthesia which included pressure

from swelling and traumatic injury (188). However, the number of subjects (86 subjects)

and number of injections given utilizing articaine (172 injections) in our study were very

low compared to the retrospective studies looking at the concerns with paresthesias and

the inferior alveolar nerve block (83,84). It was not possible to determine from our study

whether articaine carried a greater risk than other anesthetics for a mandibular buccal

infiltration. “If this injection technique results in a mental nerve block, and the observed

risk for paresthesia with articaine is associated with nerve block injections, then there is a

possibility that the injection technique used in our study may have a higher risk for

paresthesia when using articaine compared to lidocaine.” (1) Kanaa et al. (28), Corbett et

al. (174), Haase et al. (30), Robertson et al. (29), Pabst et al. (204) and McEntire (1) did

not report any incidences of paresthesias using an articaine solution with a buccal

infiltration. As the overall risk for paresthesia appears to be very low, the benefit of

increased anesthetic success may outweigh the possible risk.

In the current study, postoperative complications were reported by some subjects

in each group. Other than general pain or soreness at the site of injection, which was

quantified using the VAS, swelling was noted by relatively few subjects (Table 24 and

25). This data could not be statistically analyzed due to the low number of subjects

reporting complications. Neither trismus nor extraoral bruising or swelling was noted by

any subjects.

Generally, the postoperative complaints reported by our subjects were likely due

172 to trauma from the injection. “When muscle tissue is penetrated by the needle during the injection, it often results in localized tissue damage, which heals within a few days (32).

Some individuals may be more sensitive to this tissue damage and report discomfort, while others do not report it (32).” (1) Group 1 reported more instances of soreness at the site of injection and swelling, which were the most common complaints reported by our subjects. As discussed earlier, this is probably related more to the injection and the additional trauma caused by the injection of a larger volume of anesthetic.

173

CHAPTER 7

SUMMARY AND CONCLUSIONS

The purpose of this prospective, randomized, single-blinded, repeated-measures

study was to compare the anesthetic efficacy of pulpal anesthesia following a buccal

infiltration of the mandibular first molar using 3.6 mL of 4% articaine with 1:100,000 epinephrine and 1.8 mL of 4% articaine with 1:100,000 epinephrine.

Eighty-six healthy male and female volunteers with vital, asymptomatic mandibular teeth participated in this study. A topical anesthetic (20% benzocaine gel) was placed at the site of injection for 1 minute. The primary buccal infiltration was administered by injecting 3.6 mL of 4% articaine with 1:100,000 epinephrine (Group 1) or 1.8 mL of 4% articaine with 1:100,000 epinephrine (Group 2) buccal to the mandibular first molar bisecting the approximate location of the mesial and distal roots. The mandibular first and second molars and first and second premolars on the side of the injection were evaluated for pulpal anesthesia using a digital electric pulp tester. The test teeth were evaluated over a 90-minute time period. Subjects rated pain during injection and postoperative pain using a 170-mm visual analog scale.

There was no statistically significant difference in pain intensity between the two volumes for any of the three phases of the injections. Mean needle insertion pain ratings, mean needle placement pain ratings, and mean solution deposition pain ratings for both groups fell in the mild pain category. Needle placement was the most painful stage for

174 Group 2 (1.8 mL volume) while solution deposition was the most painful stage for Group

1 (3.6 mL volume), but both were in the mild pain category. Gender did not affect pain ratings as there was no significant difference between males or females for any stages of the injections for either group.

Three definitions of success were used to evaluate pulpal anesthesia. Success #1 was defined as achieving the first of two consecutive 80/80 readings within the first 7 minutes of testing for the molars or the first 8 minutes of testing for the premolars and recorded the last of two consecutive 80/80 readings at or after minute 58 for the molars and minute 59 for the premolars. This definition included subjects that experienced non- continuous anesthesia. There were no statistically significant differences between

Groups 1 and 2 for the second molar (p=0.0703), but the first molar, second premolar, and first premolar were significantly different (p=0.0450, <0.0001, and =0.0001, respectively).

Success #2 was defined as achieving the first of two consecutive 80/80 readings within the first 7 minutes of testing for the molars or the first 8 minutes of testing for the premolars and maintaining the 80/80 readings continuously through the minute 58 for the molars and minute 59 for the premolars. This definition excluded subjects that experienced non-continuous anesthesia. There were no statistically significant differences between Groups 1 and 2 for the second molar (p=0.1250) and first molar

(p=0.0772), but the second premolar and first premolar were significantly different

(p<0.0001, =0.0007, respectively).

Success #3 was defined as the occurrence of two consecutive 80/80 readings at any time during the testing period. There was no statistically significant difference

175 between Groups 1 and 2 for the second premolar (p=0.1797), but the second molar, first

molar, and first premolar were significantly different (p=0.0129, <0.0001, and =0.0234, respectively). Anesthetic failure was defined as no consecutive 80/80 readings at any

time during the 90-minute testing period. There was no statistically significant difference

between Groups 1 and 2 for the second premolar (p=0.1797), but the second molar, first

molar, and first premolar were significantly different (p=0.0129, <0.0001, and =0.0234, respectively).

Statistical analysis of onset times found no statistically significant difference

between the two volumes for onset of pulpal anesthesia for the first and second molars

(p=0.6318 and 0.6318, respectively), but there was a statistically significant difference in mean onset times for the first and second premolars (p=0.0012 and 0.0141, respectively) between Groups 1 and 2. The mean onset times of pulpal anesthesia ranged from 4.3 minutes (first premolar) to 4.7 minutes (second premolar) with 3.6 mL of 4% articaine with 1:100,000 epinephrine, and ranged from 4.9 minutes (second molar) to 5.6 minutes

(first premolar) with 1.8 mL of 4% articaine with 1:100,000 epinephrine.

Slow onset of anesthesia, anesthesia of short duration, and non-continuous

anesthesia were also compared for the two solutions. There were no significant

differences in the incidence of slow onset anesthesia or non-continuous anesthesia

between the two volumes. There were significantly higher percentages of short duration

of anesthesia for each of the teeth tested in Group 2 (1.8 mL volume) compared to Group

1 (3.6 mL volume).

Mean postoperative pain ratings revealed significantly higher pain ratings for

Group 1 at each of the postoperative periods. The mean post-operative pain ratings for

176 all time periods were in the “mild” category and the mean postoperative pain ratings continuously decreased from day 0 through day 3. Between gender analysis showed a significantly higher average pain rating (p=0.0240) for females at post-op day 2 for the

1.8 mL volume of 4% articaine with 1:100,000 epinephrine. No other statistically significant differences were seen between genders.

Although statistical analysis was not performed on this data, there does not seem to be a clinically significant difference between the two groups in regard to the prevalence or severity of postoperative complications. Out of 172 postoperative surveys returned, tenderness to touch at the site of injection was reported in 18.6% of Group 1 and 8.1% in Group 2. Swelling was reported by 10.5% of subjects in Group 1 and 4.7% in Group 2. Pain on opening, intraoral bruising and soreness when chewing were reported in much lower frequencies. One female subject in Group 2 reported tingling in the premolar region on post-op days 2 and 3. The complaints decreased in prevalence as the postoperative days progressed.

We concluded that a 3.6 mL volume of 4% articaine with 1:100,000 epinephrine has better anesthetic efficacy than 1.8 mL of 4% articaine with 1:100,000 epinephrine in a single primary mandibular buccal infiltration injection given next to the first molar.

Neither volume provided pulpal anesthesia with a success rate high enough to support its use as a primary injection technique in mandibular posterior teeth. A primary mandibular buccal infiltration near the root apices of the first molar with 1.8 or 3.6 mL of 4% articaine with 1:100,000 epinephrine will not provide dependable pulpal anesthesia for 60 minutes.

