Anesthetic Efficacy of 4% Articaine with 1:100000 Epinephrine

Home , Articaine, Prilocaine

Anesthetic efficacy of 4% articaine with 1:100,000 epinephrine, 4% prilocaine with 1:200,000 epinephrine, and 4% lidocaine with 1:100,000 epinephrine as a primary buccal infiltration of the mandibular first molar.

Thesis

Presented in Partial Fulfillment of the Requirements for

The Degree of Master of Science in the

Graduate School of The Ohio State University

Brett John Nydegger, D.D.S.

Graduate Program in Dentistry

The Ohio State University 2013

Master’s Examination Committee

Dr. John M. Nusstein, Advisor

Dr. Al Reader

Dr. Melissa Drum

Dr. F. Michael Beck

Brett John Nydegger

2013

Abstract

Previous studies have shown articaine to be superior to lidocaine when given as a primary buccal infiltration injection of the mandibular first molar. However, these studies compared 4% articaine to 2% lidocaine. No study has compared 4% lidocaine and 4% prilocaine to 4% articaine. Therefore, the purpose of this prospective, randomized, double-blind study was to compare three different 4% anesthetic solutions given as primary buccal infiltration injections adjacent to the mandibular first molar.

Using a cross-over design, 60 adults received mandibular buccal infiltrations using 1.8 mL of 4% articaine with 1:100,000 epinephrine, 4% lidocaine with 1:100,000 epinephrine, and 4% prilocaine with 1:200,000 epinephrine at three separate appointments. An electric pulp tester was used to test the molars and premolars for pulpal anesthesia every 3 minutes for 60 minutes. Successful pulpal anesthesia was defined as two consecutive 80/80 readings. Pain ratings for each injection and postoperative pain were recorded. Data were statistically analyzed.

For the first molar, the success rate for articaine was 55%, 33.3% for lidocaine, and 31.7% for prilocaine. There was a significant difference between articaine and both lidocaine (p=0.0259) and prilocaine (p=0.0094). There was no significant difference between lidocaine and prilocaine (p=1.0000). No differences were found for injection

and post-injection pain.

The anesthetic efficacy of articaine was better than lidocaine and prilocaine. This demonstrates that a 4% concentration of local anesthetic was not the important factor in pulpal anesthesia. It is likely the chemical structure of articaine that makes it a better anesthetic for mandibular buccal infiltrations.

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Dedication

To my beautiful wife, Megan, thank you so much for your continual love and support.

Without you I would not be where I am today. I am grateful for everything that you do

for me and our family. You are the greatest thing that ever happened to me.

To my boys, Miles and Douglas, thank you both for bringing me so much joy in my life.

I truly loved coming home from school and playing with you. Spending time with you

two took away the stresses of this thesis.

I love you all!

To my parents, Bob and Marge Nydegger, thank you for your continual support and

sacrifice to help me get where I am today.

None of this would be possible without your love and support.

Thank you!

Acknowledgements

I would like to especially thank my advisor, Dr. John Nusstein. I could not have asked for a better mentor. I truly thank you for all of the help you offered me in writing this thesis. I could not have done this without your guidance. I will remember fondly all of the seminars we had talking about all things endo and more.

I thank Dr. Al Reader for the knowledge and experience that you shared throughout residency, both in seminars and in the clinic. Your love for endodontics is contagious and it affects all of those who attend this great program. I feel so fortunate that I was accepted to this program and that I was able to study under such great faculty. Thank you for preparing me for boards and how to be an endodontist.

I thank Dr. Melissa Drum for your love of teaching. You were a great teacher in dental school and even better in residency. Thank you for making seminar fun, yet so educational. I feel truly lucky to have the experience of working with an educator as passionate about teaching as you.

I thank Dr. Michael Beck for helping me understand statistics, at least well enough to make it through my defense. I learned more about research statistics in a few meetings with you than any class I’ve had.

Thank my co-residents Shayne Perry, Vivian Click, and Emily Lammers. You all have made this process so fun and I will truly miss the daily interaction we had. I will especially miss taco Tuesday, Wednesday, Thursday, and Friday. I wish you all luck in your careers and know that you will all be successful.

I thank all of the dental students who participated in my study and helped me with countless hours of pulp testing including Chase Crowley, Jake Judy, Brandon Glenn, Tommy Burke, and Kristie Bultema.

VITA

February 7, 1982……………………………………Born – Salt Lake City, Utah

2007……………………………………………...... B.A. Russian, University of Utah

2011………………………………………………...Doctor of Dental Surgery, The Ohio State University Columbus, Ohio

2013…………………………………………………Master of Science & Specialization in Endodontics Post-Doctoral Certificate, The Ohio State University, Columbus, Ohio

FIELDS OF STUDY

Major Fields: Dentistry

Specialization: Endodontics

TABLES OF CONTENTS

Page

Abstract…………………………………………………………………………………..ii

Dedication………………………………………………………………………………..iv

Acknowledgements……………………………………………………………………....v

Vita………………………………………………………………………………………vi

Table of Contents………………………………………………………………………..vii

List of Table……………………………………………………………………………..ix

List of Figures……………………………………………………………………………xi

Chapters:

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

2. Literature Review…………………………………………………………………3

3 Materials and Methods…………………………………………………………..49

4. Results……………………………………………………………………………58

5. Discussion………………………………………………………………………..67

6. Summary and Conclusions……………………………………………………..120

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Appendices A. Tables…………………………………………………………………..124 B. Figures………………………………………………………………….142 C. Biographical Data………………………………………………………150 D. Medical History Form…………………………………………………..152 E. Consent…………………………………………………………………155 F. HIPAA Forms………………………………………………….……….162 G. Injection VAS Form and Raw VAS Pain Score Data…………………..167 H. EPT Data Collection Forms and Raw EPT Data……………………….175

References………………………………………………………………………………276

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LIST OF TABLES

Table Page

1. Biographical Data for All Subjects……………………………………………..125

2. Mean VAS Values (mm) of Injection Pain Ratings for Buccal Infiltration…....126

3. Mean VAS Values (mm) of Injection Pain Ratings for Buccal Infiltration of Three Different Anesthetic Solutions by Gender…………………….………...127

4. Summary of Pain Ratings for Needle Insertion Utilizing a Descriptive Scale………………………………………………………………………….....128

5. Summary of Pain Ratings for Needle Placement Utilizing a Descriptive Scale…………………………………………………………………………....129

6. Summary of Pain Ratings for Solution Deposition Utilizing a Descriptive Scale…………………………………………………………………………….130

7. Anesthetic Success……………………………………………………………...131

8. Second Molar 80/80 Pulp Tester Readings for all Three Anesthetic Groups…..132

9. First Molar 80/80 Pulp Tester Readings for all Three Anesthetic Groups……..133

10. Second Premolar 80/80 Pulp Tester Readings for all Three Anesthetic Groups………………………………………………………………………..…134

11. First Premolar 80/80 Pulp Tester Readings for all Three Anesthetic Groups.…135

12 Mean Anesthesia Onset Time for each Anesthetic Group by Tooth……….…..136

13. Mean VAS Values (mm) of Postoperative Pain Ratings…………………….…137

14. Summary of Pain Ratings for Postoperative Pain by Day and Anesthetic Utilizing a Numerical Scale…………………………………………………….138

15. Summary of Mean Postoperative Pain by Postoperative Day and Gender……..139

16 Frequency of Subject-reported Postoperative Complications by Day………….140

17. pH of Anesthetic Solutions……………………………………………………..141

LIST OF FIGURES

Figures Page

1. Summary of Injection Pain by Solution, Type, and Gender……………………143

2. Overall Anesthetic Success…………………………………………………..…144

3. Percent of Pulpal Anesthesia for the First Molar……………………………….145

4. Percent Pulpal Anesthesia for the Second Molar……………………………….146

5. Percent Pulpal Anesthesia for the First Premolar………………………………147

6. Percent Pulpal Anesthesia for the Second Premolar…………………………....148

7. Summary of Post-operative Pain by Day……………………………………….150

Chapter 1

Introduction

A number of studies have shown the superiority of 4% articaine with 1:100,000

epinephrine to 2% lidocaine with 1:100,000 epinephrine when used as a primary buccal

infiltration of the mandibular first molar (1-5) and as a supplemental buccal infiltration of the first molar following an inferior alveolar nerve block (6, 7).

The exact mechanism of the articaine’s increased efficacy is not known; however, we can speculate on a few mechanisms. Borchard and Drouin (8) found that a lower concentration of articaine was sufficient to block an action potential when compared with other amide anesthetics. Potocnik and colleagues (9), in a study of sensory nerve conduction in rats, found that both 2% and 4% articaine were superior to 2% lidocaine in blocking nerve conduction. However, with increased intensity of nerve stimulation, the compound action potential recovered for 2% articaine but not for 4% articaine. In a clinical study (10) comparing 2% and 4% articaine’s efficacy in infiltration anesthesia, investigators found that the 4% articaine solution had a longer duration but not an increase in efficacy. It may be that factors other than the concentration may be responsible for articaine’s clinical efficacy. For instance, the unique chemical structure

of articaine (the thiophene ring), which is not possessed by other local anesthetic agents, may facilitate better diffusion of the anesthetic solution to the teeth. A study using other

4% anesthetic solutions may help in determining the role of concentration in the increased efficacy of 4% articaine.

No study has compared 4% articaine with 1:100,000 epinephrine, 4% prilocaine with 1:200,000 epinephrine, and 4% lidocaine with 1:100,000 epinephrine in a mandibular buccal infiltration of the first molar. Therefore, the purpose of this prospective, randomized, double-blind, crossover study was to compare the degree of pulpal anesthesia obtained with 4% articaine with 1:100,000 epinephrine, 4% prilocaine with 1:200,000 epinephrine, and 4% lidocaine with 1:100,000 epinephrine as a primary infiltration in the mandibular first molar. We will also record the pain of injection and postoperative pain

Chapter 2

Literature Review

Mechanism of Action of Local Anesthetics

Local anesthetics are pharmacological agents that block nerve impulse propagation by occluding transmembrane sodium channels (11). “The active site for local anesthetics resides within the Na+ channel” (12). This prevents depolarization, or the firing of an action potential of the nerve fibers and nerve endings. The concentration of electrolytes in nerve cytoplasm and extracellular fluid and the permeability of the cell membrane to various ions, mainly sodium, potassium, and chloride, determines the electrophysiology of the nerve membrane. There is an ionic imbalance between the intracellular cytoplasm and extracellular fluid of a nerve. The intracellular concentration of potassium is approximately 110-170 mEq/L, while the extracellular concentration is 3-

5 mEq/L, which is a ratio of approximately 27:1. The intracellular concentration of sodium is 5-10 mEq/L, and the extracellular concentration is 140 mEq/L, which is a ratio of approximately 1:14. The intracellular concentration of chloride is 5-10 mEq/L, while the extracellular concentration is 110 mEq/L, which is a ratio of 1:11. This concentration imbalance is caused by the selective permeability of the cell membrane. At its resting

state, a nerve membrane is only slightly permeable to sodium ions (Na+), freely permeable to potassium ions (K+), and freely permeable to chloride ions (Cl-). Even

though the membrane is freely permeable to potassium and chloride, and there is a strong

concentration gradient encouraging diffusion of potassium out of the cell, the potassium

ions remain within the cytoplasm of the nerve cell due to the electrostatic attraction of the

nerve membrane. The negative charge of the membrane, which is on the intracellular

surface, restrains the positively charged potassium ions from diffusing through the

membrane. Despite the membrane being freely permeable to chloride ions, they remain

in the extracellular fluid. Since the resting membrane potential is negative within the

cell, electrostatic influence forces the negatively charged chloride ions out of the cell.

Despite the resting membrane potential being negative, there is no influx of positively

charged sodium ions because the membrane is relatively impermeable to sodium ions.

Excitation of the nerve membrane leads to an increased permeability of the cell

membrane to sodium ions. This leads to an influx of sodium ions which causes

depolarization of the cell membrane from its resting potential of -90 mV to the threshold

or firing level of approximately -50 to -60 mV. When the firing threshold is met, membrane permeability to sodium increases and results in a widening of the transmembrane channels. This allows a rapid influx of sodium to occur. At the end of the depolarization phase, or the end of the action potential, the nerve membrane is transformed from a potassium electrode to a sodium electrode. The electrical potential of the cell membrane becomes +40 mV. The entire process of membrane depolarization takes approximately 0.3 msec (11, 12).

Repolarization marks the end of the depolarization phase, which terminates the

action potential. This is caused by the cell membrane decreasing its permeability to

sodium and increasing its permeability to potassium ions. The return of the pre-firing chemical balance of sodium and potassium ions does not require much energy, as both ions move along their concentration gradients. The membrane potential returns to its original level of -90 mV. The process of repolarization takes about 0.7 msec. There is a small excess of sodium ions that exist within the nerve, and a small excess of potassium ions that occur extracellularly. The nerve cell expends energy in order to move excess sodium ions out. Adenosine triphosphate (ATP) is required to facilitate active transport of sodium ions from inside to outside of the nerve cell; this is done via sodium pumps.

Sodium pumps are thought to be responsible for transporting potassium ions to the inside of the cell, against its concentration gradient. The potassium ions gradually return to the inside of the cell until the electrostatic attraction of the intracellular gradient is balanced by the chemical concentration gradient across the nerve membrane (13-16).

Measurements of sodium and potassium conductance by voltage clamp techniques have shown that local anesthetics block neural sodium currents (15). It has been established that local anesthetic agents act on the sodium channel of the nerve membrane, effectively decreasing the rate of the depolarization phase of an action potential (16).

There are two main theories that attempt to explain the mechanism of action of local anesthetics: the membrane expansion theory and the specific receptor theory (11-13,

17, 18).

The membrane expansion theory proposes that anesthetics increase the fluidity of membrane lipids by the diffusion of the anesthetic molecules to the hydrophobic regions of excitable membranes. This, in turn, expands the nerve membrane in some areas and prevents an increase in permeability to sodium ions by decreasing the diameter of the sodium channel. Anesthetics that do not exist in an ionized form, such as benzocaine, work in this manner (14, 19, 20).

The specific receptor theory states that local anesthetics bind directly to the sodium channel at specific receptor sites (14). Tertiary amine local anesthetics such as articaine, lidocaine, prilocaine, mepivacaine, and bupivacaine are local anesthetics which work in this way. The receptors can be on the external or internal surface of the sodium channel. The drug properties do not change, rather they act directly on the same receptors on the sodium channel. Nerve conduction is stopped once the local anesthetic binds to the receptor on the sodium channel and Na+ influx is retarded. A developing local anesthetic block is characterized by a progressive reduction in the rate and degree of depolarization and a slowing of conduction. When the depolarization is retarded sufficiently such that repolarization processes develop before the threshold potential can be reached, nerve conduction fails (12, 14, 17, 21, 22).

In summary, the mechanism of action of local anesthetics can be broken down into 6 main events. First, the local anesthetic molecules bind to the specific receptor sites on or within the sodium channel of a nerve. Second, there is a reduction in membrane permeability to sodium, which leads to (third) a decrease in the rate of depolarization across the nerve membrane. Fourth, lack of permeability to sodium leads to a failure of

the nerve to achieve threshold potential which consequently leads to (fifth) a lack of

propagated action potential. Sixth, a conduction blockade occurs which is the result of

the local anesthetic causing a complete inhibition of sodium conductance, effectively

blocking the firing of the action potential (12, 13).

Lidocaine hydrochloride

Lidocaine hydrochloride is classified as an amide local anesthetic. Its chemical

formula is 2-Diethylamino-2’,6-acetoxylidide hydrochloride. It was first prepared by

Nils Lofgren in 1943, and in 1948 it was the first amide local anesthetic to be marketed

(17, 23). It is metabolized in the liver by microsomal, fixed-function oxidases, to N-

ethylglyceine and 2,6-xylidide. 2,6-xylidide is further metabolized to 4-hydroxy-2,6- xylidide (17, 24, 25). Lidocaine and its metabolites are largely excreted by the kidneys.

Less than 10% of lidocaine is excreted unchanged, while 80% of lidocaine is excreted as its various metabolites. Lidocaine has a pKa of 7.8 and as a plain solution it has a pH of

6.5. Lidocaine powder is not readily soluble in water, so it is dissolved in an acid. This converts lidocaine into a salt (lidocaine hydrochloride) which makes it more compatible when injected into tissues. When it is combined with a vasoconstrictor its pH is approximately 3.5 because “epinephrine becomes unstable as pH increases: at pH 4.5, epinephrine concentrations dip below minimal USP levels in less than 12 months, above pH 6, epinephrine begins to deteriorate within several hours” (26). Lidocaine has an anesthetic half-life of 1.6 hours or approximately 90 minutes (12, 17, 27).

Lidocaine is available in variable concentrations including: 0.5%, 1%, 1.5%, 2%,

4%, and 5%. However, only 2% solutions are packaged in a dental cartridge. Two

percent lidocaine can be packaged either plain, or with epinephrine of 1:50,000,

1:100,000, or 1:200,000 concentration. Epinephrine is added to serve as a

vasoconstrictor. This decreases the absorption rate of lidocaine from the injection site,

therefore increasing the local anesthetic efficacy of lidocaine. A standard 1.8 mL

cartridge of 2% lidocaine with 1:100,000 epinephrine contains 20 mg/mL lidocaine,

0.018 mg/mL epinephrine bitartate (vasoconstrictor), 6.5 mg/mL sodium chloride (to

create an isotonic solution), 1.2 mg/mL potassium metabisulfate (antioxidant), 0.25

mg/mL edetate disodium, sodium hydroxide (to adjust pH), and 1.0 mL pyrogen-free distilled water (to create the correct volume) (17, 27).

Lidocaine is classified as a pregnancy category B drug. Drugs classified as pregnancy category B have the following definition: “Either (1) adequate and well- controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy and there is no evidence of risk in later trimesters, but animal reproduction studies have shown an adverse effect on the fetus; or (2) human studies are lacking, but animal studies have failed to demonstrate a risk to the fetus” (12).

The FDA has approved lidocaine for dental use and has set its maximum dose, with or without a vasoconstrictor, to 3.2 mg/lb. or 7.0 mg/kg of body weight for both adults and pediatric patients (28, 29). Generally, lidocaine has only minor effects on the autonomic nervous system. Large doses of lidocaine, above the maximum recommended dosage, can cause respiratory depression and convulsions (12). It has limited

allergenicity, with fewer than 20 confirmed cases of serious allergic anaphylactic

reactions (25). “Commonly encountered clinical features of an overdose may be

categorized as follows. A low to moderate overdose results in clinical signs of dizziness,

disorientation, excitement, speech changes, nystagmus, elevated blood pressure, increases

in pulse and respiratory rates, flushing, and loss of consciousness. A moderate-to-severe

overdose results in generalized tonic-clonic seizures, followed by central nervous system depression along with a depressed cardiovascular status, including blood pressure, heart and respiratory rates, disorientation, drowsiness, and loss of consciousness” (17, 30). In a case report, 150 mg of bupivacaine was given as an axillary plexus blockade and 10 mL

1% lidocaine given in the operative field for cardiovascular surgery. Ninety minutes following the surgery there was a 6.4% methemoglobin level, which was not attributed specifically to either drug. The case report concluded that care should be taken when bupivacaine and lidocaine are administered to patients who are at risk for methemoglobinemia. “A methemoglobin level of 6.4% is low with respect to the total oxygen transport capacity and should usually not affect a patient’s clinical condition”

(31, 32). Seizures and muscle tremors may occur when doses of lidocaine greater than

300 mg are administered (33).

Prilocaine Hydrochloride

Prilocaine hydrochloride is classified as an amide local anesthetic. Its chemical formula is 2-Propylamino-o-propionotoluidide hydrochloride. It was first prepared by

Lofgren and Tegner in 1953 (34). According to Malamed and Yagiela, Prilocaine is less

toxic than lidocaine (17). Yagiela showed that “because the systemic toxicity of

Prilocaine is approximately half that of lidocaine, toxic effects on a milliliter basis are

essentially equal.” This is due to the fact that prilocaine is a 4% solution, which is twice

the concentration of lidocaine (12). Prilocaine is a secondary amine and is hydrolyzed by

hepatic amidases into orthotoluidine and N-propylalanine. Prilocaine and its metabolites are excreted primarily from the kidneys (17). Prilocaine has a pKa of 7.8. If prepared in a plain solution, it has a pH of 6.0 to 6.5. When a vasoconstrictor is added, the pH of prilocaine is 4.0, because epinephrine becomes more unstable the higher the pH gets. (26)

Its anesthetic half-life is 1.6 hours which is approximately 90 minutes. Prilocaine is classified as pregnancy category B (17).

Prilocaine is available in 4% solutions with 1:200,000 epinephrine, or plain.

Epinephrine serves as a vasoconstrictor, which decreases the absorption rate of prilocaine from the site of injection, therefore increasing the local efficacy of prilocaine. A standard

1.8 mL cartridge of 4% prilocaine with 1:200,000 epinephrine contains 40 mg/mL prilocaine, 0.005 mg/mL epinephrine bitartate (vasoconstrictor), 0.5 mg/mL sodium metabisulfate (epinephrine preservative), 0.2 mg/mL citric acid (preservative), sodium hydroxide and/or hypochloric acid (to adjust pH), 1.0 mL pyrogen free water (to set volume) (35).

If large doses of prilocaine are given, methemoglobinemia can occur (36).

“Prilocaine injections greater than 4 milligrams per pound (8 mg per kilogram) should not be administered” (35). This is due to the ability of orthotoluidine (breakdown product of prilocaine) to oxidize hemoglobin which induces the formation of

methemoglobin. Oxidized hemoglobin cannot bind or carry oxygen because it contains

the ferric iron rather than the ferrous iron (36). Prilocaine can reduce the blood’s oxygen

carrying capacity enough to produce signs of cyanosis (17, 36, 37). Symptoms of CNS

toxicity after overdoses of prilocaine are usually briefer and less severe than with the

same dose of lidocaine. This is in part due to plasma levels of prilocaine decreasing

faster than lidocaine (38). Due to this property, prilocaine is considered to be less toxic

systemically than lidocaine (39).

Articaine hydrochloride

Articaine hydrochloride is an amide anesthetic, but also possesses ester

characteristics. Its chemical formula is 4-methyl-3-[2-(propylamino)-proprionamido]-2- thiophene-carboxylic acid, methyl ester hydrochloride. It was first prepared by Rusching and colleagues in 1969. It is the only amide anesthetic that is derived from thiophene and contains an additional ester ring (8, 40). Hydrolysis is by plasma cholinesterase which causes a biotransformation to occur in the plasma. It is further degraded by hepatic microsomal enzymes in the liver by hydrolysis of the carboxylic acid ester groups to yield free carboxylic acid and articainic acid, which are the primary metabolites and are pharmacologically inactive (17, 41). A higher percentage of articaine is metabolized in the blood (90-95%) than in the liver (5-10%). Articaine is eliminated by the kidneys with approximately 5% to 10% unchanged and approximately 90% metabolites found in the urine (17, 41-43). Articaine has a pKa of 7.8. The pH of articaine with a vasoconstrictor

is 3.5 to 4.0, without a vasoconstrictor is 7.35. Its half-life is approximately 0.5 hours or

27 minutes (17, 42, 44).

Skjevik et al. (45) did a molecular dynamic study investigating the intramolecular hydrogen bond found in articaine. The study showed that articaine was better at traversing bone and tissue compared to other local anesthetics. This traditionally has been ascribed to the thiophene ring that is contained in articaine and not in other local anesthetics. However, thiophene itself is less hydrophobic than benzene found in traditional amides. An internal hydrogen bond forms at the same time as articaine enters the lipid membrane. This hydrogen bond is formed between the amine nitrogen and ester carbonyl oxygen groups within the molecule. Trajectory analyses show the intramolecular distances “pre” and “post” hydrogen bond formation. “Pre” hydrogen bond formation, the intramolecular distance is 5.06 Å, while the “post” hydrogen bond formation intramolecular distance is 3.11 Å. Essentially, after the hydrogen bond forms within articaine, the molecule folds over on itself (45). Kuhn et al. (46) showed that the contribution of intramolecular hydrogen bonds leads to an increased lipophilicity. The authors found that solutions that did not have the ability to form intramolecular hydrogen bonds were less lipophilic which could result in a decreased ability to penetrate bone.

Articaine is available in 1.7 mL cartridges of 4% solutions with either 1:100,000

or 1:200,000 epinephrine. Each cartridge of articaine contains 40 mg/mL articaine, 0.018

mg/mL epinephrine tartate (vasoconstrictor), 1.60 mg/mL sodium chloride, 0.50 mg/mL

sodium metabisulfate (epinephrine preservative), sodium hydroxide (to adjust pH), 1.0

mL pyrogen free water (to set volume) (44).

Articaine is classified as pregnancy category C. Drugs classified as pregnancy

category C are as follows: “No adequate and well-controlled studies have been performed

in pregnant women, but animal reproduction studies are lacking or have shown an

adverse effect on the fetus. Potential benefit may warrant use of the drug in pregnant

women despite potential risk” (12). Animal reproductive studies have been done in rats

and rabbits where doses up to more than 10 times the maximum recommended human

dose of 7 mg/kg of articaine HCl were given. Even at doses toxic to the parental animals,

there was no evidence of harm to the fetus or any aspect of reproduction (47). Leuschner

et al. (48) studied the toxicity of articaine in vitro and in vivo and showed that there was no mutagenic potential up to cytotoxic concentrations or up to the maximum tolerated dose (47). The mean maximum plasma drug concentration is 400 μg/L for articaine with

1:200,000 epinephrine, and 580 μg/L for articaine without epinephrine (49).

Moller and Covino studied the cardiac electrophysiologic effects of articaine compared with bupivacaine and lidocaine and found, “articaine appears to be equipotent to lidocaine in terms of degree of cardiac depression. At very high concentrations, articaine caused cardiac depression similar to that seen with 17.4 µM bupivacaine, but the effect was shorter lasting as compared with bupivacaine. These data suggest that the cardiac toxicity of articaine in intact animals should be similar to that seen with lidocaine rather than with bupivacaine” (50). Van Oss et al. (51) showed in a pilot study that intravenous administration of 107.7 mg of articainic acid had no effect on EEG

(electroencephalography), ECG (electrocardiography), blood pressure and heart rate.

Although methemoglobinemia has been shown to develop with lidocaine and

prilocaine (36, 37), Rupieper et al. (52) showed that when articaine, given as a central

nerve block anesthetic for urological procedures, produced no elevation in

methemoglobin (52).

Buccal Infiltration Injections

Traditionally, the inferior alveolar nerve block has been the injection of choice for

anesthetizing mandibular teeth. A number of studies have shown that the inferior

alveolar nerve block is unable to produce 100% pulpal anesthesia for mandibular teeth (3,

53-63). When pulpal anesthesia is defined by 2 consecutive readings of 80 on an electric

pulp tester (EPT), successful pulpal anesthesia ranged from 74% to 82% (second molar),

43% to 64% (first molar), 65% to 69% (second premolar), 71% to 74% ( first premolar),

29% to 40% (lateral incisor), and 9% to 15% (central incisor) in subjects with

asymptomatic teeth. It is important to note that all subjects in these studies reported lip

and tongue numbness, indicating the block injection was given properly. Due to the unpredictability in success with an inferior alveolar nerve block, several studies have investigated the anesthetic efficacy of primary buccal infiltration injections of the mandibular first molar (1-7, 64-76) and have reported similar success rates for the

mandibular molars and premolars. An advantage of administering a buccal infiltration

injection is that the duration of soft tissue anesthesia is not as long as the duration of an

inferior alveolar nerve block (17). Fernandez et al. reported that soft tissue anesthesia has

a longer duration than pulpal anesthesia (77). Patients also reported that prolonged soft

14 tissue anesthesia has the potential to interfere with daily activities such as: eating, drinking, or speak, and can also create an altered physical appearance and a lack of functionality (78). Administering a buccal infiltration injection instead of an inferior alveolar nerve block may help diminish the unwanted effects of prolonged soft tissue anesthesia.

Articaine Mandibular Buccal Infiltration Success Rates

Articaine is different from the other amide local anesthetics. It contains a thiophene ring, which allows greater lipid solubility, allowing better diffusion across the lipid-rich nerve membrane (79). Skjevik et al. states that it is the ability of articaine to form an intramolecular hydrogen bond, which changes the shape of the articaine molecule, that increases its lipophilicity (45). Recent studies have investigated the anesthetic efficacy of articaine given as mandibular infiltration injections. Potocnik et al. first showed that both 2% articaine and 4% articaine more effectively depressed the CAP

(compound action potential) of the A fibers in the isolated rat sural nerve than either 2% or 4% lidocaine, or 3% mepivacaine (9).

Haas et al. investigated the efficacy of 4% articaine with 1:200,000 epinephrine and 4% prilocaine with 1:200,000 epinephrine when given as mandibular infiltration injections of the second molar and canine. Twenty adult volunteers participated in this double-blind, randomized study. Pulpal anesthesia was determined using an EPT. One and a half milliliters of each solution were administered adjacent to the target teeth. After waiting 1 minute, EPT testing was conducted for 25 minutes. Anesthesia was considered

successful if the subject did not respond to the maximum output on the electric pulp tester

at any time during the study. The second molar achieved defined success 63% and the

canine achieved defined success 65% of the time using the articaine formulation. The

second molar achieved anesthetic success 53% and the canine achieved defined success

50% of the time using the prilocaine formulation (64).

Using the same methods described in the previous study, Haas et al. compared the

anesthetic efficacy of 1.5 mL of 4% articaine with 1:200,000 epinephrine and 1.5 mL of

4% prilocaine with 1:200,000 epinephrine given as a buccal infiltration injection of the

mandibular canine. Twenty adult volunteers participated in this study and received both

of the anesthetic solutions injected next to the mandibular canine at two separate

appointments. Efficacy was evaluated by electric pulp tester over 25 minutes. Articaine

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

prilocaine (65).

Kanaa et al. investigated the difference between 4% articaine with 1:100,000

epinephrine and 2% lidocaine with 1:100,000 epinephrine given as a primary buccal

infiltration injection of the mandibular first molar. Thirty-one subjects participated in

this prospective, randomized, double blind cross-over trial. Each subject was given 1.8 mL of 2% lidocaine with 1:100,000 epinephrine or 1.8 mL of 4% articaine with

1:100,000 epinephrine at two separate appointments. Articaine was found to be much more effective at obtaining pulpal anesthesia for the mandibular first molar than lidocaine. Articaine had a success rate of 64.5%, while lidocaine had a success rate of

38.7%. Based on the number of episodes of no sensation on maximal stimulation with

the electric pulp tester over the period of the trial. This difference was significant

(p<0.001) (1).

Robertson et al. investigated the anesthetic efficacy of articaine in buccal

infiltration of mandibular posterior teeth. Sixty, blinded adult subjects randomly received

two buccal infiltrations. At separate appointments, each subject either received one

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

with 1:100,000 epinephrine given over the mandibular first molar. They used an EPT to

assess pulpal anesthesia. Pulpal anesthesia was considered successful when two

consecutive readings of 80 were obtained with the electric pulp tester (EPT). The success rates for articaine were as follows: 75% for the 2nd molar, 87% for the 1st molar, 92% for the 2nd premolar, and 86% for the 1st premolar. The success rates for lidocaine were as follows: 45% for the 2nd molar, 57% for the 1st molar, 67% for the 2nd premolar, and

61% for the 1st premolar. The authors showed that one cartridge of 4% articaine with

1:100,000 epinephrine produced statistically significant (p=0.0001) more successful pulpal anesthesia than one cartridge of 2% lidocaine with 1:100,000 epinephrine (2).