177

APPENDIX A

TABLES

178

# of Subjects Age Range (years) Mean Age (years) Males 43 21-32 26.6

Females 43 20-45 24.6 Totals 86 20-45 25.6

Table 1. Biographical data for all subjects.

179

Variable Group 1* Group 2** p-value† (N=86) (N=86)

Insertion 25.4 + 21.6 26.8 + 21.9 1.0000

Placement 36.2 + 23.3 39.1 + 27.1 1.0000

Deposition 36.8 + 28.6 36.8 + 27.2 1.0000

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine. †Statistical analysis performed using a Multiple Wilcoxon matched-pairs, signed-ranks tests and was adjusted using the Step-down Bonferroni method of Holm.

Table 2. Mean VAS Values (mm) of Procedural Discomfort Ratings for Buccal Infiltration of 3.6 and 1.8 mL 4% Articaine with 1:100,000 Epinephrine.

180

Variable Males Females p-value† (N=43) (N=43)

Insertion Group 1* 27.1 + 16.9 23.8 + 25.5 1.0000 Group 2** 31.0 + 22.7 22.6 + 20.4 0.8952 p-value† 1.0000 1.0000

Placement Group 1* 33.5 + 20.0 38.9 + 26.1 1.0000 Group 2** 40.7 + 28.5 37.5 + 26.0 1.0000 p-value† 1.0000 1.0000

Deposition Group 1* 41.7 + 28.3 31.9 + 28.4 1.0000 Group 2** 36.9 + 27.3 36.6 + 27.5 1.0000 p-value† 1.0000 1.0000

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine. † Statistical analysis performed using a Multiple Wilcoxon matched-pairs, signed-ranks tests and was adjusted using the Step-down Bonferroni method of Holm.

Table 3. Mean VAS Values (mm) of Procedural Discomfort Ratings for Males and Females by Group.

181

None Mild Moderate Severe

Total 30 (17.4%) 132 (76.7%) 9 (5.2%) 1 (0.6%) (N = 172) ------Group 1* 16 (18.6%) 67 (77.9%) 2 (2.3%) 1 (1.2%) (N = 86) Group 2** 14 (16.3%) 65 (75.6%) 7 (8.1%) 0 (0%) (N = 86) ------Male 6 (7.0%) 73 (84.9%) 7 (8.1%) 1 (1.2%) (N = 86) Female 24 (27.9%) 59 (68.6%) 2 (2.3%) 0 (0%) (N = 86)

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine.

Table 4. Summary of Pain Ratings for Needle Insertion Utilizing a Numerical Scale.

182

None Mild Moderate Severe

Total 12 (7.0%) 134 (77.9%) 26 (15.1%) 0 (0%) (N = 172) ------Group 1* 4 (4.7%) 72 (83.7%) 10 (11.6%) 0 (0%) (N = 86) Group 2** 8 (9.3%) 62 (72.1%) 16 (18.6%) 0 (0%) (N = 86) ------Male 6 (7.0%) 65 (75.6%) 15 (17.4%) 0 (0%) (N = 86) Female 6 (7.0%) 69 (80.2%) 11 (12.8%) 0 (0%) (N = 86)

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine.

Table 5. Summary of Pain Ratings for Needle Placement Utilizing a Numerical Scale.

183

None Mild Moderate Severe

Total 22 (12.8%) 120 (69.8%) 30 (17.4%) 0 (0%) (N = 172) ------Group 1* 12 (14.0%) 59 (68.6%) 15 (17.4%) 0 (0%) (N = 86) Group 2** 10 (11.6%) 61 (70.9%) 15 (17.4%) 0 (0%) (N = 86) ------Male 6 (7.0%) 62 (72.1%) 18 (20.9%) 0 (0%) (N = 86) Female 16 (18.6%) 58 (67.4%) 12 (14.0%) 0 (0%) (N = 86)

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine.

Table 6. Summary of Pain Ratings for Solution Deposition Utilizing a Numerical Scale.

184

Post-injection Group 1* Group 2** p-value (raw)*† p-value (adjusted)† Time (min) (%) (%)

1 22.1 16.3 0.4244 1.0000 4 51.2 37.2 0.0357 0.8211 7 57.0 43.0 0.0290 0.7529 10 60.5 41.9 0.0009 0.0471 13 57.0 46.5 0.0636 1.0000 16 55.8 41.9 0.0075 0.2519 19 55.8 34.9 0.0000 0.0006 22 54.7 32.6 0.0001 0.0046 25 54.7 26.7 0.0000 0.0000 28 51.2 26.7 0.0000 0.0001 31 53.5 25.6 0.0000 0.0001 34 47.7 18.6 0.0000 0.0000 37 46.5 17.4 0.0000 0.0000 40 43.0 12.8 0.0000 0.0000 43 36.0 12.8 0.0000 0.0002 46 34.9 10.5 0.0000 0.0001 49 25.6 9.3 0.0001 0.0079 52 23.3 8.1 0.0002 0.0149 55 19.8 7.0 0.0010 0.0518 58 15.1 7.0 0.0391 0.8594 61 17.4 2.3 0.0010 0.0518 64 15.1 2.3 0.0034 0.1333 67 12.8 1.2 0.0020 0.0824 70 12.8 0.0 0.0010 0.0518 73 7.0 0.0 0.0313 0.7813 76 5.8 0.0 0.0625 1.0000 79 3.5 0.0 0.2500 1.0000 82 4.7 0.0 0.1250 1.0000 85 3.5 0.0 0.2500 1.0000 88 3.5 0.0 0.2500 1.0000

N=86 *Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine. *† Exact McNemar test. † Step-down Bonferroni method of Holm adjusted for 120 comparisons.

Table 7. Between-group Comparisons of Percent 80/80 for the Second Molar.

185

Post-injection Group 1* Group 2** p-value (raw)*† p-value (adjusted)† Time (min) (%) (%)

1 20.9 11.6 0.0963 1.0000 4 45.3 34.9 0.0931 1.0000 7 65.1 46.5 0.0009 0.0471 10 66.3 48.8 0.0007 0.0415 13 68.6 46.5 0.0001 0.0046 16 68.6 46.5 0.0000 0.0003 19 69.8 43.0 0.0000 0.0002 22 66.3 44.2 0.0001 0.0046 25 64.0 38.4 0.0000 0.0003 28 58.1 32.6 0.0000 0.0003 31 58.1 31.4 0.0000 0.0002 34 57.0 29.1 0.0000 0.0001 37 54.7 27.9 0.0000 0.0000 40 50.0 24.4 0.0000 0.0001 43 44.2 23.3 0.0000 0.0028 46 37.2 19.8 0.0007 0.0415 49 34.9 16.3 0.0001 0.0090 52 27.9 14.0 0.0018 0.0824 55 26.7 12.8 0.0018 0.0824 58 24.4 11.6 0.0034 0.1333 61 18.6 5.8 0.0010 0.0518 64 18.6 2.3 0.0001 0.0079 67 16.3 2.3 0.0018 0.0824 70 15.1 2.3 0.0010 0.0518 73 12.8 2.3 0.0117 0.3516 76 9.3 2.3 0.0703 1.0000 79 8.1 2.3 0.1250 1.0000 82 8.1 2.3 0.1250 1.0000 85 7.0 2.3 0.2188 1.0000 88 7.0 2.3 0.2188 1.0000

N=86 *Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine. *† Exact McNemar test. † Step-down Bonferroni method of Holm adjusted for 120 comparisons.

Table 8. Between-group Comparisons of Percent 80/80 for the First Molar.