Jung et al. evaluated the efficacy of pulpal anesthesia for mandibular buccal infiltration injections vs. inferior alveolar nerve blocks in mandibular molars. Using a crossover design, 35 subjects received a standard inferior alveolar nerve block (IANB), or a buccal infiltration of 1.7 mL of 4% articaine with 1:100,000 epinephrine at two different appointments. Pulpal anesthesia was determined using an EPT for 30 minutes after the injection. Anesthesia was considered successful if the subject did not respond to the maximum output on the EPT for two consecutive readings. Anesthetic success rates

17 occurred 54% of the time for the buccal infiltration group and 43% of the time for the

IANB group; the difference was not significant (p=0.34) (3).

Corbett et al. compared buccal infiltration of 1.8 mL of 4% articaine with

1:100,000 epinephrine to 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. Thirty-one adults participated in this randomized controlled trial. At one appointment, buccal infiltration of 1.8 mL of 4% articaine with 1:100,000 adjacent to the mandibular first molar. At the other appointment, a buccal infiltration of 0.9 mL of 4% articaine with 1:100,000 epinephrine plus lingual infiltration of 0.9 mL of 4% articaine with 1:100,000 epinephrine given adjacent to the mandibular first molar. The criterion for successful pulpal anesthesia was no response to the maximum output on the EPT for two or more consecutive readings over the test period of 30 minutes. Success for the buccal infiltration alone was 64.5%, while success for buccal plus lingual infiltrations was 67.7%. This difference was not significant (p=1.000) (4).

Pabst et al. investigated the efficacy of a repeated mandibular buccal infiltration of articaine in prolonging the duration of pulpal anesthesia in the mandibular first molar using a prospective, randomized, single-blind, crossover study. Eighty-six subjects participated in this study. An initial infiltration injection of 4% articaine with 1:100,000 epinephrine was given at both appointments. At each appointment, 25 minutes after the initial infiltration injection, each subject either received an additional injection of 4% articaine with 1:100,000 epinephrine, or a mock injection. Each infiltration injection was given over the first molar. The group that received the initial infiltration of articaine plus

the mock injection had significantly lower success rates than the group that received the

initial infiltration injection of articaine plus the additional infiltration injection of

articaine at 25 minutes. Anesthesia was considered successful when 2 consecutive 80

readings with the EPT were obtained within 10 minutes of the initial injection. The

success rates for the group that received the initial articaine infiltration plus the mock

injection were as follows: 69.8% for the 2nd molar, 66.3% for the 1st molar, 78.8% for

the 2nd premolar, and 80.7% for the 1st premolar. The success rates for the group that

received the initial articaine infiltration plus the additional articaine infiltration at 25

minutes were as follows: 84.9% for the 2nd molar, 83.7% for the 1st molar, 97.7% for the

2nd premolar, and 92.8% for the 1st premolar. The group that received the initial infiltration of articaine plus the mock injection had significantly (p<0.05) lower success rates than the group that received the initial infiltration injection of articaine plus the additional infiltration injection of articaine at 25 minutes (67).

Abdulwahab et al. investigated the efficacy of six anesthetic formulations when given as a mandibular buccal infiltration injection administered adjacent to the first molar. Eighteen adult subjects participated in this randomized, double-blind, controlled

clinical trial comparing 2% lidocaine with 1:100,000 epinephrine, 4% articaine with

1:100,000 epinephrine, 4% articaine with 1:200,000 epinephrine, 4% prilocaine with

1:200,000 epinephrine, 3% mepivacaine plain, and 0.5% bupivacaine with 1:200,000

epinephrine. Each patient received 0.9 mL of each solution at six different

appointments. Only the mandibular first molar on the anesthetized side was tested for

pulpal anesthesia for 20 minutes with an electric pulp tester. Successful pulpal anesthesia

19 was defined as 1 or more 80 readings with an EPT. The success rates for each of the anesthetic solutions were as follows: 38.9% for 4% articaine with 1:100,000 epinephrine,

33.3% for 4% articaine with 1:200,000 epinephrine, 33.3% for 3% mepivacaine plain,

22.2% for 4% prilocaine with 1:200,000 epinephrine, 16.7% for 2% lidocaine with

1:100,000 epinephrine, and 11.1% for 0.5% bupivacaine with 1:200,000 epinephrine. In comparison with the lidocaine control group, only 4% articaine with 1:100,000 epinephrine was significantly different (p=0.029) (5).

Nuzum et al. investigated the efficacy of articaine for combination labial plus lingual infiltration injections compared to labial infiltration injection plus a mock lingual injection in mandibular lateral incisors. Eighty-two adult subjects participated in this prospective, randomized, single-blind, crossover study. The two sets of injections were given at two separate appointments. One set of infiltration injections consisted of an initial labial infiltration of 1.8 mL of 4% articaine with 1:100,000 epinephrine plus a lingual infiltration of 1.8 mL of 4% articaine with 1:100,000 epinephrine. The other set of infiltrations consisted of an initial labial infiltration of 1.8 mL of 4% articaine with

1:100,000 epinephrine plus a mock lingual infiltration. No response from the subject at the maximum output (80 reading) with an EPT was used as the criterion for pulpal anesthesia. Anesthesia was considered successful when 2 consecutive 80 readings with the pulp tester were obtained within 10 minutes of the initial injection. Labial plus lingual infiltration produced 98% success. Labial infiltration plus mock lingual infiltration produced 76% success, which was significantly lower (p=0.0001) than the labial plus lingual infiltration (70).

Meechan et al. investigated the efficacy of buccal versus lingual articaine infiltration for pulpal anesthesia of mandibular teeth. Twenty adults participated in this prospective, randomized, double blind, cross-over trial. At separate appointments, two different anesthetic regimens were given. At one appointment, 1.8 mL of 4% articaine with 1:100,000 epinephrine was given as a buccal infiltration injection next to the first molar, plus a mock lingual injection next to the same tooth. At the other appointment,

1.8 mL of 4% articaine with 1:100,000 epinephrine was given as a lingual infiltration injection next to the mandibular first molar, plus a mock buccal infiltration injection of the same tooth. The mandibular first molar, mandibular premolar, and mandibular lateral incisor, all of the same side, were tested for pulpal anesthesia for 47 minutes with an EPT. With the definition of success being two consecutive readings of 80 with the

EPT, the buccal infiltration showed significantly better (p<0.001) success than lingual infiltrations. The success of the buccal infiltration injection was as follows: 65% for the first molar, 90% for the premolar, and 55% for the lateral incisor. The success of the lingual infiltration was as follows: 10% for the molar, 15% for the premolar, and 25% for the lateral incisor (71).

McEntire et al. investigated the anesthetic efficacy of 4% articaine with 1:200,000 epinephrine compared to 4% articaine with 1:100,000 epinephrine when given as a primary buccal infiltration injection of the mandibular first molar. Eighty-six adult subjects participated in this prospective, randomized, double-blind study using a crossover design. At one appointment, 1.8 mL of 4% articaine with 1:200,000 epinephrine was given. At the other appointment 1.8 mL of 4% articaine with 1:100,000 epinephrine was

given. The mandibular first and second molars and premolars were electric pulp tested

for 60 minutes. With the criteria of success being two consecutive readings of 80 with the EPT, there were no significant differences between the test solutions in frequency of pulpal anesthesia for any of the teeth tested. Success rates were as follows for the solution containing 4% articaine with 1:100,000 epinephrine: 59.3% for the 2nd molar,

67.4% for the 1st molar, 84.9% for the 2nd premolar, and 73.8% for the 1st premolar.

Success rates were as follows for the solution containing 4% articaine with 1:200,000:

59.3% for the 2nd molar, 59.3% for the 1st molar, 79.1% for the 2nd premolar, and

75.0% for the 1st premolar. No significant differences were found between the two

anesthetic formulations (73).

Martin et al. investigated the anesthetic efficacy of 1.8 mL versus 3.6 mL of 4%

articaine with 1:100,000 epinephrine as a primary buccal infiltration of the mandibular first molar. Eighty-six adults took part in this prospective, randomized, single-blind,

crossover study. The subjects randomly received either 1.8 mL or 3.6 mL of 4% articaine

with 1:100,000 epinephrine in two separate appointments. The mandibular first and

second molars and premolars were tested for 90 minutes with an EPT. Successful pulpal

anesthesia was defined as two or more consecutive readings of 80 with the EPT. The

success rates of the 1.8 mL solution of articaine were as follows: 48.8% for the 2nd

molar, 52.3% for the 1st molar, 87.1% for the 2nd premolar, and 81.4% for the 1st

premolar. The success rates of the 3.6 mL solution of articaine were as follows: 65.1%

for the 2nd molar, 75.6% for the 1st molar, 92.9% for the 2nd premolar, and 81.4% for

the 1st premolar. They showed that 3.6 mL of 4% articaine with 1:100,000 epinephrine

was statistically better than 1.8 mL of 4% articaine with 1:100,000 epinephrine

(p=0.0001) when given as a primary buccal infiltration injection of the mandibular first molar (74).

Dressman et al. investigated the anesthetic efficacy of repeated injections of 4%

articaine with 1:100,000 epinephrine. One hundred blinded 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 20 minutes later using 1.8 mL of 4% articaine with 1:100,000 epinephrine or a repeated mock infiltration injection 20 minutes later, in two separate appointments. The injections were given adjacent to the second premolar. The mandibular first molar, first and second premolars, canine, and lateral and central incisors were tested for 90 minutes with an EPT.

Successful pulpal anesthesia was defined as two or more consecutive readings of 80 with the EPT. The success rates for the repeated injection group were as follows: 79.0% for the first molar, 94.9% for the second premolar, 96.8% for the first premolar, 80.0% for the canine, 47.0% for the lateral incisor, 32.0% for the central incisor. The success rates for the primary injection plus the mock injection were as follows: 60.0% for the first molar, 81.8% for the second premolar, 90.5% for the first premolar, 61.0% for the canine,

24.0% for the lateral incisor, 22.0% for the central incisor. The difference between the two anesthetic techniques was significantly different (76).

Articaine Buccal Infiltration as Supplemental Injection to Inferior Alveolar

Nerve Blocks

As previously discussed, the inferior alveolar nerve block has been the injection of choice for anesthetizing mandibular teeth. A number of studies have shown that the inferior alveolar nerve block is unable to produce 100% pulpal anesthesia for mandibular teeth (3, 53-63). When pulpal anesthesia is defined by 2 consecutive readings of 80 on an electric pulp tester (EPT), successful pulpal anesthesia ranged from 74% to 82% (second molar), 43% to 64% (first molar), 65% to 69% (second premolar), 71% to 74% ( first premolar), 29% to 40% (lateral incisor), and 9% to 15% (central incisor) in subjects with asymptomatic teeth. It is important to note that all subjects in these studies reported lip and tongue numbness, indicating the block injection was given properly. Due to the unpredictability of success rates from inferior alveolar nerve blocks, supplemental anesthesia is often needed to produce higher success rates of pulpal anesthesia. Many studies have been conducted to determine the anesthetic efficacy of different solutions and concentrations of local anesthetics given as mandibular buccal infiltration (1-6, 64-

76) . These injections have been given as primary injections or as supplemental injections to the inferior alveolar nerve block. The mandibular buccal infiltration injection is generally given in the buccal vestibule from a superior, lateral direction, adjacent to the mandibular first molar. It has also been used adjacent to the 2nd premolar and anterior teeth. The needle is advanced to the approximate level of the root apices.

After a negative aspiration is achieved, the anesthetic is deposited at approximately 1.8 mL/min.

“Supplemental injections are essential when anesthesia from conventional

injections is inadequate and the pain is too severe for the dentist to proceed. If the patient

has profound lip numbness and experiences pain on restorative or endodontic treatment,

repeating the inferior alveolar nerve block (IANB) does not help the problem” (80).

Haase et al. compared the anesthetic efficacy of articaine versus lidocaine as a

supplemental buccal infiltration of the mandibular first molar after an IANB injection in

asymptomatic patients. Seventy-three blinded adult subjects all received a standard

IANB injections with a cartridge of 4% articaine with 1:100,000 epinephrine. The subjects then randomly received buccal infiltration injections of one cartridge of 2% lidocaine with 1:100,000 epinephrine at one appointment or one cartridge of 4% articaine with 1:100,000 epinephrine at a second appointment. Both infiltration injections were given buccal to the mandibular first molar. An electric pulp tester was used to test pulpal anesthesia of the mandibular first molar for 60 minutes. Successful anesthesia was determined by two or more consecutive readings of 80 on the electric pulp tester. Buccal infiltration with articaine showed a success rate of 64%. Buccal infiltration with lidocaine showed a success rate of 52%. With a p-value of 0.01, the two anesthetic combinations were significantly different (6).

Kanaa et al. evaluated the efficacy of articaine given as a buccal infiltration after an inferior alveolar nerve block of lidocaine. Thirty-six adults received IANB injections of 2.0 mL of 2% lidocaine with 1:80,000 epinephrine at both appointments. At one appointment, the subjects also received a buccal infiltration of 2.0 mL of 4% articaine with 1:100,000 epinephrine given next to the mandibular first molar. At the other visit, a

mock injection was performed next to the mandibular first molar. The mandibular first

molar, a premolar, and the lateral incisor were tested for 45 minutes. Successful pulpal

anesthesia was determined when two or more consecutive readings of 80 were achieved

with electric pulp testing. The success rates for the IANB with the articaine buccal

infiltration were as follows: 91.7% for the first molar, 88.9% for the premolar, and

77.8% for the lateral incisor. The success rates for the IANB with mock buccal

infiltration were as follows: 55.6% for the first molar, 66.7% for the premolar, and

19.4% for the lateral incisor. The IANB with supplementary articaine infiltration

produced significantly more success than IANB alone in first molar (p<0.001) (7).

Articaine Given as Buccal Infiltration Injection in Irreversible Pulpitis

As previously discussed, the IANB does not provide adequate pulpal anesthesia in

asymptomatic patients. In patients diagnosed with irreversible pulpitis the success rates

reported are even lower (13%-65%) (62, 68, 72, 75, 81-86). The problem is that patients may have adequate lip and tongue numbness, indicating success, but they may not have pulpal anesthesia. There are several possible reasons why success is lower. A possible explanation is that the nerves arising from inflamed tissue have altered resting potentials and lowered membrane excitability thresholds (87). Modaresi et al. (87) and Wallace et al. (88) showed that local anesthetic agents were not sufficient to prevent impulse transmission due to lowered excitability thresholds (80). Roy et al. showed that a class of tetrodotoxin-resistant (TTX-r) sodium channels can be resistant to the action of local

anesthetics (89). Sorenson et al. further showed that there is an increased expression of

sodium channels in pulps diagnosed with irreversible pulpitis (90).

Matthews et al. investigated articaine for supplemental buccal infiltration of the

mandibular molar in patients with irreversible pulpitis when an inferior alveolar nerve

block failed. Eighty-two adult patients, 42 men and 40 women, participated in this study

and were given standard IANB injections and long buccal infiltrations of 2% lidocaine

with 1:100,000 epinephrine. Overall success of the IANB alone was 33% (27/82). Fifty-

five patients required an infiltration injection of one cartridge of 4% articaine with

1:100,000 epinephrine which was administered when it was determined that the IANB

had failed to achieve adequate pulpal anesthesia upon endodontic access or pulp removal.