186

Post-injection Group 1* Group 2** p-value (raw)*† p-value (adjusted)† Time (min) (%) (%)

2 41.2 28.2 0.0522 1.0000 5 76.5 61.2 0.0072 0.2519 8 88.2 76.5 0.0213 0.5743 11 88.2 82.4 0.2669 1.0000 14 88.2 85.9 0.7539 1.0000 17 91.8 84.7 0.1460 1.0000 20 88.2 82.4 0.3018 1.0000 23 89.4 76.5 0.0074 0.2519 26 89.4 72.9 0.0013 0.0630 29 85.9 71.8 0.0075 0.2519 32 83.5 67.1 0.0013 0.0630 35 83.5 61.2 0.0000 0.0016 38 83.5 60.0 0.0000 0.0026 41 78.8 50.6 0.0000 0.0001 44 80.0 48.2 0.0000 0.0000 47 75.3 43.5 0.0000 0.0000 50 75.3 37.6 0.0000 0.0000 53 68.2 32.9 0.0000 0.0000 56 61.2 31.8 0.0000 0.0002 59 55.3 27.1 0.0000 0.0003 62 48.2 21.2 0.0000 0.0002 65 44.7 17.6 0.0000 0.0002 68 41.2 12.9 0.0000 0.0000 71 43.5 10.6 0.0000 0.0000 74 36.5 10.6 0.0000 0.0000 77 36.5 10.6 0.0000 0.0000 80 31.8 9.4 0.0000 0.0003 83 29.4 9.4 0.0000 0.0012 86 29.4 8.2 0.0000 0.0006 89 29.4 8.2 0.0000 0.0006

N=85 *Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine. *† Exact McNemar test. † Step-down Bonferroni method of Holm adjusted for 120 comparisons.

Table 9. Between-group Comparisons of Percent 80/80 for the Second Premolar.

187

Post-injection Group 1* Group 2** p-value (raw)*† p-value (adjusted)† Time (min) (%) (%)

2 44.2 27.9 0.0066 0.2380 5 75.6 58.1 0.0015 0.0685 8 84.9 69.8 0.0024 0.0940 11 87.2 77.9 0.0768 1.0000 14 88.4 76.7 0.0129 0.3752 17 89.5 80.2 0.0574 1.0000 20 89.5 75.6 0.0042 0.1547 23 90.7 70.9 0.0000 0.0012 26 87.2 69.8 0.0003 0.0162 29 86.0 62.8 0.0001 0.0058 32 84.9 58.1 0.0000 0.0005 35 82.6 54.7 0.0000 0.0007 38 81.4 46.5 0.0000 0.0000 41 75.6 37.2 0.0000 0.0000 44 73.3 34.9 0.0000 0.0000 47 66.3 29.1 0.0000 0.0000 50 61.6 23.3 0.0000 0.0000 53 54.7 22.1 0.0000 0.0000 56 47.7 16.3 0.0000 0.0001 59 38.4 14.0 0.0000 0.0015 62 30.2 11.6 0.0004 0.0233 65 30.2 8.1 0.0000 0.0016 68 25.6 4.7 0.0001 0.0079 71 24.4 2.3 0.0000 0.0003 74 20.9 2.3 0.0000 0.0022 77 17.4 2.3 0.0002 0.0149 80 12.8 1.2 0.0020 0.0824 83 10.5 1.2 0.0078 0.2519 86 9.3 1.2 0.0156 0.4375 89 8.1 1.2 0.0313 0.7813

N=86 *Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine. *† Exact McNemar test. † Step-down Bonferroni method of Holm adjusted for 120 comparisons.

Table 10. Between-group Comparisons of Percent 80/80 for the First Premolar.

188 Adjusted Odds Ratio † Parameter Tooth LCB.95 UCB.95 p-value Gender 2nd Molar 1.69 0.85 3.34 0.1325 (female vs. male) 1st Molar 1.18 0.60 2.33 0.6267 2nd Premolar 1.85 0.98 3.49 0.0592 1st Premolar 1.60 0.89 2.90 0.1174 Anesthetic 2nd Molar 3.12 2.33 4.18 <.0001 (Group 1* vs. Group 2**) 1st Molar 2.34 1.76 3.11 <.0001 2nd Premolar 3.05 2.25 4.12 <.0001 1st Premolar 3.75 2.68 5.24 <.0001

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine. † Statistical analysis using the logistic regression model.

Table 11. Adjusted Odds Ratios for Pulpal Anesthesia.

189

Tooth Definition 1* Definition 2** Definition 3*** 2nd Molar (N=86) Group 1 (3.6 mL) 12 (14.0%) 11 (12.8%) 56 (65.1%) Group 2 (1.8 mL) 6 (7.0%) 6 (7.0%) 42 (48.8%)

p-value† 0.0703 0.1250 0.0129 1st Molar (N=86) Group 1 (3.6 mL) 19 (22.1%) 18 (20.9%) 65 (75.6%) Group 2 (1.8 mL) 10 (11.6%) 10 (11.6%) 45 (52.3%)

p-value† 0.0450 0.0772 <0.0001 2nd Premolar (N=85) Group 1 (3.6 mL) 46 (54.1%) 44 (51.8%) 79 (92.9%) Group 2 (1.8 mL) 22 (25.9%) 20 (23.5%) 74 (87.1%)

p-value† <0.0001 <0.0001 0.1797 1st Premolar (N=86) Group 1 (3.6 mL) 32 (37.2%) 29 (33.7%) 79 (91.9%) Group 2 (1.8 mL) 12 (14.0%) 12 (14.0%) 70 (81.4%)

p-value† 0.0001 0.0007 0.0234 *Success #1 defined as the first of two consecutive 80/80 readings by minute 7 for molars or minute 8 for premolars and obtained the last of two consecutive 80/80 readings at or after minute 58 for molars or 59 for premolars (includes non-continuous anesthesia). **Success #2 defined as the first of two consecutive 80/80 readings by minute 7 for molars or minute 8 for premolars and maintained continuously through minute 58 for molars or 59 for premolars (excludes non-continuous anesthesia). ***Success #3 defined as obtaining two consecutive 80/80 readings at any time within the testing period. † Exact McNemar test and adjusted with the Step-down Bonferroni method of Holm adjusted for 4 comparisons.

Table 12. Anesthetic Success by Group and Definition of Success.

190

Tooth Group 1* Group 2** p-value† 2nd Molar 30 (34.9%) 44 (51.2%) 0.0129 (N=86) 1st Molar 21 (24.4%) 41 (47.7%) <0.0001 (N=86) 2nd Premolar 6 (7.1%) 11 (12.9%) 0.1797 (N=85) 1st Premolar 7 (8.1%) 16 (18.6%) 0.0234 (N=86)

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine. † Exact McNemar test and adjusted with the Step-down Bonferroni method of Holm adjusted for 4 comparisons.

Table 13. Anesthetic Failure by Tooth and Group.

191

Tooth Group 1* Group 2** Difference p-value†

Second Molar (N=38) Onset 4.6 + 5.0 4.9 + 3.8 0.3 + 6.4 0.6318 Duration†* 47.0 + 20.8 27.9 + 18.3 19.0 + 15.2

First Molar (N=45) Onset 4.4 + 3.4 5.4 + 4.2 1.0 + 5.0 0.6318 Duration†* 49.3 + 22.8 32.9 + 20.6 16.5 + 16.8

Second Premolar (N=72) Onset 4.7 + 4.2 5.5 + 3.5 0.8 + 4.2 0.0141† Duration†* 62.8 + 21.2 42.3 + 21.4 20.5 + 16.8

First Premolar (N=69) Onset 4.3 + 3.2 5.6 + 4.0 1.3 + 3.2 0.0012† Duration†* 55.0 + 18.4 36.2 + 18.1 18.8 + 17.5

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine. † Statistical analysis performed using a Wilcoxon matched pairs, signed-ranks test and adjusted with the Step-down Bonferroni method of Holm adjusted for 4 comparisons. †*Statistical analysis was not performed for duration because the study was not open-ended.