The success of the supplemental buccal infiltration injection was defined as the ability to

continue access of the pulp chamber, place initial files, and instrument the tooth without

pain (VAS score of 0) or mild pain (VAS score 0 or less than or equal to 54 mm on a 170

mm VAS). The success rates for the IANB with the articaine buccal infiltration were as

follows: 58% for the first molar, 48% with the second molar, 100% for the first and

second premolars, and the overall success rate being 58% (66).

Aggarwal et al. evaluated the anesthetic efficacy of supplemental buccal and lingual infiltrations of articaine and lidocaine after an inferior alveolar nerve block in patients diagnosed with irreversible pulpitis. Eighty-four adult patients participated in this prospective, randomized, double-blind study. All patients received a standard IANB of 2% lidocaine with 1:200,000 epinephrine. Twenty-four patients did not receive any supplemental anesthesia, this was the control group. Thirty patients received

supplemental buccal and lingual infiltrations of 4% articaine with 1:200,000 epinephrine.

Thirty patients received buccal and lingual infiltrations of 2% lidocaine with 1:200,000

epinephrine. Successful pulpal anesthesia was determined if no pain or weak-to-mild pain was experienced during access preparation and pulp extirpation. The control group had successful anesthesia 33% of the time. The group that received supplemental articaine infiltrations had successful anesthesia 67% of the time. The group that received supplemental lidocaine infiltrations had successful anesthesia 47% of the time. There was a significant difference (p<0.05) between the groups (69).

Fan et al. investigated the anesthetic efficacy of a standard inferior alveolar nerve block plus either a buccal infiltration of articaine or periodontal ligament injection in patients diagnosed with irreversible pulpitis of the mandibular first molar. Fifty-nine adult patients participated in this study. All patients received a standard IANB of 1.7 mL of 4% articaine with 1:100,000 epinephrine. Patients then received a supplemental anesthesia of either a buccal infiltration injection of 0.4 mL of 4% articaine with

1:100,000 epinephrine or a periodontal ligament injection of 0.4 mL 4% articaine with

1:100,000 epinephrine. Both supplemental injections were given next to the tooth being treated. Success was defined as mild or no pain upon endodontic access. The group that received the buccal infiltration injection had successful anesthesia 81.5% of the time.

The group that received the periodontal ligament injection had successful anesthesia

83.3% of the time. No significant difference (p>0.05) was observed between the groups

(68).

Aggarwal et al. compared articaine, articaine plus ketorolac, and dexamethasone

as supplemental injections to an inferior alveolar nerve block in patients who were

diagnosed with irreversible pulpitis in a mandibular molar. Ninety-four adults participated in this prospective, randomized, double-blind study. All patients received a standard IANB with 1.8 mL of 2% lidocaine with 1:200,000 epinephrine. The subjects were then split into four groups. Group 1 patients, the control group, did not receive any supplemental anesthetic. Group 2 patients received a supplemental infiltration injection of 1.8 mL of 4% articaine with 1:100,000 given directly over the tooth being treated.

Group 3 patients received a supplemental buccal infiltration injection of 0.9 mL of 4% articaine with 1:100,000 epinephrine first, then 1.0 mL/30.0 mg of ketorolac tromethamine injected after. Both injections were given at the approximate level of the apices of the tooth being treated. Group 4 patients received a supplemental buccal infiltration of 1.0 mL/4 mg of dexamethasone given at the approximate level of the apices of the tooth being treated. The IANB alone was successful 39% of the time. Buccal infiltration with articaine alone increased the success rate to 54%. Supplementary dexamethasone infiltration was successful 45% of the time. Buccal infiltration with articaine plus ketorolac increased the success rate to 62%. There was no significant difference (p>0.05) between the groups (72).

Poorni et al. investigated the anesthetic efficacy of 4% articaine for pulpal anesthesia given as a buccal infiltration for mandibular molars diagnosed with irreversible pulpitis. The patients were divided into three groups: 52 patients received a standard IANB of 1.8 mL of 4% articaine with 1:100,000 epinephrine, 52 patients

received a buccal infiltration injection of 1.8 mL of 4% articaine with 1:100,000

epinephrine without an IANB, and 52 patients received a standard IANB of 2% lidocaine

with 1:100,000 epinephrine. Success was defined as no or little pain when the test teeth

were accessed and when the pulp was extirpated. Buccal infiltration of articaine alone

showed success rates of 69.2% upon access preparation and 65.4% upon pulp extirpation.

IANB with articaine showed success rates of 75% upon access preparation and 69.2%

upon pulp extirpation. IANB with lidocaine showed success rates of 69.2% upon access

preparation and 65.4% upon pulp extirpation. There were no significant differences

(p>0.05) between the groups (75).

Kanaa et al. evaluated different supplementary anesthetic techniques after failure of an inferior alveolar nerve block (IANB) in patients with irreversible pulpitis in mandibular teeth. This randomized clinical trial included 182 patients diagnosed with irreversible pulpitis. A standard IANB was given with 2.0 mL of 2% lidocaine with

1:80,000 epinephrine. Success was defined as a single reading of 80 on an EPT. Success in molars after the IANB was 32.1%. Success in premolars after the IANB was 44.4%.

After 2.0 mL of 4% of articaine with 1:100,000 (given as a buccal infiltration adjacent to the apices of the tooth being treated) success rates increased to 83.3 to 85% in the molars and premolars, respectively (84).

Lidocaine Buccal Infiltration Success Rates

Multiple studies have shown that labial or lingual infiltration injections of various

concentrations and volumes of lidocaine alone are not effective for pulpal anesthesia in

mandibular teeth (1-2, 5, 64-65, 91-92).

Yonchak et al. investigated the anesthetic efficacy of buccal infiltrations in mandibular anterior teeth. Eighty adult subjects participated in this prospective, randomize, double-blind, cross-over trial. Forty subjects randomly received a labial infiltration at the lateral incisor apex of either 1.8 mL of 2% lidocaine with 1:100,000 epinephrine or 1.8 mL of 2% lidocaine with 1:50,000 epinephrine at 2 separate appointments. An additional 40 subjects received a lingual infiltration at the lateral incisor apex of 1.8 mL of 2% lidocaine with 1:100,000 epinephrine following the labial infiltrations. No response from the subject to the maximum output (80 reading) of the

EPT was used for criterion for pulpal anesthesia. Anesthesia was considered successful when 2 consecutive 80 readings were obtained. For the 3 infiltrations, success rates for the lateral incisor ranged from 43% to 50%. There was no significant difference (p>0.05) in success between the labial infiltration of 2% lidocaine with 1:100,000 epinephrine and

2% lidocaine with 1:50,000 epinephrine or the lingual infiltration of 2% lidocaine with

1:100,000 epinephrine when compared with the labial infiltration of 2% lidocaine with

1:100,000 epinephrine (91).

this prospective, randomized, double-blind, cross-over trial. Each subject was given 1.8 mL of 2% lidocaine with 1:100,000 epinephrine or 1.8 mL of 4% articaine with

38.7%. There was a significant difference between lidocaine and articaine (p<0.001) (1).

Meechan et al. evaluated pulpal anesthesia for mandibular first molar teeth in a double-blind, randomized, cross-over trial comparing buccal and buccal plus lingual infiltration injections. At one appointment 1.8 mL of 2% lidocaine with 1:100,000 epinephrine given as a buccal infiltration next the mandibular first molar. At the other appointment 0.9 mL of 2% lidocaine with 1:100,000 epinephrine given as a buccal infiltration of the mandibular first molar, and 0.9 mL of 2% lidocaine with 1:100,000 epinephrine given as a lingual infiltration. Buccal infiltration alone was successful in

38.7% of cases compared to 32.7% success in the combined buccal and lingual infiltration group. There was no significant differences between the groups (p=0.63)

(92).

Robertson et al. investigated the anesthetic efficacy of articaine and lidocaine in buccal infiltration of mandibular posterior teeth. Sixty blinded adult subjects randomly received two buccal infiltrations. At separate appointments, each subject either received one cartridge of 2% lidocaine with 1:100,000 epinephrine, or one cartridge of 4% articaine with 1:100,000 epinephrine given over the mandibular first molar. As noted earlier the success rates for lidocaine were as follows: 45% for the 2nd molar, 57% for

the 1st molar, 67% for the 2nd premolar, and 61% for the 1st premolar. The authors

showed that one cartridge of 4% articaine with 1:100,000 epinephrine was statistically

and significantly more successful (p=0.0001) than one cartridge of 2% lidocaine with

1:100,000 epinephrine (2).

Abdulwahab et al. investigated the efficacy of six anesthetic formulations when

given as a mandibular buccal infiltration injection. Eighteen adult subjects participated in

this randomized, double-blind, controlled clinical trial as previously mentioned. Each

patient received 0.9 mL of each solution at six different appointments. The posterior

mandibular teeth were tested for pulpal anesthesia for 20 minutes with an electric pulp

tester. The success rate was 16.7% for 2% lidocaine with 1:100,000 epinephrine, which

was significantly less successful than 4% articaine with 1:100,000 epinephrine (p=0.029), but not significantly different from the rest of the anesthetic solutions (5).

To date, no studies have been performed utilizing 4% lidocaine given as a mandibular buccal infiltration injection. However, Vreeland et al. evaluated the

anesthetic efficacy of 1.8 mL of 4% lidocaine with 1:100,000 epinephrine compared to

1.8 mL of 2% lidocaine with 1:100,000 epinephrine, and 3.6 mL 2% lidocaine with

1:200,000 epinephrine given as an inferior alveolar nerve block. Anesthetic success was

defined as having the first of consecutive readings of 80 on an EPT within 16 minutes of

the injection and continuously sustained for 55 minutes. Success rates of 1.8 mL of 2%

lidocaine with 1:100,000 epinephrine and 3.6 mL of 2% lidocaine with 1:200,000

epinephrine were 63.3%. The success rate for 1.8 mL of 4% lidocaine with 1:100,000

epinephrine was 53.3%. There were no significant differences between the three

33 anesthetics. The increase in lidocaine concentration (increase in the number of lidocaine molecules to block nerve conduction) did not improve IANB success.

Lidocaine Buccal Infiltration as Supplemental Injections to Inferior Alveolar

Nerve Blocks

Foster et al. evaluated the anesthetic efficacy of buccal and lingual infiltrations of lidocaine following an inferior alveolar nerve block (IANB) in mandibular posterior teeth. The study utilized three sets of injections including: an IANB plus a mock buccal and a mock lingual infiltration, an IANB plus a buccal infiltration and mock lingual infiltration, and an IANB plus a mock buccal infiltration and lingual infiltration. For the buccal infiltration, the injection was administered buccal to the mandibular first molar at the approximate level of the root apices. For the lingual infiltration, the injection was administered into alveolar mucosa just below the most apical extent of the lingual attached gingiva adjacent to the first molar. All IANB injections were 3.6 mL of 2% lidocaine with 1:100,000 epinephrine. All infiltration injections were 1.8 mL of 2% lidocaine with 1:100,000 epinephrine. Anesthesia was considered successful when 2 consecutive 80 readings on an EPT were obtained within 15 minutes, and the 80 reading was continuously sustained for 60 minutes. For the IANB plus mock buccal and lingual infiltrations, anesthetic success ranged from 53% to 74% from the second molar to second premolar. For the IANB plus buccal infiltration and mock lingual infiltration, successful pulpal anesthesia ranged from 57% to 69% from the second molar to the second premolar. For the IANB plus mock buccal infiltration and lingual infiltration,

34 successful pulpal anesthesia ranged from 54% to 76% from the second molar to the second premolar. There was no significant difference between the IANB plus buccal or lingual infiltrations. Adding 1.8 mL of 2% lidocaine with 1:100,000 epinephrine to an

IANB did not significantly increase (p>0.05) anesthetic efficacy in mandibular posterior teeth (93).

Haase et al. compared the anesthetic efficacy of articaine versus lidocaine as a supplemental buccal infiltration of the mandibular first molar after an inferior alveolar nerve block. Seventy-three blinded adult subjects all received a standard IANB with a cartridge of 4% articaine with 1:100,000 epinephrine. The subjects then randomly received buccal infiltration injections of one cartridge of 2% lidocaine with 1:100,000 epinephrine at one appointment and one cartridge of 4% articaine with 1:100,000 epinephrine at another appointment as previously discussed. Buccal infiltration of the first molar with articaine showed a success rate of 88%. Buccal infiltration of the first molar with lidocaine showed a success rate of 71%. There was a significant difference between the two groups (p>0.05) (6).

Lidocaine Given as Buccal Infiltration Injection in Irreversible Pulpitis

Aggarwal et al. evaluated the anesthetic efficacy of supplemental buccal and lingual infiltrations of articaine and lidocaine after an inferior alveolar nerve block in patients diagnosed with irreversible pulpitis. Eighty-four adult volunteers participated in this prospective, randomized, double-blind study. All patients received a standard IANB of 2% lidocaine with 1:200,000 epinephrine. Twenty-four patients did not receive any

supplemental anesthesia (control group). Thirty patients received supplemental buccal

and lingual infiltrations of 4% articaine with 1:200,000 epinephrine. Thirty patients

received buccal and lingual infiltrations of 2% lidocaine with 1:200,000 epinephrine.

Successful pulpal anesthesia was achieved if no pain or weak-to-mild pain was

experienced during access preparation and pulp extirpation. The control group had

successful anesthesia 33% of the time. The group that received supplemental articaine

infiltrations had successful anesthesia 67% of the time, which was significantly more

successful (p>0.05) than the group that received supplemental lidocaine infiltrations,

which had successful anesthesia 47% of the time (60).

Parirokh et al. investigated the efficacy of combining a buccal infiltration injection with an inferior alveolar nerve block for patients diagnosed with irreversible pulpitis of a mandibular molar. Eighty-four patients were randomly assigned to one of three groups. Group 1 received a standard IANB of 1.8 mL of 2% lidocaine with

1:80,000 epinephrine, while Group 2 received a standard IANB of 3.6 mL of 2% lidocaine with 1:80,000 epinephrine. Group 3 received a standard IANB of 2% lidocaine with 1:80,000 epinephrine plus 1.8 mL of 2% lidocaine with 1:80,000 epinephrine given as a buccal infiltration injection next to the tooth being treated. Anesthesia was considered successful if endodontic access and canal instrumentation could be completed without pain. The success rate for the IANB alone was 14.8%. Success for Group 2 was

39.3%. Success for Group 3 was 65.4%. Group 3 showed significantly better anesthesia when compared with Group 1 (p<0.001). There was no significant difference between

Group 2 and Group 3 (94).

Prilocaine Buccal Infiltration Success Rates

Limited studies have been done on the efficacy of 4% prilocaine given as a buccal infiltration injection of mandibular posterior teeth.

Haas et al. investigated the efficacy of 4% articaine with 1:200,000 epinephrine and 4% prilocaine with 1:200,000 epinephrine when given as a mandibular infiltration injection of the second molar and canine. This double-blind, randomized study defined success of pulpal anesthesia using an electric pulp tester. One and a half milliliters of each solution were administered. Anesthesia was considered successful if the subject did not respond to the maximum output on the electric pulp tester at any time during the study. The second molar achieved defined success 63% and the canine achieved defined success 65% of the time using the articaine formulation. The second molar achieved anesthetic success 53% and the canine achieved defined success 50% of the time using the prilocaine formulation. No significant differences were found between articaine and prilocaine (p>0.05) (64-65).

Abdulwahab et al. investigated the efficacy of six anesthetic formulations when given as a mandibular buccal infiltration injection. Eighteen adult subjects participated in this randomized, double-blind, clinical trial which included 4% prilocaine with 1:200,000 epinephrine. Each patient received 0.9 mL of each solution at six different appointments.

The posterior mandibular teeth were tested for pulpal anesthesia for 20 minutes with an electric pulp tester. The success rate was 22.2% for 4% prilocaine with 1:200,000 epinephrine, which was significantly less successful than articaine. There was no

37 significant difference between 2% lidocaine with 1:100,000 epinephrine and 4% prilocaine with 1:200,000 epinephrine solutions (5).

Buccal Infiltration Injection Pain

Anesthetic injection pain can vary with location, anesthetic type, speed of injection, gender of the patient/subject, and possibly the gender of the provider. The mandibular buccal infiltration has been reported to be a mildly painful dental injection.

The pain of an injection can be broken down into three parts: needle insertion pain - pain reported as the needle penetrates the oral mucosa; needle placement pain - pain related to guiding the needle through soft tissues to the target site; and solution deposition pain - pain due to injection of a particular anesthetic solution. Several studies have investigated the anesthetic efficacy of different anesthetic formulations for the buccal infiltration injection and have also recorded the pain ratings for the injections.

Kanaa et al. investigated the difference between 4% articaine with 1:100,000 epinephrine and 2% lidocaine with 1:100,000 epinephrine given as a primary buccal infiltration injection of the mandibular first molar. Thirty-one asymptomatic subjects participated in this prospective, randomized, double blind cross-over trial. Each subject was given 1.8 mL of 2% lidocaine with 1:100,000 epinephrine or 1.8 mL of 4% articaine with 1:100,000 epinephrine at two separate appointments. The overall pain experienced during each injection was self-recorded by patients on a 100 mm visual analogue scale

(VAS), with 0 mm meaning no pain, and 100 mm meaning unbearable pain. No topical anesthesia was used. The mean VAS scores following lidocaine and articaine

38 infiltrations were 17.8 mm and 20.9 mm, respectively. They did not classify these pain ratings. There was no significant difference in injection discomfort between anesthetics.

No adverse effects were recorded during any visit (1).

Robertson et al. investigated the anesthetic efficacy of articaine in buccal infiltration of mandibular posterior teeth. Sixty, blinded adult subjects randomly received two buccal infiltrations. At separate appointments, each subject either received one cartridge of 2% lidocaine with 1:100,000 epinephrine or one cartridge of 4% articaine with 1:100,000 epinephrine given over the mandibular first molar. A 170 mm VAS was used to rate the three stages of the injection. No topical anesthesia was used. Mean VAS scores for each stage of the injection for the articaine solution were as follows: needle insertion (24±25 mm), needle placement (33±29 mm), and solution deposition (36±30 mm). Mean VAS scores for each stage of the injection for the lidocaine solution were as follows: needle insertion (27±26 mm), needle placement (32±25 mm), and solution deposition (37±63 mm). The authors reported there were no significant differences between the two anesthetic formulations on pain of injection. All of these VAS ratings were considered mild pain. The only reported postinjection complications were bruising and slight swelling in the area of the injection (2).

Corbett et al. compared buccal infiltration of 1.8 mL of 4% articaine with

39 mandibular first molar. At the other appointment, a buccal infiltration of 0.9 mL of 4% articaine with 1:100,000 epinephrine plus lingual infiltration of 0.9 mL of 4% articaine with 1:100,000 epinephrine given adjacent to the mandibular first molar. No topical anesthesia was used. A 100 mm VAS was used to rate the overall pain of the injection.

Lingual infiltration of 0.9 mL of 4% articaine had a mean pain rating of 21.5 mm, while the buccal infiltration of 0.9 mL of 4% articaine had a mean pain rating of 15.2 mm. The buccal infiltration of 1.8 mL of 4% articaine was significantly more painful (p=0.017) with a mean pain rating of 20.9 mm. The pain ratings were not classified on the VAS (4).

Pabst et al. investigated the efficacy of repeated buccal infiltration injections of

1.8 mL of 4% articaine with 1:100,000 epinephrine adjacent to the mandibular first molar. Before each injection 20% benzocaine was applied for 60 seconds at the injection site. A 170 mm VAS was used to rate the three stages of the injection. For the initial infiltration injection, which each subject received, needle insertion pain ratings were as follows: 19.6-21.7 mm on VAS with no pain (28%-29%), 67%-70% mild pain, 2%-3% moderate pain, and no severe pain. Needle placement pain ratings were as follows: 34.3-

41.7 mm on the VAS with 3%-5% no pain, 78%-86% mild pain, 9%-19% moderate pain, and no severe pain. Solution deposition pain ratings were as follows: 34.3-35.5 mm on the VAS with 16%-20% no pain, 60%-72% mild pain, 12%-19% moderate pain, and 0%-1% severe pain. Sixteen percent (14/86) of subjects reported slight swelling with the repeated infiltration, while only 9% (8/86) of subjects reported slight swelling with the mock infiltration. There were no significant differences noted between the two groups of infiltration injections (67).

Abdulwahab et al. investigated the anesthetic efficacy of six local anesthetic formulations administered as a primary buccal infiltration injection of the mandibular first molar. No topical anesthetic was used. Patients were asked to rate the pain of the injection on a 100 mm VAS. The injection was rated as an overall experience and not broken down into phases. Mean VAS pain ratings were as follows: 26.2 mm for 4% articaine with 1:100,000 epinephrine, 24.1 mm for 4% articaine with 1:200,000 epinephrine, 27.6 mm for 2% lidocaine with 1:100,000 epinephrine, and 21.0 mm for 4% prilocaine with 1:200,000 epinephrine. The author did not categorize the pain levels on the VAS. There were only minor adverse reactions to the injections and were not dependent on which local anesthetic was used. The author did not state whether or not there was significance between the different solutions for the pain of the injections (5).

McEntire et al. investigated the anesthetic efficacy of 4% articaine with either

1:100,000 epinephrine or 1:200,000 epinephrine as a primary buccal infiltration injection of the mandibular first molar. A 170 mm VAS was used to rate the three stages of the injection. Before each injection 20% benzocaine (topical anesthetic gel) was applied at the injection site for 60 seconds. Pain ratings for 4% articaine with 1:100,000 epinephrine were as follows for needle insertion: 36.9 mm on the VAS broken down to

2% no pain, 83% mild pain, 15% moderate pain, and no severe pain reported. Pain ratings for 4% articaine with 1:100,000 epinephrine were as follows for needle placement: 37.3 mm on the VAS with 6% no pain, 76% mild pain, 19% moderate pain, and no reports of severe pain. Pain ratings for 4% articaine with 1:100,000 epinephrine were as follows for solution deposition: 30.1 mm on the VAS with 11% no pain, 76%

mild pain, 14% moderate pain, and no severe pain. Pain ratings for 4% articaine with

1:200,000 epinephrine were as follows for needle insertion: 37.2 mm on the VAS broken

down to 4% no pain, 74% mild pain, 21% moderate pain, and 1% severe pain. Pain

ratings for 4% articaine with 1:200,000 epinephrine were as follows for needle

placement: 40.1 mm on the VAS broken down to 6% no pain, 74% mild pain, 19%

moderate pain, and 1% severe pain. Pain ratings for 4% articaine with 1:200,000 epinephrine were as follows for solution deposition: 30.0 mm on the VAS reported as

12% no pain, 76% mild pain, 12% moderate pain, and 1% severe pain. There were no significant differences between the 2 anesthetic formulations for pain of injection. Post-

injection complications reported were initial tenderness at site of injection (5%-7%),

intraoral bruising (1%-4%), and slight subjective swelling (1%-2%) in the area of

injection (73).

Martin et al. investigated the anesthetic efficacy of 1.8 mL versus 3.6 mL of 4%

articaine with 1:100,000 epinephrine as a primary buccal infiltration injection of the

mandibular first molar. A 170 mm VAS was also used to rate each stage of the injection.

Before each injection 20% benzocaine (topical anesthetic gel) was applied at the injection

site for 60 seconds. Pain ratings for the 1.8 mL solution group for needle insertion were

as follows: 26.8 mm on the VAS broken down to 16% no pain, 76% mild pain, 8%

moderate pain, and no severe pain. Pain ratings for the 1.8 mL group for needle

placement: 39.1 mm on the VAS with 5% no pain, 84% mild pain, 12% moderate pain,

and no severe pain. Pain ratings for the 1.8 mL group for solution deposition: 36.8 mm

on the VAS with 12% no pain, 71% mild pain, 17% moderate pain, and no severe pain.

Pain ratings for the 3.6 mL solution group for needle insertion were as follows: 25.4 mm on the VAS reported as 19% no pain, 78% mild pain, 2% moderate pain, and 1% severe pain. Pain ratings for the 3.6 mL group for needle placement: 36.2 mm on the VAS with

6% no pain, 74% mild pain, 19% moderate pain, and 1% severe pain. Pain ratings for the

3.6 mL solution group for solution deposition: 36.8 mm on the VAS reported as 14% no pain, 69% mild pain, 17% moderate pain, and no severe pain. Although there were no significant differences in the pain of injection between groups, the 3.6 mL solution group had significantly more postoperative pain than the 1.8 mL solution group at each postoperative day (Days 0-3). Post-injection complications reported were initial tenderness (6%-13%) and slight subjective swelling (4%-9%) in the area of the injection

(74).

Dressman et al. investigated the anesthetic efficacy of repeated injections of 4% articaine with 1:100,000 epinephrine. A 170 mm VAS was used to rate pain at each stage of the injection. Before each injection 20% benzocaine (topical anesthetic gel) was applied at the injection site for 60 seconds. The initial buccal infiltration injection pain ratings for needle insertion were as follows: 30.9-31.0 mm on the VAS broken down into

9% no pain, 80% mild, 11% moderate pain, and no severe pain. Pain ratings for needle placement were as follows: 22.4-25.7 mm on the VAS reported as 33% no pain, 59% mild pain, 8% moderate pain, and no severe pain. Pain ratings for solution deposition were as follows: 32.4-33.8 mm on the VAS reported as 22% no pain, 56% mild pain,

22% moderate pain, and no severe pain. There were no significant differences between groups for any stage of the injection. Mean postoperative pain ratings showed

43 significantly higher pain ratings for Group 1 (repeat injection with articaine) at all postoperative time periods. All postoperative time period pain ratings decreased from

Day 0 to 3 and all were in the mild category (76).

Adverse Anesthetic Reactions - Paresthesia

Local anesthetics are capable of causing paresthesia, which can present as persistent numbness, tingling, anesthesia, hyperesthesia, dysethesia, or altered sensation well beyond the expected duration of anesthesia (17, 95). Paresthesia may be caused by trauma to any nerve or nerve sheath, which can be produced by the needle during the injection. Many patients report the sensation of an ‘electric shock’ throughout the distribution of the involved nerve. With the size of the needles used in dentistry, it is difficult to sever a nerve trunk or even the nerve fibers during an injection, however, trauma to a nerve may occur by contact with the needle, which may be all that is needed to produce paresthesia (17, 96).

The majority of adverse reactions associated with the use of local anesthetics are due to the administration of the drug or the procedure performed, rather than the actual drug itself (97-98). Nickel et al. conducted a retrospective study of paresthesia which reviewed 4,987 cases of dental surgical patients and uncovered 46 inferior alveolar and lingual nerve paresthesia cases – a 0.92% incidence for all exodontias. Of the 46 cases,

30 were the result of surgery in which 3% mepivacaine or 2% lidocaine with 1:100,000 epinephrine were used as the anesthetic. The remaining 16 cases had no surgical explanation; 7 of these cases were associated with the use of 3% mepivacaine (0.32%

incidence) and 9 were associated with 2% lidocaine with 1:100,000 epinephrine (0.32%

incidence). From the entire group, 27 cases of paresthesia lasted less than one month, 8

cases lasted from two to six months, 5 lasted from 7-12 months, and 2 lasted more than

12 months (99). Hillerup et al. reprted that nonsurgical cases of paresthesia are almost

exclusively related to the IANB. The lingual nerve was affected more frequently than the

inferior alveolar nerve (100-101). Studies have shown that 85%-94% of non-surgical paresthesias resolve spontaneously within 8 weeks; however, about two-thirds of those who do not recover quickly may never fully recover (102). Gaffen et al. conducted a retrospective study to analyze cases of nonsurgical paresthesia that were voluntarily reported to the Professional Liability Program (PLP) associated with the Royal College of

Dental Surgeons of Ontario (RCDSO) over the 10-year period from 1999 to 2008.

During the 10-year period, 182 reports of nonsurgical paresthesia were made to the PLP

(102). Approximately 13 million local anesthetic injections were administered in Ontario during 2007 (103). Sixty-four cases of nonsurgical paresthesia were reported to the PLP

in 2007. The approximate incidence of nonsurgical paresthesia, as reported to the PLP,

was 1 in 609,000 injections (102).

Garisto et al. studied the occurrence of paresthesia after dental local anesthetic

administration in the U.S. Reports of paresthesia involving dental procedures were

obtained from the time period of November 1997 through August 2008 from the U.S.

Food and Drug Administration Adverse Event Reporting System. The study showed that

248 cases of paresthesia occurred after dental treatment during the study period. Most

cases (94.5%) involved the IANB. The lingual nerve was affected in 89.0% of the cases.

Only one type of anesthetic was used in 226 of the 248 cases reported and 22 cases

involved multiple anesthetics. Of the reports when only one type of anesthetic was used,

116 (51.3%) cases involved 4% articaine, 97 (42.9%) cases involved 4% prilocaine, 11

(4.9%) cases involved 2% lidocaine, one (0.4%) case involved 0.5% bupivacaine, and one (0.4%) case involved 3% mepivacaine (104).

Moore et al. showed that most persistent paresthesias are most commonly reported after oral surgical procedures in dentistry. Needle trauma and the use of local anesthetic solutions, and oral pathologies have been less frequently documented (105).

During the removal of third molars, the inferior alveolar nerve and the lingual nerve are the most likely to be injured. Bataineh et al. showed that the incidence of lingual nerve paresthesia was 0% to 23% and that of inferior alveolar nerve paresthesia was 0.4% to

8.4%. Risk factors for these surgical parasthesias included: elevation of lingual flaps and osteotomies, operator experience, tooth angulations, and vertical root sectioning (106).

Pogrel et al. evaluated 83 individuals who obtained permanent nerve involvement in the year 1995 and determined that only on rare occasion does an inferior alveolar nerve block permanently alter the sensation of the lingual nerve, the inferior alveolar nerve, or both. His results showed that the lingual nerve was affected 79% of the time and the inferior alveolar nerve was affected 21% of the time. Of the 83 cases evaluated, only 68 cases had record of which anesthetic was used. Two percent lidocaine with 1:100,000 epinephrine accounted for 33 cases (49%), 4% prilocaine with 1:200,000 epinephrine accounted for 32 cases (47%) and 3% mepivacaine without epinephrine accounted for 3 cases (4.0%). There were no cases of paresthesia associated with articaine (96); this

46 could be due to the fact that articaine was not made available in the U.S. by the FDA until the year 2000 (17).

Pogrel et al. conducted a clinical evaluation of 57 cases of paresthesia associated with local anesthetics given in dental procedures. Lidocaine was responsible for 35% of cases, articaine for 29.8% of cases, and prilocaine for 29.8% of cases (107). These numbers may be misleading as lidocaine has approximately 54% of the market share of local anesthetics in the U.S. at the time. Articaine has approximately 25% of the market share and prilocaine has approximately 6% of the market share as of March 2004 (17).

Haas et al. conducted a 21 year retrospective study of reports of paresthesia following local anesthetic administration. During the study period, 143 cases of paresthesia not associated with surgery were reported. Articaine accounted for 50 (33.6%) of the 143 cases. Prilocaine accounted for 43 (28.9%) of the 143 cases. Lidocaine accounted for 5

(3.4%) of the 143 cases. Mepivacaine accounted for 4 (2.7%) of the 143 cases (101).