Table 14. Mean Onset and Duration (minutes) of Pulpal Anesthesia.

192

Tooth Group 1* Group 2** p-value†

Second Molar 4 6 1.0000 (N=38) (10.5%) (15.8%)

First Molar 4 5 1.0000 (N=45) (8.9%) (11.1%)

Second Premolar 4 9 0.5391 (N=72) (5.6%) (12.5%)

First Premolar 3 9 0.1252 (N=69) (4.3%) (13.0%)

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine. † Statistical analysis performed using a Wilcoxon matched pairs, signed-ranks test and adjusted with the Step-down Bonferroni method of Holm adjusted for 4 comparisons. N represents the number of matched pairs of teeth attaining anesthesia and excludes matched pairs of teeth in which one or both teeth were considered a failure.

Table 15. Slow Onset Anesthesia by Group and by Tooth.

193

Tooth Group 1* Group 2** p-value†

Second Molar 24 32 0.0215 (N=38) (63.2%) (84.2%)

First Molar 24 35 0.0068 (N=45) (53.3%) (77.8%)

Second Premolar 27 50 <0.0001 (N=72) (37.5%) (69.4%)

First Premolar 37 57 0.0001 (N=69) (53.3%) (82.6%)

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine. † Statistical analysis performed using a Wilcoxon matched pairs, signed-ranks test and adjusted with the Step-down Bonferroni method of Holm adjusted for 4 comparisons. N represents the number of matched pairs of teeth attaining anesthesia and excludes matched pairs of teeth in which one or both teeth were considered a failure.

Table 16. Short Duration Anesthesia (<60 minutes) by Group and by Tooth.

194

Tooth Group 1* Group 2** p-value†

Second Molar 4 3 1.0000 (N=38) (10.5%) (7.9%)

First Molar 3 3 1.0000 (N=45) (6.7%) (6.7%)

Second Premolar 10 5 1.0000 (N=72) (13.9%) (6.9%)

First Premolar 7 7 1.0000 (N=69) (10.1%) (10.1%)

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine. † Statistical analysis performed using a Wilcoxon matched pairs, signed-ranks test and adjusted with the Step-down Bonferroni method of Holm adjusted for 4 comparisons. N represents the number of matched pairs of teeth attaining anesthesia and excludes matched pairs of teeth in which one or both teeth were considered a failure.

Table 17. Noncontinuous Anesthesia by Group and by Tooth.

195

Variable Group 1* Group 2** p-value†

Post op Day 0 35.8 + 28.6 24.3 + 23.7 0.0004

Post op Day 1 30.8 + 27.5 17.1 + 19.8 0.0004

Post op Day 2 24.9 + 27.9 13.4 + 20.8 0.0004

Post op Day 3 17.9 + 25.9 9.1 + 18.3 0.0004 N=86 *Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine. † Statistical analysis performed using a Wilcoxon matched pairs, signed-ranks test and adjusted with the Step-down Bonferroni method of Holm adjusted for 4 comparisons.

Table 18. Mean VAS Values (mm) of Postoperative Discomfort Ratings.

196

Variable Males Females p-value† (N=43) (N=43)

Post-op Day 0 Group 1* 28.3 + 25.8 43.3 + 29.6 0.0973 Group 2** 22.1 + 25.4 26.5 + 22.0 0.5490 p-value† 0.0429 0.0014

Post-op Day 1 Group 1* 24.3 + 23.7 37.3 + 29.8 0.1495 Group 2** 12.1 + 13.8 22.1 + 23.4 0.1092 p-value† 0.0042 0.0042

Post-op Day 2 Group 1* 19.5 + 25.9 30.3 + 29.2 0.2976 Group 2** 6.7 + 14.0 20.0 + 24.3 0.0240 p-value† 0.0014 0.0570

Post-op Day 3 Group 1* 14.8 + 26.4 21.0 + 25.4 0.5490 Group 2** 6.3 + 14.9 11.8 + 21.0 0.5043 p-value† 0.0576 0.0680

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine. †Statistical analysis using a Multiple Wilcoxon matched-pairs, signed-ranks tests and adjusted with the Step-down Bonferroni method of Holm adjusted adjusted for 16 comparisons.

Table 19. Mean VAS Values (mm) of Post-op Pain Ratings for Males and Females by Group.

197

None Mild Moderate Severe

Total 31 (18.0%) 117 (68.0%) 23 (13.4%) 1 (0.6%) (N = 172) ------Group 1* 10 (11.6%) 57 (66.3%) 18 (20.9%) 1 (1.2%) (N = 86) Group 2** 21 (24.4%) 60 (69.8%) 5 (5.8%) 0 (0%) (N = 86) ------Male 15 (17.4%) 61 (70.9%) 9 (10.5%) 1 (1.2%) (N = 86) Female 16 (18.6%) 56 (65.1%) 14 (16.3%) 0 (0%) (N = 86)

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine.

Table 20. Summary of Pain Ratings for Post-op Day 0 Utilizing a Numerical Scale.

198

None Mild Moderate Severe

Total 48 (27.9%) 106 (61.6%) 18 (10.5%) 0 (0%) (N = 172) ------Group 1* 18 (20.9%) 53 (61.6%) 15 (17.4%) 0 (0%) (N = 86) Group 2** 30 (34.9%) 53 (61.6%) 3 (3.5%) 0 (0%) (N = 86) ------Male 23 (26.7%) 59 (68.6%) 4 (4.7%) 0 (0%) (N = 86) Female 25 (29.1%) 47 (54.7%) 14 (16.3%) 0 (0%) (N = 86)

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine.

Table 21. Summary of Pain Ratings for Post-op Day 1 Utilizing a Numerical Scale.

199

None Mild Moderate Severe

Total 77 (44.8%) 82 (47.7%) 13 (7.6%) 0 (0%) (N = 172) ------Group 1* 32 (37.2%) 44 (51.2%) 10 (11.6%) 0 (0%) (N = 86) Group 2** 45 (52.3%) 38 (44.2%) 3 (3.5%) 0 (0%) (N = 86) ------Male 44 (51.2%) 39 (45.3%) 3 (3.5%) 0 (0%) (N = 86) Female 33 (38.4%) 43 (50.0%) 10 (11.6%) 0 (0%) (N = 86)

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine.

Table 22. Summary of Pain Ratings for Post-op Day 2 Utilizing a Numerical Scale.

200

None Mild Moderate Severe

Total 101 (58.7%) 62 (36.0%) 9 (5.2%) 0 (0%) (N = 172) ------Group 1* 44 (51.2%) 35 (40.7%) 7 (8.1%) 0 (0%) (N = 86) Group 2** 57 (66.3%) 27 (31.4%) 2 (2.3%) 0 (0%) (N = 86) ------Male 54 (62.8%) 28 (32.6%) 4 (4.7%) 0 (0%) (N = 86) Female 47 (54.7%) 34 (39.5%) 5 (5.8%) 0 (0%) (N = 86)

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine.

Table 23. Summary of Pain Ratings for Post-op Day 3 Utilizing a Numerical Scale.