Purpose

Borchard and Drouin (8) found that a lower concentration of articaine was sufficient to block an action potential when compared with other amide anesthetics.

Potocnik and colleagues (9), in a study of sensory nerve conduction in rats, found that both 2% and 4% articaine were superior to 2% lidocaine in blocking nerve conduction.

Clinical studies have reported the superior effectiveness of 4% articaine solutions over

2% lidocaine with 1:100,000 epinephrine when administered as mandibular buccal infiltration injections (1-6). There is some thought that this increased success may be due

47 to the concentration of articaine (4%) versus lidocaine (2%). A higher concentration solution may offer more molecules of anesthetic to penetrate the bone and enter the nerve sheath versus a lower concentrated solution. Although Skjevik et al. (45) demonstrated a difference in the molecular 3-dimensional shape of articaine due to internal hydrogen bonding, it is important to rule out anesthetic concentration as a source for the differences in anesthetic effectiveness.

No study has compared 4% articaine with 1:100,000 epinephrine, 4% prilocaine with 1:200,000 epinephrine, and 4% lidocaine with 1:100,000 epinephrine given as a primary infiltration injection of the mandibular first molar. Therefore, the purpose of this prospective, randomized, double-blind, crossover study was to compare the degree of pulpal anesthesia obtained with 1.8 mL of 4% articaine with 1:100,000 epinephrine, 1.8 mL of 4% prilocaine with 1:200,000 epinephrine, and 1.8 mL of 4% lidocaine with

1:100,000 epinephrine as a primary infiltration injection of the mandibular first molar.

Pain of injection, which was categorized by three phases of the injection (needle insertion, needle placement, and solution deposition) and the postoperative pain for each injection were also recorded.

Chapter 3

Materials and Methods

Sixty adult subjects participated in this study, thirty males and thirty females. All

subjects were in good health and were not taking any medications that would alter pain

perception as determined by a written health history (Appendix D) and oral questioning.

Exclusion criteria were as follows: younger than 18 or older than 65 years of age;

allergies to local anesthetics or sulfites; pregnancy; history of significant medical

conditions (ASA Class II or higher); taking any medications (over-the-counter pain relieving medications, narcotics, sedatives, anti-anxiety or anti-depressant medications) which could affect anesthetic assessment; active sites of pathosis in the area of injection; and inability to give informed consent. The Ohio State University Human Subjects

Review Committee approved the study and written informed consent and a Health

Insurance Portability and Accountability Act (HIPAA) release form was obtained from each subject (Appendix F). Female subjects were asked if they were pregnant or breastfeeding. If pregnancy was suspected or unknown, female subjects were required to take a QuickVue® pregnancy test (Quidel® Corporation, San Diego, CA).

Using a crossover design, all 60 subjects received three injections consisting of a single, primary mandibular first molar infiltration of 1.8 mL of 4% articaine with

1:100,000 epinephrine (Articadent, Dentsply Pharmaceutical, York, PA), 1.8 mL of 4% prilocaine with 1:200,000 epinephrine (Citanest Forte, Dentsply Pharmaceutical, York,

PA), and 1.8 mL of 4% lidocaine with 1:100,000 epinephrine (Central Ohio

Compounding Pharmacy, Columbus, OH), in three separate appointments spaced at least one week apart. Each subject only received one injection at each appointment.

With the crossover design, 180 infiltrations were administered for the mandibular first molar and each subject served as his or her own control. Ninety infiltrations were administered on the left side and ninety infiltrations were administered on the right side.

The same side chosen for the first infiltration injection was used again for the second and third subsequent injections. The test teeth chosen for the experiment were the mandibular first molar, mandibular second molar, and mandibular first and second premolars. The mandibular contralateral canine was used as the control to ensure that the pulp tester was operating properly and that the subject was responding appropriately. A visual and clinical examination was conducted prior to subject inclusion to ensure that all test teeth were free of caries, large restorations, crowns, periodontal disease, and that none had a history of trauma or sensitivity.

Before the injection, at all three appointments, the experimental teeth and the contralateral canine (control) were tested 2 times with the electric pulp tester (EPT)

(Kerr, Analytic Endodontics, Redmond, WA) to ensure tooth vitality and obtain baseline

information. The subject held the metal end of the lip clip between their thumb and

forefinger. This was attached to the EPT probe handle by a wire and ensured grounding

of the system. The teeth were isolated with cotton rolls and dried with an air syringe.

Crest Prohealth® toothpaste (Proctor & Gamble Co., Cincinnati, OH) was applied to the

EPT probe tip which was placed in the middle third of the buccal surface of the tooth

being tested. The subject was asked to raise their hand when they felt the current in their

tooth and the probe was removed, or drop the metal lip clip from their thumb and finger

which would interrupt the current. The value at the initial sensation of each of the teeth

tested was recorded. If the patient did not feel any sensation on one of the potential test

teeth on the designated side to be tested, the contralateral side of the mandible was

evaluated. If there were teeth that did not respond vital to the EPT on both sides of the

posterior mandible, the subject was not eligible to participate in the study. This did not

occur with any subjects. The current rate was set at 25 seconds to increase from no

output (0) to the maximum output (80). Trained personnel, who were blinded to the

anesthetic formulations utilized at each subject event, administered all pre-injection and

post-injection pulp tests.

Before the experiment, the participants were randomly assigned a six-digit

identification number using a random number generator. Each subject was randomly

assigned to determine the order of the 3 anesthetic formulations that was administered at

each appointment. A master list with the subject’s six-digit number and the order of which they received the anesthetic formulations was kept with the receptionist in the graduate endodontic clinic. A research assistant had access to the master list and would

51 refer to it prior to preparing the anesthetic formulations. Only the random numbers were recorded on the data collection sheets to further blind the experiment. A master list was kept with each patient’s random number and combination of anesthetic formulations.

The principle investigator and co-investigator had access to this master list.

Under sterile conditions, 1.8 mL of 4% articaine or 4% prilocaine solutions were loaded into separate, sterile 5 mL Luer-Lok disposable syringes (Becton-Dickinson &

Co., Rutherford, NJ) by aspirating the standard cartridge contents using 30-gauge needles into appropriate syringes by trained personnel and not the principal investigator. Thus, the principal investigator was blinded to which anesthetic formulation was being administered. All anesthetic solution cartridges were checked to ensure that the anesthetic solution was not expired. Each formulation contained either 72 mg of 4% articaine (18 µg epinephrine) or 4% prilocaine (9 µg epinephrine).

For the 4% lidocaine formulation, syringes were prepared as follows: under sterile conditions, 1.8 mL of 4% lidocaine (Central Ohio Compounding Pharmacy,

Columbus, OH) was drawn into a sterile 5 mL Luer-Lok disposable syringe using a 30- gauge needle (Becton-Dickinson & Co., Rutherford, NJ). To this syringe 18 µg of epinephrine from a 1 mL ampule of 1:1000 epinephrine (Abbott Laboratories, North

Chicago, IL) was added using a calibrated micropipette (Sherwood Medical, St. Louis,

MO). The micropipette was calibrated according to the settings in the user manual. The

1:1000 epinephrine ampules were only used once and then discarded. The 1.8 mL formulation contained 72 mg of 4% lidocaine with 18 µg epinephrine.

The infiltration injections were administered using the syringes equipped with a

27-gauge 1¼-inch needle (Monoject; Sherwood Services, Mansfield, MA). Before the

infiltration injection, each subject was instructed on how to rate the pain for each phase of

the injection: needle insertion, needle placement, and deposition of anesthetic solution

using a Heft-Parker visual analogue scale (VAS) (Appendix G). The VAS was divided

into four categories. No pain corresponded to 0 mm. Mild pain was defined as greater

than 0 mm and less than or equal to 54 mm. Mild pain included the descriptors of

“faint”, “weak”, and “mild” pain. Moderate pain was defined as greater than 54 mm but

less than 114 mm. Moderate pain included the descriptor “moderate”. Severe pain was

defined as equal to or greater than 114 mm. Severe pain included the descriptors

“strong”, “intense” and “maximum possible”. During each phase of the injection, the

principal investigator informed the subject when each phase of the injection was

completed. Immediately after the infiltration, the subject rated the pain for each injection

phase by marking an “X” on the point on the line that best described the pain on the

VAS. The principal investigator informed the patient of each phase of the injection.

Before each injection, the mucosa was dried with a 2”x2” piece of gauze and 0.2

mL topical anesthetic gel (20% Benzocaine, Patterson Dental Supply, Inc., St. Paul, MN)

was passively placed with a cotton tip applicator for 60 seconds at the injection site. A

mandibular infiltration injection was administered, at three separate appointments, using

1.8 mL 4% articaine with 1:100,000 epinephrine, 1.8 mL 4% prilocaine with 1:200,000 epinephrine, and 1.8 mL 4% lidocaine with 1:100,000 epinephrine, given in random order as determined by the random number list. The injection target site was centered over the

53 buccal root apices of the mandibular first molar. The lip was gently retracted and the 27- gauge needle was gently placed into the alveolar mucosa (needle insertion phase) with the face of the bevel directed towards the bone, and was advanced within two to three seconds until the needle was estimated to be at or just superior to the apices of the tooth

(needle placement phase). After aspiration, the anesthetic solution was deposited over a period of 1 minute (solution deposition phase). The area where the injection was given was gently massaged for 10-15 seconds. All infiltrations were given by one operator,

(BN).

The depth of anesthesia was monitored with the EPT. At 1 minute after the infiltration injection, EPT readings were obtained for the mandibular first molar. At two minutes, the second molar and second premolar were tested. At three minutes, the first premolar and contralateral mandibular canine were tested. The testing continued in 3- minute cycles for a total of 60 minutes. The testing procedure was similar to the pre- study testing previously described. No response by the subject after the EPT reached maximum output was recorded as an 80 on the data collection sheet (Appendix I). If the tested tooth did not achieve 80 on the EPT, then whatever number achieved was recorded. At every third cycle the control tooth, the contralateral canine, was tested by an inactivated EPT to test the reliability of the subject. This was done by completely drying the tooth and the EPT tip so no contact was established and the EPT would not be activated. If the subject responded positively to an inactivated pulp tester then they were not considered reliable and were not used in the study. The subject was unaware that this was being done so as to maintain the reliability of the testing.

All subjects were asked to complete post-injection surveys after each appointment, using a similar VAS as previously described (Appendix H), immediately after the numbness wore off and again each morning upon rising for the next three days.

They were asked to rate any discomfort, soreness, or pain at the area of the injection.

Patients were also instructed to describe and record any problems, other than pain, that they experienced following the injections. The 3-day surveys were either returned directly to the co-investigator, or to the receptionist for the Graduate Endodontic clinic.

Once the last 3-day survey was turned in, each subject was paid $90. All 60 subjects turned in all of the 3-day surveys. There were no subjects who dropped out or had to be

eliminated from the study.

No response from the subject at the maximum output (80 reading) of the pulp

tester was used as the criterion for pulpal anesthesia. Anesthesia was considered

successful when two consecutive 80 readings with the EPT were recorded during the 60

minutes of testing. The time for onset of pulpal anesthesia was recorded as the first of

two consecutive 80 readings. The duration was measured from the first of two

consecutive 80 readings, to the last of consecutive 80 readings. Values were entered for

each individual tooth for the duration of the 60 minutes. Each value was entered as either

having pulpal anesthesia (reading of 80 on the EPT), or no pulpal anesthesia (any reading

less than 80 on the EPT).

Each anesthetic solution was tested using an Orion Star A111 pH Tester (Thermo

Scientific, Beverly, MA). Random anesthetic samples were tested 3 times, spaced 1

week apart. Before each sample was tested, the pH tester was calibrated using pH buffers

(NIST Traceable Solution, OAKTON®, Vernon Hills, IL)

With a non-directional alpha risk of 0.05 and assuming a total proportion of

discordant pairs of 0.5, a sample size of 60 subjects was required to demonstrate a

difference of ±25 percentage points in anesthetic success with a power of 0.82. With a

non-directional alpha risk of 0.05 and assuming a standard deviation of 30.3, a sample

size of 60 subjects provided a power of 0.82 to demonstrate a difference ± 15 points in

pain on the visual analogue scale.

The data from this study were collected and statistically analyzed. Comparisons between the anesthetic formulations for anesthetic success, and incidence of pulpal anesthesia were made using multiple McNemar tests with p-values adjusted using the step-down Bonferroni method of Holm. Differences between the anesthetic formulations for needle insertion pain, needle placement pain, solution deposition pain, and postoperative pain were assessed using analysis of variance and the Tukey procedure.

Differences in onset times were analyzed using multiple Wilcox, matched-pairs, signed- ranks tests with p-values adjusted using the step-down Bonferroni method of Holm.

Comparisons were considered significant at p<0.05.

(1:1000) used in this study were sampled separately three times, then as a proportionately

56 mixed solution. An Orion Star AIII pH meter (Thermo Scientific) was used to measure pH. The data were analyzed using an analysis of variance and the Tukey procedure.

Chapter 4

Results

Sixty subjects participated in this study, 30 males and 30 females, ranging in age from 20 to 38 years. The average age of all participants was 25.8 years (Table 1).

The mean VAS pain ratings for needle insertion for the anesthetics were as follows: articaine (32.2±22.3 mm), lidocaine (31.2±20.1 mm), and prilocaine (32.5±21.5 mm) (Table 2). There was no significant difference between needle insertion between any of the anesthetics (p>0.05). The means for all three anesthetics fell into the “mild” category on the VAS. Table 4 shows the summary of pain ratings for needle insertion for each anesthetic group using a numerical scale. For articaine, 51 subjects (85.0%) reported “none” to “mild” pain and 9 subjects (15.0%) reported “moderate” to “severe” pain. For lidocaine, 53 subjects (88.3%) reported “none” to “mild” pain and 7 subjects

(11.7%) reported “moderate” to “severe” pain. For prilocaine, 51 subjects (85.0%) reported “none” to “mild” pain and 9 subjects (15.0%) reported “moderate” to “severe” pain. There were no subjects who reported “severe” pain for needle insertion for each anesthetic group (Table 4).

The mean VAS pain ratings for needle placement for the anesthetics were as follows: articaine (33.1±28.0 mm), lidocaine (33.0±28.2 mm), and prilocaine (34.3±30.4 mm) (Table 2). There was no significant difference between needle placement between any of the anesthetics (p>0.05). The means for all three anesthetics fell into the “mild” category on the VAS. Table 5 shows the summary of pain ratings for needle placement for each anesthetic. For articaine, 49 subjects (81.7%) reported “none” to “mild” pain and 11 subjects (18.3%) reported “moderate” to “severe” pain. For lidocaine, 54 subjects

(90.0%) reported “none” to “mild” pain and 6 subjects (10.0%) reported “moderate” to

“severe” pain. For prilocaine, 49 subjects (81.7%) reported “none” to “mild” pain and 11 subjects (18.3%) reported “moderate” to “severe” pain (Table 5).

The mean VAS pain ratings for solution deposition for the anesthetics were as follows: articaine (52.3±29.6 mm), lidocaine (50.4±25.1 mm), and prilocaine (40.7±25.0 mm) (Table 2). There was no significant difference between solution deposition between any of the anesthetics (p>0.05). The means for all three anesthetics fell into the “mild” category on the VAS, although the articaine group was on the verge of the moderate category (>54mm). Table 6 shows the summary of pain ratings for solution deposition for each anesthetic. For articaine, 38 subjects (63.3%) reported “none” to “mild” pain and 22 subjects (36.7%) reported “moderate” to “severe” pain. For lidocaine, 44 subjects

(73.3%) reported “none” to “mild” pain and 16 subjects (26.7%) reported “moderate” to

“severe” pain. For prilocaine, 45 subjects (75.0%) reported “none” to “mild” pain and 15 subjects (25.0%) reported “moderate” to “severe” pain (Table 6).