201

Post op Day 0 Post op Day 1 Post op Day 2 Post op Day 3

Tender to palpation Group 1 8 (9.3%) 11 (12.8%) 10 (11.6%) 6 (7.0%) Group 2 3 (3.5%) 5 (5.8%) 3 (3.5%) 2 (2.3%) Swelling Group 1 8 (9.3%) 5 (5.8%) 1 (1.2%) 0 (0%) Group 2 3 (3.5%) 1 (1.2%) 1 (1.2%) 0 (0%) Pain on opening Group 1 0 (0%) 0 (0%) 0 (0%) 0 (0%) Group 2 0 (0%) 1 (1.2%) 0 (0%) 0 (0%) Prolonged Motor Deficit Group 1 1 (1.2%) 0 (0%) 0 (0%) 0 (0%) Group 2 1 (1.2%) 0 (0%) 0 (0%) 0 (0%) Prickly Numbness Group 1 2 (2.3%) 0 (0%) 0 (0%) 0 (0%) Group 2 0 (0%) 0 (0%) 0 (0%) 0 (0%) Ear Pain Group 1 0 (0%) 0 (0%) 0 (0%) 0 (0%) Group 2 0 (0%) 1 (1.2%) 0 (0%) 0 (0%) Light Headed Group 1 1 (1.2%) 0 (0%) 0 (0%) 0 (0%) Group 2 1 (1.2%) 1 (1.2%) 0 (0%) 0 (0%) Injection Site Itched Group 1 0 (0%) 0 (0%) 0 (0%) 0 (0%) Group 2 1 (1.2%) 0 (0%) 0 (0%) 0 (0%) Throbbing Group 1 1 (1.2%) 0 (0%) 0 (0%) 0 (0%) Group 2 0 (0%) 0 (0%) 0 (0%) 0 (0%) Prolonged Numbness Group 1 3 (3.5%) 0 (0%) 0 (0%) 0 (0%) Group 2 1 (1.2%) 0 (0%) 0 (0%) 0 (0%) Tingling in Premolar Region Group 1 0 (0%) 0 (0%) 0 (0%) 0 (0%) Group 2 0 (0%) 0 (0%) 1 (1.2%) 1 (1.2%) Sore to chew Group 1 2 (2.3%) 1 (1.2%) 1 (1.2%) 0 (0%) Group 2 1 (1.2%) 0 (0%) 1 (1.2%) 1 (1.2%) Headache Group 1 2 (2.3%) 0 (0%) 0 (0%) 0 (0%) Group 2 2 (2.3%) 1 (1.2%) 0 (0%) 0 (0%) *Group 1 3.6 mL 4% Articaine with 1:100,000 Epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 Epinephrine.

Table 24. Frequency of Subject-reported Postoperative Complications by Day.

202

Complication Group 1* Group 2** (N = 86) (N = 86)

Tender to Palpation 16 (18.6%) 7 (8.1%)

Swelling 9 (10.5%) 4 (4.7%)

Pain on Opening 0 (0%) 1 (1.2%)

Prolonged Motor Deficit 1 (1.2%) 1 (1.2%)

Sore to Chew 1 (1.2%) 1 (1.2%)

Prickly Numbness 2 (2.3%) 0 (0%)

Ear Pain 0 (0%) 1 (1.2%)

Light Headed 1 (1.2%) 2 (2.3%)

Headache 2 (2.3%) 2 (2.3%)

Throbbing 1 (1.2%) 0 (0%)

Prolonged Numbness 3 (3.5%) 1 (1.2%)

Tingling in Premolar Region 0 (0%) 1 (1.2%)

Injection Site Itched 0 (0%) 1 (1.2%)

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine.

Table 25. Postoperative Complications Associated with Buccal Infiltration Injection.

203

APPENDIX B

FIGURES

204

Mean Pain Ratings by Group and Stage of Injection

45.0 40.0 35.0 30.0 25.0 Group 1* 20.0 Group 2** 15.0 mm VAS Pain mm 10.0 5.0 0.0 Insertion Placement Deposition Stage of Injection

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine.

Figure 1. Pain Ratings for Needle Insertion, Needle Placement, and Solution Deposition.

205

Second Molar Pulpal Anesthesia

100.0 90.0 80.0 70.0 60.0 50.0 40.0

mean % 80/80 % mean 30.0 20.0 10.0 0.0 1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61 64 67 70 73 76 79 82 85 88 Time Period (Mins.)

Group 1* Group 2**

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine.

Figure 2. Percent 80/80 Readings for the Second Molar by Group and Time Period.

206

First Molar Pulpal Anesthesia

100.0 90.0 80.0 70.0 60.0 50.0 40.0

mean % 80/80 mean 30.0 20.0 10.0 0.0 1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61 64 67 70 73 76 79 82 85 88 Time Period (Mins.)

Group 1* Group 2**

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine.

Figure 3. Percent 80/80 Readings for the First Molar by Group and Time Period.

207

Second Premolar Pulpal Anesthesia

100.0 90.0 80.0 70.0 60.0 50.0 40.0

mean % 80/80 mean 30.0 20.0 10.0 0.0 2 5 8 11 14 17 20 23 26 29 32 35 38 41 44 47 50 53 56 59 62 65 68 71 74 77 80 83 86 89 Time Period (Mins.)

Group 1* Group 2**

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine.

Figure 4. Percent 80/80 Readings for the Second Premolar by Group and Time Period.

208

First Premolar Pulpal Anesthesia

100.0 90.0 80.0 70.0 60.0 50.0 40.0

mean % 80/80 30.0 20.0 10.0 0.0 2 5 8 11 14 17 20 23 26 29 32 35 38 41 44 47 50 53 56 59 62 65 68 71 74 77 80 83 86 89 Time Period (Mins.)

Group 1* Group 2**

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine.

Figure 5. Percent 80/80 Readings for the First Premolar by Group and Time Period.

209 Post-op Pain by Group and Period

40.0 35.0 30.0 25.0 Group 1* 20.0 Group 2** 15.0

mm VAS Pain 10.0 5.0 0.0 0123 Time Period (Days)

*Group 1 3.6 mL 4% Articaine with 1:100,000 epinephrine. **Group 2 1.8 mL 4% Articaine with 1:100,000 epinephrine.

Figure 6. Post-op pain Ratings for Anesthetic Cessation Day 0, Day 1, Day 2, and Day 3.

210

APPENDIX C

BIOGRAPHICAL DATA

211 BIOGRAPHICAL DATA

SUBJECT SEX AGE SUBJECT SEX AGE 1 female 34 44 female 22 2 female 25 45 male 26 3 male 30 46 female 24 4 male 21 47 female 25 5 male 31 48 female 22 6 male 26 49 male 26 7 female 27 50 female 25 8 male 26 51 male 30 9 female 22 52 female 24 10 female 22 53 female 23 11 male 23 54 male 26 12 male 31 55 female 23 13 female 22 56 male 24 14 female 21 57 male 26 15 male 25 58 male 32 16 male 25 59 female 25 17 female 22 60 female 24 18 male 27 61 female 25 19 male 26 62 male 27 20 male 25 63 male 26 21 male 21 64 male 21 22 female 45 65 male 25 23 male 23 66 male 28 24 female 20 67 male 27 25 male 30 68 female 24 26 female 22 69 male 27 27 male 26 70 male 30 28 female 20 71 female 27 29 male 26 72 female 23 30 female 22 73 female 24 31 female 27 74 male 26 32 female 24 75 female 25 33 male 23 76 male 30 34 male 25 77 male 27 35 male 26 78 male 30 36 female 26 79 female 24 37 male 27 80 female 25 38 female 25 81 female 24 39 female 21 82 female 25 40 male 32 83 male 28 41 female 28 84 female 21 42 male 25 85 female 27 43 female 26 86 female 25

212

APPENDIX D

MEDICAL HISTORY FORM

THE OHIO STATE UNIVERSITY Patient ID# ______

213 COLLEGE OF DENTISTRY Date ______

Medical History

1. Do you have or have you had any of the following?

a. rheumatic fever or rheumatic heart disease……………………. NO YES b. heart murmur or mitral valve prolapse………………………… NO YES c. heart disease or heart attack…………………………………… NO YES d. artificial heart valve…………………………………………… NO YES e. irregular heart beat…………………………………………….. NO YES f. pacemaker……………………………………………………… NO YES g. high blood pressure……………………………………………. NO YES h. chest pains or angina…………………………………………… NO YES i. stroke…………………………………………………………… NO YES j. artificial joint…………………………………………………… NO YES k. hepatitis/liver disease………………………………………….. NO YES l. tuberculosis…………………………………………………….. NO YES m. thyroid problem………………………………………………. NO YES n. kidney disease…………………………………………………. NO YES o. diabetes (sugar)………………………………………………… NO YES p. asthma…………………………………………………………. NO YES q. HIV or other immunosuppressive disease…………………….. NO YES r. radiation or cancer therapy…………………………………….. NO YES