Solution deposition had the highest pain ratings compared to both needle insertion and needle placement ratings for all anesthetic groups. Articaine solution deposition was significantly more painful than articaine needle insertion (p=0.0003), and articaine needle placement (p=0.0008). Lidocaine solution deposition was significantly more painful than lidocaine needle insertion (p=0.0008), and lidocaine needle placement (p=0.0040).

Prilocaine solution deposition had a higher mean pain rating than prilocaine needle insertion (p=0.6771), and prilocaine needle placement (p=0.8886). However, the differences were not significant (Table 2).

There were no significant differences between males and females for any of the injection stages or between anesthetic groups. Females generally reported more pain for each anesthetic group and each stage of the injection. For solution deposition, females rated their pain in the “moderate” category (>54mm) for articaine and lidocaine, but in the “mild” category (<54mm) for prilocaine.

Anesthetic success was defined as receiving 80/80 (maximum reading) on an electric pulp tester (EPT) for two consecutive test periods at any time during the 60- minute testing period. The second molar success rates were as follows: 61.7% for articaine, 45.0% for lidocaine, and 36.7% for prilocaine. Articaine was significantly more successful than lidocaine (p=0.0309, adjusted p=0.1862) and prilocaine (p= 0.0015, adjusted p=0.0179). There was no significant difference between lidocaine and prilocaine (p= 0.3693, adjusted p=1.0000) (Table 7).

The first molar success rates were as follows: 55.0% for articaine, 33.3% for lidocaine, and 31.7% for prilocaine. Articaine was significantly more successful than

lidocaine (p=0.0024, adjusted p=0.0259) and prilocaine (p=0.0094, adjusted p=0.0842).

There was no significant difference between lidocaine and prilocaine (p=1.0000, adjusted

p=1.0000) (Table 7).

The second premolar success rates were as follows: 58.2% for articaine, 38.2%

for lidocaine, and 30.9% for prilocaine. Articaine was significantly more successful than

lidocaine (p=0.0266, adjusted p=0.1862) and prilocaine (p=0.0026, adjusted p=0.0260).

There was no significant difference between lidocaine and prilocaine (p=0.4807, adjusted

p=1.0000) (Table 7).

The first premolar success rates were as follows: 50.0% for articaine, 41.4% for

lidocaine, and 31.0% for prilocaine. There was no significant difference between

articaine and lidocaine (p=0.3593, adjusted p=1.0000) and lidocaine and prilocaine

(p=0.1796, adjusted p=0.8978). Articaine was significantly more successful than

prilocaine (p=0.0127, adjusted p=0.1018). Articaine was better than lidocaine and

prilocaine for all teeth (Table 7).

The EPT readings for all three anesthetics broken down by time intervals can be

seen in Tables 8-11. Tables 8 and 9 report the percentage of 80/80 EPT readings for all three anesthetics for the second molar and first molar, respectively. It shows that percent pulpal anesthesia peaks between minutes 25 and 28, then begins to drop-off after minute

28. Tables 10 and 11 report the percentage of 80/80 EPT readings for all three

anesthetics for the second premolar and first premolar, respectively. It shows that percent

pulpal anesthesia peaks between 25 and 28 minutes, but the drop-off from pulpal

anesthesia is more gradual than for the second and first molar.

Mean onset times for each anesthetic and for each tooth can be seen in Table 12.

The mean onset time (minutes) for the second molar was 7.0±6.2 for articaine, 13.9±13.4 for lidocaine, and 8.5±9.1 for prilocaine. For the second molar, there was a significant difference between the onset of articaine and prilocaine (p=0.0000), and there were no significant differences between articaine and lidocaine (p=0.3736) and between lidocaine and prilocaine (p=0.0000). The mean onset time for the first molar was 11.6±11.4 for articaine, 10.8±7.8 for lidocaine, and 8.4±6.4 for prilocaine. For the first molar, there was a significant difference between articaine and prilocaine (p=0.0000), however, there were no significant differences between lidocaine and prilocaine and between articaine and lidocaine (p=0.0000 for both). The mean onset time for the second premolar was

8.3±5.8 for articaine, 6.0±3.9 for lidocaine, and 7.0±3.1 for prilocaine. For the second premolar, there was a significant difference between articaine and prilocaine (p=0.0000), however, there were no significant differences between lidocaine and prilocaine and between articaine and lidocaine (p=1.0000 for both). The mean onset time for the first premolar was 5.8±2.2 for articaine, 6.8±5.8 for lidocaine, and 7.0±3.1 for prilocaine. For the first premolar, there was a significant difference between articaine and prilocaine

(p=0.0000), however, there were no significant differences between lidocaine and prilocaine and between articaine and lidocaine (p=1.0000 and p=1.0000, respectively).

According to the results shown in Table 12, the first premolar generally achieved successful pulpal anesthesia the fastest, followed by the second premolar, the first molar, and the second molar.

The mean postoperative VAS pain ratings for Day 0 for the anesthetic groups

were as follows: articaine (37.4±27.4 mm), lidocaine (23.0±19.1 mm), and prilocaine

(21.9±19.9). On Day 0, articaine caused significantly more pain than lidocaine

(p=0.0038) and significantly more pain than prilocaine (p=0.0011). There were no

significant differences between the anesthetic groups on Day 1, Day 2, and Day 3. Mean

pain ratings for all three anesthetics fell into the “mild” category on the VAS. Pain

generally decreased for all anesthetic groups from Day 0 through Day 3 (Table 13).

A summary of pain ratings for articaine at each postoperative day can be seen in

Table 14. For Day 0, 47 subjects (78.3%) reported “none” to “mild” pain and 13 subjects

(21.7%) reported “moderate” to “severe” pain. For Day 1, 55 subjects (91.7%) reported

“none” to “mild” pain and 5 subjects (8.3%) reported “moderate” to “severe” pain. For

Day 2, 57 subjects (95.0%) reported “none” to “mild” pain and 3 subjects (5.0%) reported “moderate” to “severe” pain. For Day 3, 57 subjects (95.0%) reported “none” to

“mild” pain and 3 subjects (5.0%) reported “moderate” to “severe” pain. There were no subjects who reported “severe” pain for any postoperative day for articaine (Table 14).

A summary of pain ratings for lidocaine at each postoperative day can be seen in

Table 14. For Day 0, 55 subjects (91.7%) reported “none” to “mild” pain and 5 subjects

(8.3%) reported “moderate” to “severe” pain. For Day 1, 57 subjects (95.0%) reported

“none” to “mild” pain and 3 subjects (5.0%) reported “moderate” to “severe” pain. For

Day 2, 58 subjects (96.7%) reported “none” to “mild” pain and 2 subjects (3.3%) reported “moderate” to “severe” pain. For Day 3, 59 subjects (98.3%) reported “none” to

“mild” pain and 1 subject (1.7%) reported “moderate” to “severe” pain. There were no subjects who reported “severe” pain for any postoperative day for lidocaine (Table 14).

A summary of pain ratings for prilocaine at each postoperative day can be seen in

Table 14. For Day 0, 58 subjects (96.7%) reported “none” to “mild” pain and 2 subjects

(3.3%) reported “moderate” to “severe” pain. For Day 1, 56 subjects (93.3%) reported

“none” to “mild” pain and 4 subjects (6.7%) reported “moderate” to “severe” pain. For

Day 2, 57 subjects (95.0%) reported “none” to “mild” pain and 3 subjects (5.0%) reported “moderate” to “severe” pain. For Day 3, 59 subjects (98.3%) reported “none” to

“mild” pain and 1 subject (1.7%) reported “moderate” to “severe” pain. There were no subjects who reported “severe” pain for any postoperative day for prilocaine (Table 14).

A summary of mean postoperative pain by postoperative day and gender can be seen in Table 15. For Day 0, females reported significantly more pain than males for articaine (p=0.0186), while for lidocaine and prilocaine there was no significant difference (p=0.9985, and p=1.0000, respectively). For Day 1, there was no significant difference between males and females for articaine, lidocaine, or prilocaine (p=0.2033, p=0.9516, and p=0.9986, respectively). For Day 2, there was no significant difference between males and females for articaine, lidocaine, and prilocaine (p=0.5200, p=1.0000, and p=1.0000, respectively). For Day 3, there was no significant difference between males and females for articaine, lidocaine, and prilocaine (p=1.0000, p=1.000, and p=1.0000, respectively). Overall, females reported more postoperative pain than males for each anesthetic and for each postoperative day.

A summary of postoperative complications by anesthetic for each postoperative day can be seen in Table 16. Tenderness to palpation at the injection site was the most common postoperative complication, followed by subjective swelling at the injection site, pain on opening, prolonged numbness, headache, light-headedness, and nausea. The number of subjects who experienced tenderness to palpation at the injection site with articaine was 8.7% for Day 0, 16.7% for Day 1, 5.0% for Day 2, and 0% for Day 3. The number of subjects who experienced tenderness to palpation at the injection site with lidocaine was 8.3% for Day 0, 16.7% for Day 1, 8.3% for Day 2, and 8.3% for Day 3.

The number of subjects who experienced tenderness to palpation at the injection site with prilocaine was 3.3% for Day 0, 10.0% for Day 1, 10.0% for Day 2, and 8.3% for Day 3.

The number of subjects who experienced swelling at the injection site with articaine was

10.0% for Day 0, 3.3% for Day 1, 3.3% for Day 2, and 0% for Day 3. The number of subjects who experienced swelling at the injection site for lidocaine was 5.0% for Day 0, and 0% for Day 1, Day 2, and Day 3. The number of subjects who experienced swelling at the injection site with prilocaine was 1.7% for Day 0, 1.7% for Day 1, and 0% for Day

2 and Day 3. The number of subjects who experienced pain on opening with articaine was 3.3% for Day 0, 1.7% for Day 1, and 0% for Day 2 and Day 3. Only 1.7% of subjects experienced pain on opening with lidocaine and prilocaine, both of which were on Day 2. The number of subjects who experienced prolonged numbness was 3.3% for

Day 0 for each solution. This complication resolved by the next day. The number of subjects who experienced a headache was 1.7% for Day 0 for articaine and lidocaine.

Only 1.7% of subjects experienced light-headedness for articaine at Day 0. Only 1.7% of

subjects experienced nausea for lidocaine at Day 1. Due to the low number of

incidences, no statistical analysis was performed on postoperative complications (Table

16).

Chapter 5

Discussion

Sixty adult subjects participated in this study, 30 males and 30 females, ranging in age from 20 to 38 years. The average age of all subjects was 25.8 years, with the average ages of females being 25.5 years and the average age of males being 26.1 years (Table 1).

Nordenram et al. (108) compared the effect of infiltration anesthesia of lidocaine, prilocaine, and mepivacaine between healthy elderly subjects and younger subjects. The author showed that elderly subjects had a highly significantly shorter onset time compared to the young group. The possible explanations for this shorter onset time are: a higher pain threshold, decreased vascularity, and an increased amount of secondary dentin formation in the elderly subjects. Therefore, subjects older than 65 years of age were excluded from this study. Subjects under the age of 18 were excluded from this study because it was required that subjects provide their own consent (Appendix E) and subjects younger than 18 years of age are considered minors and are not able to do so under state law. Therefore the results of this study may not hold true for these two age groups.

As stated earlier, an equal number of males and females were used for this study.

Several studies have shown that men and women tend to report pain differently (109-

111). Liddell et al. showed that females tend to report to have more anxiety and fear than

males about receiving dental treatment (109). Keogh et al. reported that females had a

significantly lower tolerance for cold pressor pain than males (110). Fillingim et al.

studied thermal pain thresholds between men and women and showed that women

reported a significantly lower thermal pain threshold, warmth detection threshold, and

thermal pain tolerance than men (111). Therefore, an equal number of men and women

were used in this study in order to balance the potential influence of gender on the overall

results. If a disproportionate number of women or men were used for this study, the

results of the pain of the various stages of the injection and postoperative pain may not be indicative of the general population. To better represent the population as a whole, it was best to use an equal number of males and females.

All subjects who participated in this study were required to complete a written health history (Appendix D) and oral questioning about their health status. Subjects who had any known allergy to local anesthetics, were pregnant, had a history of significant medical conditions (ASA Class II or higher), were currently taking any medications

(over-the-counter pain relieving medications, narcotics, sedatives, anti-anxiety, or anti-

depressant medications) which could affect anesthetic assessment, had active sites of

pathosis in the site of injection, or were unable to give informed consent were also

excluded from the study. These exclusion criteria existed because we wanted to

eliminate as many independent variables from the study, such as anything that could alter

the metabolism or efficacy of a local anesthetic. Pain medications (narcotics and

sedatives) and anxiolytic drugs could alter the perception of the amount of pain

experienced during the injection, which could potentially alter the results. Furthermore,

many local anesthetics, such as: lidocaine, prilocaine, and to a lesser extent articaine, are

metabolized in the liver. Any medications that are metabolized in the liver may alter the

metabolism of local anesthetics, which could either prolong or shorten the duration of the

anesthetics. Pregnant patients were eliminated because articaine is classified as

pregnancy category C. As described in the literature review section, drugs classified as

pregnancy category C are as follows: “No adequate and well-controlled studies have been performed in pregnant women, but animal reproduction studies are lacking or have shown an adverse effect on the fetus.” (12).

Mandibular Buccal Infiltration Pain

Before the infiltration injection, each subject was instructed on how to rate the

pain for each phase of the injection: needle insertion, needle placement, and deposition of

the anesthetic solution using a Heft-Parker visual analogue scale (VAS) (Appendix G).

The VAS was divided into four categories. No pain corresponded to 0 mm. Mild pain

was defined as greater than 0 mm and less than or equal to 54 mm. Mild pain included descriptors of “faint”, “weak”, and “mild” pain. Moderate pain was defined as greater than 54 mm but less than 114 mm. Moderate pain included the descriptor of “moderate”.

Severe pain was defined as equal to or greater than 114 mm. Severe pain included the descriptors “strong”, “intense”, and “maximum possible”. Heft and Parker (112) reported that using a scale that had characteristic spacing of quantitative values that were not homogenous (evenly spaced), which also included meaningful words such as: “faint”,

“weak”, “mild”, “moderate”, “strong”, and “intense” were best for rating pain. Kreimer et al. (86) investigated the anesthetic efficacy of 2% lidocaine with 1:100,000 epinephrine and 2% lidocaine with 1;100,000 epinephrine combined with mannitol given as an inferior alveolar nerve block (IANB) and used a 170 mm VAS and numerical scale which consisted of 4 pain ratings from 0 (no pain) to 4 (severe pain), to rate the pain. The authors found a high correlation between the VAS and the numerical scale. However, the

VAS was easier to analyze statistically than the numerical scale. Therefore, a 170 mm

VAS was used to rate the pain from the injection and postoperative pain in the current study.