2. Do you or have you had any disease, condition, or problem not listed here? NO YES

3. Have you ever been hospitalized? NO YES

4. Have you had excessive or prolonged bleeding requiring special treatment? NO YES

5. Have you had an allergic reaction to any drugs or medications? (Circle all that apply: penicillin; codeine; aspirin; anesthetics; other) NO YES

6. Are you currently under the care of a physician (M.D., D.O.)? NO YES When were you last seen by a physician?______Name of Physician______Street address______City, State, and Zip Code______Phone______

7. Are you pregnant or nursing? Estimated date of delivery______NO YES

8. Do you have any lumps or sores in your mouth now? NO YES

9. Do you smoke or use smokeless tobacco? NO YES

10. Have you consumed alcohol within the last 48 hrs? NO YES

11. Are you currently taking any drugs or medications

214 (such as antibiotics, heart medicine, birth control pills?) NO YES

Current Medications

Trade Name Generic Name Dose/Frequency Reason

Summary of Patient’s Medical Status:______

Medical Risk Assessment

ASA I (healthy individual) ASA III (severe disease but not incapacitating) ASA II (mild systemic disease) ASA IV (incapacitating systemic disease)

Medical Consultation Required No (healthy and/or stabilized disease)

Yes (ASA III or IV; cardiac murmur; vague hx; recent major disease; recent diagnosis/operation; uncontrolled disease; blood pressure; etc.)

To the best of my knowledge, the above information is correct and complete.

______Patient’s Signature Date

215

APPENDIX E

CONSENT

216 The Ohio State University Consent to Participate in Research

Anesthetic efficacy of an infiltration of a 3.6 mL volume of Study Title: articaine in mandibular posterior teeth.

Principal Investigator: Dr. John Nusstein

Sponsor:

• This is a consent form for research participation. It contains important information about this study and what to expect if you decide to participate. Please consider the information carefully. Feel free to discuss the study with your friends and family and to ask questions before making your decision whether or not to participate. • Your participation is voluntary. You may refuse to participate in this study. If you decide to take part in the study, you may leave the study at any time. No matter what decision you make, there will be no penalty to you and you will not lose any of your usual benefits. Your decision will not affect your future relationship with The Ohio State University. If you are a student or employee at Ohio State, your decision will not affect your grades or employment status. • You may or may not benefit as a result of participating in this study. Also, as explained below, your participation may result in unintended or harmful effects for you that may be minor or may be serious depending on the nature of the research. • You will be provided with any new information that develops during the study that may affect your decision whether or not to continue to participate. If you decide to participate, you will be asked to sign this form and will receive a copy of the form. You are being asked to consider participating in this study for the reasons explained below.

1. Why is this study being done? Articaine is a numbing solution approved by the FDA for routine use in the dental office. Articaine is given as a shot next to the tooth. The purpose of this study is to see if additional volumes of articaine are better at making my teeth numb during a dental procedure.

2. How many people will take part in this study? One-hundred (100) people will take part in this study.

3. What will happen if I take part in this study? I will receive injections (shots) of articaine with epinephrine (a numbing solution like “novocaine”) in the back of my lower jaw. The articaine numbing solution used is not experimental. It is routinely used in the dental office and has been approved by the FDA

217 for dental use. Prior to the first injection, I will be required to complete a medical history questionnaire. A device called an electric pulp tester will be used to test my teeth for numbness. The electric pulp tester is a battery operated device that delivers a very small amount of current to the tooth resulting in a tingling sensation that might be uncomfortable or cause pain in the tooth being tested and which may last up to one second. It will be used on my teeth before the injections of numbing solution. Four of my lower back teeth as well as a tooth on the opposite side (control tooth) will be tested with the electric pulp tester to be sure that my teeth respond (the nerves are alive and teeth have not had root canal treatment). This will take about 6 minutes. I will have two appointments spaced at least one week apart. I will receive one injection (shot) at each appointment. After topical numbing anesthetic (Patterson Dental Topical Anesthetic – 20% Benzocaine), a gel that numbs the gum tissue, has been applied to the injection (shot) site for one minute, I will receive 1.8 mL (a little more than one third of a teaspoon) of 4% articaine with 1:100,000 epinephrine or 3.6 mL (a little less than three quarters of a teaspoon) of 4% articaine with 1:100,000 epinephrine. Whether I receive the larger or smaller volume of articaine solution will be determined at random (by chance, like flipping a coin). I will be blindfolded during these injections. I will not know which injection, using either the larger or smaller volume of articaine numbing solution, I will receive. My doctor will know which injection I receive. My numb tooth and the adjacent teeth (in front and behind this tooth) will then be pulp tested every 3 minutes for a total of 90 minutes to determine how well the injection (shot) gets my teeth numb. In addition, the electric pulp tester will be used on one of my teeth on the opposite side (where I am not numb). Teeth that are not numb or are being used as a control will experience a tingling sensation or discomfort at which time the device will be removed immediately. I will be asked to rate the amount of pain I feel when the injections are being given. I will do this by marking my pain experience on a line graph with a pen. I will be asked to complete a short survey after each appointment to rate any pain or discomfort I have at the injection site over a three-day period following each appointment. I will also report any other side effects not relating to pain or discomfort. This survey will take about one minute to fill out each morning.

4. How long will I be in the study? I am aware that I will have two appointments, each will last approximately 120 minutes - 10 minutes for baseline pulp testing and filling out health information and receiving the initial injection. My teeth will be pulp tested for a total of 90 minutes. The questionnaires will take about 1 minute to fill out on the day of the appointment and for each morning for 3 days following each appointment. After completing the questionnaires, I will either mail them in a pre-addressed stamped envelope or personally deliver it to the endodontic clinic front office. This will take about five minutes.

5. Can I stop being in the study? I may leave the study at any time. If I decide to stop participating in the study, there will be no penalty to me, and I will not lose any benefits to which I am otherwise entitled. My decision will not affect my future relationship with The Ohio State University.

218 If I am a student or staff member at OSU and choose not to participate in this study, my grades and/or employment will not be affected.

6. What risks, side effects or discomforts can I expect from being in the study? I may have pain associated with the local anesthetic (numbing solution) or soreness at the site of the injections (shots) for approximately two days. Where I receive the injection, I may have swelling (hematoma-a collection of blood in my mouth) or a bruise may develop. I may experience a feeling of anxiety, lightheadedness or fainting, and or a temporary increase in my heart rate. The tingling sensation and/or slight discomfort (pain) produced by the pulp tester may be uncomfortable to me. I may have an allergic reaction to the local anesthetic (itching or hives, very rare), or have an unexpected infection (rare) which could result in permanent nerve damage. I may have soreness of my gum tissue for a few days or a possible altered sensation of my lip or tongue that may last up to a few weeks. My tooth may feel sore to bite on for a few days.

If I am a woman able to have children, I will be questioned regarding pregnancy or suspected pregnancy and will not be allowed to participate if pregnant, suspect a pregnancy, trying to become pregnant, or nursing. Additionally, I will be required to take a urine pregnancy test before I can start this study. If I am a woman, I must also be using a reliable method of contraception (oral contraceptives, condoms, diaphragm, or abstinence) during the next 24 hours. The reason for excluding pregnant or potentially pregnant women is an attempt to minimize this population in the study because the potential risks to the fetus and nursing baby are unknown. There are no adequate and well-controlled studies of articaine in pregnant women. This test will be paid for by the investigator.

7. What benefits can I expect from being in the study? I will not directly benefit from this study. Society may benefit if the additional infiltration (shot next to the tooth) of articaine makes my teeth anesthetized (being numb) for a longer time.

8. What other choices do I have if I do not take part in the study? I may choose not to participate without penalty or loss of benefits to which I am otherwise entitled. If I am a student or staff member at OSU and choose not to participate in this study, my grades and/or employment will not be affected. There are no other choices other than to participate or not participate in the study.

9. Will my study-related information be kept confidential? Efforts will be made to keep your study-related information confidential. However, there may be circumstances where this information must be released. For example, personal information regarding your participation in this study may be disclosed if required by

219 state law. Also, your records may be reviewed by the following groups (as applicable to the research):

• Office for Human Research Protections or other federal, state, or international regulatory agencies; • U.S. Food and Drug Administration; • The Ohio State University Institutional Review Board or Office of Responsible Research Practices; • The sponsor supporting the study, their agents or study monitors; and • Your insurance company (if charges are billed to insurance).

If the study involves the use of your protected health information, I may also be asked to sign a separate Health Insurance Portability and Accountability Act (HIPAA) research authorization form.

10. What are the costs of taking part in this study? The study will pay for the cost of the study drug (articaine) and urine pregnancy test.

11. Will I be paid for taking part in this study? Yes, I will be paid $75 for my participation. I will receive $75.00 for completing all aspects of the study. If I am unable or unwilling to complete both sessions of the study, I will be paid a pro-rated $30.00 per session and an additional pro-rated $7.50 per completed and returned questionnaire form. After completing the questionnaires, I will personally deliver them to the endodontic clinic front office, at which time I will receive payment for the completed parts of the study for which I have not yet received payment. Payment is to compensate me for time and travel expenses. By law, payments to subjects are considered taxable income.

12. What happens if I am injured because I took part in this study? If I suffer an injury from participating in this study, I should notify the researcher or study doctor immediately, who will determine if I should obtain medical treatment at The Ohio State University Medical Center.

The cost for this treatment will be billed to me or my medical or hospital insurance. The Ohio State University has no funds set aside for the payment of health care expenses for this study.

13. What are my rights if I take part in this study?

If I choose to participate in the study, I may discontinue participation at any time without penalty or loss of benefits. By signing this form, I do not give up any personal legal rights I may have as a participant in this study.

I will be provided with any new information that develops during the course of the research that may affect my decision whether or not to continue participation in the study.

220 I may refuse to participate in this study without penalty or loss of benefits to which I am otherwise entitled.

An Institutional Review Board responsible for human subjects research at The Ohio State University reviewed this research project and found it to be acceptable, according to applicable state and federal regulations and University policies designed to protect the rights and welfare of participants in research.

14. Who can answer my questions about the study?

For questions, concerns, or complaints about the study you may contact Dr. John Nusstein or Dr. Matthew Martin at 614 – 292-5399.

For questions about your rights as a participant in this study or to discuss other study- related concerns or complaints with someone who is not part of the research team, you may contact Ms. Sandra Meadows in the Office of Responsible Research Practices at 1-800-678-6251.

If you are injured as a result of participating in this study or for questions about a study-related injury, you may contact Dr. John Nusstein or Dr. Matthew Martin at 614 – 292-5399.

221 Signing the consent form

I have read (or someone has read to me) this form and I am aware that I am being asked to participate in a research study. I have had the opportunity to ask questions and have had them answered to my satisfaction. I voluntarily agree to participate in this study.

I am not giving up any legal rights by signing this form. I will be given a copy of this form.

Printed name of subject Signature of subject

AM/PM Date and time

Printed name of person authorized to consent for subject Signature of person authorized to consent for subject (when applicable) (when applicable)

AM/PM Relationship to the subject Date and time

Investigator/Research Staff

I have explained the research to the participant or his/her representative before requesting the signature(s) above. There are no blanks in this document. A copy of this form has been given to the participant or his/her representative.

Printed name of person obtaining consent Signature of person obtaining consent

AM/PM Date and time

Witness(es) - May be left blank if not required by the IRB

Printed name of witness Signature of witness

AM/PM Date and time

Printed name of witness Signature of witness

AM/PM Date and time

222

APPENDIX F

HIPAA FORMS

223 THE OHIO STATE UNIVERSITY

AUTHORIZATION TO USE

PERSONAL HEALTH INFORMATION IN RESEARCH

Title of the Study: Anesthetic efficacy of an infiltration of a 3.6 mL volume of articaine in mandibular posterior teeth.

OSU Protocol Number:

Principal Investigator: Dr. John Nusstein

Subject Name______

Before researchers use or share any health information about you as part of this study, The Ohio State University is required to obtain your authorization. This helps explain to you how this information will be used or shared with others involved in the study.

• The Ohio State University and its hospitals, clinics, health-care providers and researchers are required to protect the privacy of your health information. • You should have received a Notice of Privacy Practices when you received health care services here. If not, let us know and a copy will be given to you. Please carefully review this information. Ask if you have any questions or do not understand any parts of this notice. • If you agree to take part in this study your health information will be used and shared with others involved in this study. Also, any new health information about you that comes from tests or other parts of this study will be shared with those involved in this study. • Health information about you that will be used or shared with others involved in this study may include your research record and any health care records at the Ohio State University. For example, this may include your medical records, x-ray or laboratory results. Psychotherapy notes in your health records (if any) will not, however, be shared or used. Use of these notes requires a separate, signed authorization.

Please read the information carefully before signing this form. Please ask if you have any questions about this authorization, the University’s Notice of Privacy Practices or the study before signing this form.

Initials/Date: ______

Page 1 of 3

224 Those Who May Use, Share And Receive Your Information As Part Of This Study

• Researchers and staff at The Ohio State University will use, share and receive your personal health information for this research study. Other Ohio State University staff not involved in the study but who may become involved in your care for study-related treatment will have access to your information. • Those who oversee the study will have access to your information, including: • Members and staff of the Ohio State University’s Institutional Review Boards, including the Western Institutional Review Board • The Office for Responsible Research Practices • University data safety monitoring committees • The Ohio State University Research Foundation • Your health information may also be shared with federal and state agencies that have oversight of the study or to whom access is required under the law. These may include: • The Food and Drug Administration • The Office for Human Research Protections • The National Institutes of Health • The Ohio Department of Human Services

These researchers, companies and/or organization(s) outside of The Ohio State University may also use, share and receive your health information in connection with this study:

• NONE

The information that is shared with those listed above may no longer be protected by federal privacy rules.

Initials/Date______

Page 2 of 3

225 Authorization Period

This authorization will not expire unless you change your mind and revoke it in writing. There is no set date at which your information will be destroyed or no longer used. This is because the information used and created during the study may be analyzed for many years, and it is not possible to know when this will be complete. Signing the Authorization

• You have the right to refuse to sign this authorization. Your health care outside of the study, payment for your health care, and your health care benefits will not be affected if you choose not to sign this form. • You will not be able to take part in this study and will not receive any study treatments if you do not sign this form. • If you sign this authorization, you may change your mind at any time. Researchers may continue to use information collected up until the time that you formally changed your mind. If you change your mind, your authorization must be revoked in writing. To revoke your authorization, please write to: Dr. John Nusstein at the College of Dentistry, 305 w 12th avenue, the Ohio State University, Columbus, Ohio 43218 or Dr. Stanley Vermilyea at the College of Dentistry, 305 w 12th avenue, the Ohio State University, Columbus, Ohio 43218. • Signing this authorization also means that you will not be able to see or copy your study- related information until the study is completed. This includes any portion of your medical records that describes study treatment.

Contacts for Questions

• If you have any questions relating to your privacy rights, please contact Dr. Stanley Vermilyea at the College of Dentistry, 305 w 12th avenue, the Ohio State University, Columbus, Ohio 43218. • If you have any questions relating to the research, please contact Dr. John Nusstein at the College of Dentistry, 305 w 12th avenue, the Ohio State University, Columbus, Ohio 43218. Signature

I have read (or someone has read to me) this form and have been able to ask questions. All of my questions about this form have been answered to my satisfaction. By signing below, I permit Dr. John Nusstein and the others listed on this form to use and share my personal health information for this study. I will be given a copy of this signed form.

Signature______(Subject or Legally Authorized Representative)

Name ______(Print name above) (If legal representative, also print relationship to subject.)

Date______Time ______AM / PM Page 3 of 3

226

APPENDIX G

RANDOM CODE LIST

227

Patient Gender Side Injection Random # 1 f r 1.8 mL 60063 3.6 mL 454654 2 f l 3.6 mL 77764 1.8 mL 487964 3 m r 3.6 mL 101194 1.8 mL 789431 4 m l 3.6 mL 107058 1.8 mL 465328 5 m r 1.8 mL 150248 3.6 mL 456782 6 m r 1.8 mL 7239 3.6 mL 789642 7 f r 1.8 mL 80623 3.6 mL 785452 8 m l 1.8 mL 14516 3.6 mL 387845 9 f l 3.6 mL 31341 1.8 mL 486734 10 f r 1.8 mL 154637 3.6 mL 238786 11 m r 1.8 mL 20417 3.6 mL 687845 12 m l 1.8 mL 73871 3.6 mL 287975 13 f l 3.6 mL 98819 1.8 mL 678974 14 f r 1.8 mL 125089 3.6 mL 587469 15 m l 3.6 mL 159569 1.8 mL 854789 16 m l 1.8 mL 185612 3.6 mL 788785 17 f r 3.6 mL 201508 1.8 mL 578868 18 m l 3.6 mL 246969 1.8 mL 578689 19 m r 3.6 mL 264673 1.8 mL 986834 20 m l 1.8 mL 288185 3.6 mL 176588 21 m r 3.6 mL 337584 1.8 mL 356534 22 f r 1.8 mL 375871

228 3.6 mL 456832 23 m l 1.8 mL 453684 3.6 mL 248424 24 f l 1.8 mL 506969 3.6 mL 245725 25 m l 1.8 mL 538172 3.6 mL 782722 26 f l 1.8 mL 595101 3.6 mL 786864 27 m r 3.6 mL 636894 1.8 mL 478755 28 f l 3.6 mL 668249 1.8 mL 689786 29 m r 3.6 mL 712877 1.8 mL 786687 30 f r 1.8 mL 729325 3.6 mL 587867 31 f l 3.6 mL 770113 1.8 mL 687678 32 f l 1.8 mL 821899 3.6 mL 658767 33 m r 3.6 mL 845195 1.8 mL 578678 34 m r 1.8 mL 891042 3.6 mL 669686 35 m r 1.8 mL 953723 3.6 mL 697856 36 f l 3.6 mL 988234 1.8 mL 586786 37 m l 3.6 mL 174672 1.8 mL 696876 38 f r 1.8 mL 178399 3.6 mL 896896 39 f r 3.6 mL 186672 1.8 mL 378693 40 m l 1.8 mL 195925 3.6 mL 763893 41 f r 3.6 mL 210091 1.8 mL 869878 42 m l 3.6 mL 226344 1.8 mL 678968 43 f l 1.8 mL 253588 3.6 mL 789689 44 f r 1.8 mL 263929 3.6 mL 468966

229 45 m r 3.6 mL 268777 1.8 mL 387937 46 f l 1.8 mL 277656 3.6 mL 378989 47 f l 3.6 mL 308655 1.8 mL 398983 48 f r 3.6 mL 316848 1.8 mL 789898 49 m l 3.6 mL 337739 1.8 mL 978288 50 f r 1.8 mL 375589 3.6 mL 698769 51 m l 1.8 mL 381042 3.6 mL 786987 52 f r 1.8 mL 421824 3.6 mL 896893 53 f r 3.6 mL 466411 1.8 mL 876869 54 m l 3.6 mL 503202 1.8 mL 898658 55 f l 1.8 mL 512857 3.6 mL 789789 56 m r 3.6 mL 531615 1.8 mL 453878 57 m r 3.6 mL 569833 1.8 mL 896777 58 m r 3.6 mL 576995 1.8 mL 456786 59 f r 3.6 mL 610644 1.8 mL 867896 60 f l 1.8 mL 630463 3.6 mL 869897 61 f l 1.8 mL 659438 3.6 mL 485678 62 m l 3.6 mL 666806 1.8 mL 867864 63 m r 3.6 mL 672411 1.8 mL 786574 64 m l 1.8 mL 685255 3.6 mL 467867 65 m r 1.8 mL 715992 3.6 mL 786738 66 m r 3.6 mL 716544 1.8 mL 454678 67 m l 3.6 mL 742269

230 1.8 mL 784545 68 f l 1.8 mL 757987 3.6 mL 896854 69 m r 1.8 mL 811698 3.6 mL 565656 70 m l 3.6 mL 816049 1.8 mL 638968 71 f r 3.6 mL 825435 1.8 mL 389879 72 f l 3.6 mL 837109 1.8 mL 689687 73 f r 3.6 mL 848219 1.8 mL 738989 74 m r 1.8 mL 867098 3.6 mL 653454 75 f l 1.8 mL 910279 3.6 mL 789896 76 m l 3.6 mL 923311 1.8 mL 389789 77 m r 3.6 mL 957491 1.8 mL 789686 78 m l 3.6 mL 976219 1.8 mL 768689 79 f l 1.8 mL 988581 3.6 mL 986478 80 f r 1.8 mL 990672 3.6 mL 689689 81 f r 1.8 mL 123456 3.6 mL 999991 82 f l 3.6 mL 132456 1.8 mL 999910 83 m l 3.6 mL 123999 1.8 mL 979917 84 f r 1.8 mL 162210 3.6 mL 888888 85 f l 3.6 mL 555555 1.8 mL 222777 86 f r 3.6 mL 333870 1.8 mL 454917

231

APPENDIX H

VAS FORM AND RAW VAS PAIN SCORE DATA

232

233 None Faint Weak Mild Moderate Strong Intense Maximum Possible

0-54 mm …….. mild pain

55-111 mm……moderate pain

112-170 mm…..severe pain

APPENDIX I

EPT DATA COLLECTION FORMS AND RAW EPT DATA

234 EPT Values Date______Patient #______Sex ______Patient Age ______Side______

2nd 1st 2nd 1st Contra- lateral premolar premolar molar molar canine Min. Pre- test Min. Pre- test Base-line

* indicates tooth will be tested with a mock electrode 2nd 1st 2nd 1st Contra- lateral premolar premolar molar molar canine 1

2

3

4

5

6

7

8

9 *

10

11

12

13

235 2nd 1st 2nd 1st Contra- lateral premolar premolar molar molar canine 14

15

16

17

18 *

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

236 2nd 1st 2nd 1st Contra- lateral premolar premolar molar molar canine 35

36 *

37

38

39

40

41

42

43

44

45 *

46

47

48

49

50

51

52

53

54 *

55

237 2nd 1st 2nd 1st Contra- lateral premolar premolar molar molar canine 56

57

58

59

60

61

62

63 *

64

65

66

67

68

69

70

71

72 *

73

74

75

238 2nd 1st 2nd 1st Contra- lateral premolar premolar molar molar canine 76

77

78

79

80

81 *

82

83

84

85

86

87

88

89

90 *

239

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