Prior to each injection, 0.2 mL of topical anesthetic (20% benzocaine gel) was passively placed adjacent to the mandibular first molar with a cotton tip applicator for 1 minute. Robertson et al. (2), Pabst et al. (67), McEntire et al. (73), and Martin et al. (74) all reported using topical anesthetic at the injection site for a mandibular buccal infiltration. This study wished to mimic the methods of those studies so that comparisons in results could be made. Mikesell et al. reported no significant difference between 0.2 mL of 20% benzocaine compared to a placebo for infiltration injections for the maxillary lateral incisor for the needle insertion phase of the injection (113). Nusstein et al. also reported that 20% benzocaine had no effect on needle insertion for inferior alveolar nerve

70 block and maxillary posterior buccal infiltration injections. However, they did show that topical anesthetic reduced the amount of needle insertion pain for maxillary anterior infiltrations (114). Martin et al. (115) investigated the pharmacological and psychological effects of topical anesthesia. Subjects were assigned to one of two groups: one group was led to believe that they were the placebo group, and the other group was led to believe that they would receive the active topical anesthetic. However, all subjects received the same set of injections with the same treatment. One injection was preceded by the placebo, and one injection was preceded by the active topical anesthetic. Whether injections were preceded by the placebo or the active topical anesthetic did not alter the subjects’ reported pain. Subjects who believed that they were receiving the active topical anesthetic anticipated significantly less pain than subjects who thought they were receiving the placebo. Nusstein et al. reported no significant difference between 0.2 mL of 20% benzocaine and a placebo prior palatal anterior superior alveolar nerve block

(116). Gill and Orr reported that topical anesthetic application for 1 minute is effective for maxillary infiltrations, but had no significant difference when compared with a placebo for an inferior alveolar nerve block (117). These studies suggest that the mere knowledge by the patient that they are receiving topical anesthetic could lower the pain scores caused by needle insertion. Kohli et al. (118) surveyed 3,051 pediatric dentists and reported that the majority of dentists used topical anesthetic prior to local anesthetic injections in private practice. Due to the placebo effect and since most dentists think that topical anesthetic reduces the pain of the injection, topical anesthetic was used in the current study. To date, no studies have compared the use of benzocaine as a topical

anesthetic versus a placebo for mandibular buccal infiltration injections. This would be a

possible area for further research.

Pain on Needle Insertion

A summary of pain ratings for needle insertion using a numerical scale (0-3) can be seen in Table 4. Regardless of type of anesthetic used, there was no significant difference between males and females for needle insertion pain (p=0.1897). As seen in

Table 3, when comparing needle insertion pain reported by males and females for each anesthetic group, females consistently reported higher mean levels of pain for needle insertion. However, mean pain for each anesthetic group was in the “mild” category on the VAS. There was no significant difference between males and females when comparing needle insertion pain for articaine, lidocaine, and prilocaine (p=0.9968, p=0.8931, and p=1.0000, respectively). Table 4 shows that, overall, 86.1% of subjects

(males and females) reported needle insertion for all anesthetics in the none-to-mild pain

category, while 13.9% of subjects reported pain in the moderate-to-severe category. For

articaine, 51 subjects (85.0%) reported none-to-mild pain and 9 subjects (15.0%) reported

moderate-to-severe pain. For lidocaine, 53 subjects (88.3%) reported none-to-mild pain and 7 subjects (11.7%) reported moderate-to-severe pain. For prilocaine, 51 subjects

(85.0%) reported none-to-mild pain and 9 subjects (15.0%) reported moderate-to-severe

pain. There were no subjects who reported “severe” pain for needle insertion in any

anesthetic group (Table 4). All injections were given by the principal investigator (B.N.);

therefore, potential operator difference was controlled and was not a confounder in this

study. Keogh et al. (110) and Fillingim et al. (111) reported that females had lower

thresholds for pain than males when testing thermal stimuli; this could be the reason that

females reported more pain than males did in the current study. Each subject received all

three injections on the same side of the mandible. This eliminated potential physiologic

differences between sides. To further control the study, subjects and operator were

blinded to which anesthetic was given at each appointment. Each solution was given in

an unmarked 5 mL Luer-Lok syringe using a 27-gauge needle.

Pain ratings for 4% articaine in this study can be compared to studies which also

investigated 4% articaine given at the same injection site using a 170 mm VAS. After

using 0.2 mL of 20% benzocaine, Robertson et al. (2) administered 1.8 mL of 4%

articaine with 1:100,000 epinephrine as a primary buccal infiltration injection adjacent to

the mandibular molar using a 27-gauge needle. Using a 170 mm VAS, they reported a mean of 24 mm for needle insertion pain for the 4% articaine solution and 27 mm for needle insertion pain for the 2% lidocaine solution. No significant difference was found between genders for articaine needle insertion (p=0.9998). In this study, for articaine needle insertion, females reported a mean of 26.6 mm and males reported a mean of 21.2 mm on the VAS. For lidocaine needle insertion, there was no significant difference between males and females (p=1.0000). Females reported a mean of 28.5 mm, and males reported a mean of 25.5 mm on the VAS. All were considered “mild” pain. Pabst et al.

(67) used 0.2 mL of 20% benzocaine, then administered 1.8 mL of 4% articaine with

1:100,000 epinephrine as a primary buccal infiltration injection adjacent to the

mandibular first molar, followed by an additional infiltration injection with the same

solution at the same site with a 27-gauge needle. Using a 170 mm VAS, they reported a

pain level of 20-22 mm for initial injection needle insertion. No significant difference

was found between females and males (p=1.0000), but females did report more pain than

males (21.4 mm and 17.8 mm, respectively). McEntire et al. (73) applied 0.2 mL of 20%

benzocaine, prior to administration of 1.8 mL of 4% articaine with 1:100,000 and 1.8 mL

of 4% articaine with 1:200,000 epinephrine as primary buccal infiltration injections

adjacent to the mandibular first molar with a 27-gauge needle. Using a 170 mm VAS, the

mean pain rating for needle insertion for both solutions was 37 mm, which was

considered “mild” pain. However, contrary to the current study, females reported less

pain for needle insertion than males. For articaine with 1:100:000 epinephrine, females

reported a mean pain rating of 34.2 mm, while males reported a mean pain rating of 39.7

mm. For articaine with 1:200,000 epinephrine, females reported a mean pain rating of

32.0 mm, while males reported a mean pain rating of 42.4 mm (all “mild” pain). The

results between genders were not significantly different (p>0.05 for both solutions).

Martin et al. (74) applied 0.2 mL of 20% benzocaine, then administered 1.8 mL of 4%

articaine with 1:100,000 epinephrine as a primary buccal infiltration injection adjacent to

the mandibular first molar with a 27-gauge needle. Utilizing a 170 mm VAS, the overall mean pain rating for needle insertion was 27.0 mm. Females reported less pain (22.6 mm) than males (31.0 mm) for needle insertion. The difference between genders was not significant (76). These studies reported pain level means in the “mild” category on the

VAS, which is comparable to the results of the current study. Possible explanations for differences in needle insertion pain between the studies could be: gender of the patient

74 and depth and location of the needle insertion, which in all studies was approximated, not measured, to be at the apex of the mandibular first molar. Otto et al. (119) reported that operator gender had no significant difference in perceived subject pain on electrical stimulation of the patient’s finger. Female subjects reported a significantly lower pain threshold and pain tolerance than male subjects. Lehtinen and Oksala (120) reported a significant difference between needle designs for needle insertion pain. Needles that had a sharper angle profile required less force to penetrate the tissue and produced less pain.

The type of anesthetic used should not influence the pain of needle insertion because no solution was deposited as the needle penetrated the mucosa in this study. The current study used a Luer-Lok syringe. It is possible that there could be differences in needle insertion pain between a Luer-Lok syringe and a standard syringe as the tactile feel of the two syringes is not the same. The results of the current study showed no significant difference in needle insertion pain and the mean pain ratings were all in the mild range.

Several other studies have reported on the pain of injection of a mandibular buccal infiltration injection using articaine. However these studies did not breakdown the pain of the injections into the three stages (needle insertion, needle placement, and solution deposition). Kanaa et al. (1) administered 1.8 mL of 4% articaine with

1:100,000 epinephrine as a primary buccal infiltration injection and recorded pain on a

100 mm VAS. No topical anesthetic was used, and the solution was delivered using a 30- gauge needle. The mean pain rating for articaine was 20.9 mm on the 100 mm VAS, which corresponds to 35.5 mm on a 170 mm VAS. This would be categorized as “mild” pain. Corbett et al. (4) also used a 100 mm VAS to assess the injection pain of 1.8 mL of

4% articaine with 1:100,000 epinephrine given as a primary buccal infiltration injection of the mandibular first molar. No topical anesthetic was used. Articaine had a mean pain rating of 20.9 mm, which on a 170 mm VAS corresponds to 35.5 mm. This also would be considered “mild” on a 170 mm VAS. Abdulwahab et al. (5) administered 0.9 mL of

4% articaine with 1:100,000 epinephrine and 0.9 mL of 4% articaine with 1:200,000 epinephrine, at separate appointments, as a primary buccal infiltration injection adjacent to the mandibular first molar. A 30-gauge needle was used without topical anesthetic. A

100 mm VAS was used to rate pain. Articaine with 1:100,000 epinephrine had a mean pain rating 26.2 mm and articaine with 1:200,000 epinephrine had a mean pain rating of

24.1 mm, which corresponds to 41.0 mm and 46.9 mm, respectively. Both of these are considered “mild” on a 170 mm VAS. These studies (1, 4, 5) did not use a topical anesthetic and, as mentioned earlier, did not break down the pain of the injection into the categories of needle insertion, needle placement, and solution deposition. The reported

VAS values are from the injection as a whole. The studies also did not look at differences between genders for pain, and only Abdulwahab et al. (5) mentioned whether or not the subject numbers were gender balanced to include an equal number of males and females, which in their study 12 females and 6 males participated. Their results (1, 4,

5) showed “mild” pain, which is similar to the results in our study. It is, however, difficult to distinguish how much of the pain rated by subjects was from the needle insertion, needle placement, or the solution deposition. As seen in Table 3, the results from the current study showed that solution deposition pain was greater than needle insertion and needle placement. Other studies that were reviewed, (2, 67, 73, 74, 76) also

showed that solution deposition was more painful than the other stages of the injection,

so the pain rated in studies where the injection is not broken down by stage is likely from

the solution deposition stage of the injection, rather than needle insertion or needle

placement. However this is only speculation.

Dressman et al. (76) administered 1.8 mL of 4% articaine with 1:100,000 epinephrine in the area of the mental foramen over the second premolar and had a mean pain rating of 31 mm for needle insertion on a 170 mm VAS. Although the injections were given in the area of the mental foramen, this is in the general anatomic region where the injections were given in our study; the results were similar to those of the current study.

Abdulwahab et al. (5) is the only study to date to report injection pain using 0.9 mL if 4% prilocaine with 1:200,000 epinephrine given as a primary buccal infiltration injection adjacent to the mandibular first molar. A 30-gauge needle was used with no topical anesthetic. The author did not break down the injection by stage (needle insertion, needle placement, and solution deposition) in recording pain of injection.

Subjects reported a mean pain level of 21 mm for the injection on a 100 mm VAS, which corresponds to 35.7 mm on a 170 mm VAS. This is considered “mild” pain. The authors did not compare gender differences for pain of the injection. Twelve females and 6 males participated in the study. As previously discussed, it is difficult to compare the results of this study to the current study because the injection was rated as a whole, rather than by stage. The results however, were similar to the findings of the current study.

No study to date has investigated 4% lidocaine with 1:100,000 epinephrine given as a primary buccal infiltration injection adjacent to the mandibular first molar.

Robertson et al. (2) administered 1.8 mL of 2% lidocaine with 1:100,000 epinephrine as a primary buccal infiltration injection adjacent to the mandibular first molar. The mean pain rating for needle insertion was 27±26 mm. Although the concentration used in

Robertson’s study (2) was half the concentration used in the current study, the pain ratings were higher than in the current study, but were comparable, in that both were in the “mild” category. Kanaa et al. (1) administered 1.8 mL of 2% lidocaine with

1:100,000 epinephrine and recorded pain on a 100 mm VAS looking at the injection as a whole, not separated into three phases. A 30-gauge needle was used. The mean pain rating for lidocaine was 17.8 mm on a 100 mm VAS, which corresponds to 30.3 mm on a

170 mm VAS. This too would be categorized as “mild” pain. Abdulwahab et al. (5) administered 0.9 mL of 2% lidocaine with 1:100,000 epinephrine given as a primary buccal infiltration injection adjacent to the mandibular first molar and reported a mean pain rating of 27.6 mm on a 100 mm VAS. A 30-gauge needle was used. This rating corresponds to 46.9 mm on a 170 mm VAS. This would be considered “mild” pain and is similar to the results of our study. Both Kanaa (1) and Abdulwahab (5) did not use topical anesthetic and did not break down the pain of the injection by injection stage, rather rated the pain of the injection as a whole. Again, Abdulwahab (5) reported that 12 females and 6 males participated in the study, but did not analyze differences between genders. Kanaa (1) did not report the number of males and females who participated and did not analyze gender differences. Both of their studies showed pain ratings in the

“mild” category, but as previously discussed, it is difficult to compare the pain ratings of

our study to their studies due the fact that one is unable to distinguish the amount of pain

recorded due to needle insertion, needle placement, or solution deposition.

Overall, 86.1% of subjects reported none-to-mild pain for needle insertion with a mean VAS ranging from 31.2 mm to 32.5 mm which is in the “mild” category. The results of the current study are similar to the results of other studies where needle insertion pain is reported (2, 67, 73, 74, 76). As shown in the current study, the type of anesthetic used did not affect needle insertion pain, as no solution was deposited during this phase of the injection.

Pain on Needle Placement

The mean VAS pain ratings for needle placement for the anesthetics were as follows: 33.1±28.0 mm for articaine, 33.0±28.2 mm for lidocaine, and 34.3±30.4 mm for prilocaine (Table 2). There was no significant difference in needle placement pain

between any of the anesthetics (p>0.05). The means for all three anesthetics fell into the

“mild” category on the VAS. Table 5 shows the summary of pain ratings for needle

placement for each anesthetic. For articaine, 49 subjects (81.7%) reported none-to-mild

pain and 11 subjects (18.3%) reported moderate-to-severe pain. For lidocaine, 54 subjects (90.0%) reported none-to-mild pain and 6 subjects (10.0%) reported moderate-

to-severe pain. For prilocaine, 49 subjects (81.7%) reported none-to-mild pain and 11

subjects (18.3%) reported moderate-to-severe pain (Table 5).

There was no significant difference between males and females for needle

placement pain for each solution (p>0.05). Females did report more pain on needle

placement with each anesthetic solution than males did. Females reported a mean needle

placement pain rating of 43.3±31.7 mm for articaine, 36.8±31.0 mm for lidocaine, and

40.8±36.1 mm for prilocaine, while males reported a mean needle placement pain rating

of 22.8±19.5 mm for articaine, 29.2±25.1 mm for lidocaine, and 27.7±22.0 mm for

prilocaine. Although females reported higher levels of pain for needle placement, both

males and females reported mean pain ratings in the “mild” category on the VAS.

Table 5 shows the summary of overall pain ratings for needle placement using a numerical scale as well as ratings by gender. For needle placement overall, regardless of the anesthetic used, females reported none-to-mild pain 76.7% of the time, and reported moderate-to-severe pain 23.3% of the time. Males reported none-to-mild pain 92.2% of the time, and reported moderate-to-severe pain 7.8% of the time. Although these results are not significant, they support the theory that females will tend to report more pain than males (111).

Needle placement pain ratings for the articaine solution in this study can be compared to studies which also investigated articaine given at the same injection site using a 170 mm VAS and which also used a 27-gauge needle. Robertson et al. (2) administered 1.8 mL of 4% articaine with 1:100,000 epinephrine as a primary buccal infiltration injection adjacent to the mandibular first molar. They reported a mean of 33 mm for needle placement pain for articaine. Pabst et al. (67) administered 1.8 mL of 4%

articaine with 1:100,000 epinephrine as a primary buccal infiltration injection adjacent to

80 the mandibular first molar, followed by an additional infiltration injection with the same solution at the same site. They reported 36 mm at one appointment and 42 mm for needle placement at the other appointment. McEntire et al. (73) administered 1.8 mL of 4% articaine with 1:100,000 and 1.8 mL of 4% articaine with 1:200,000 epinephrine as primary buccal infiltration injections adjacent to the mandibular first molar. The mean pain rating for needle placement of articaine with 1:100,000 epinephrine was 37 mm and

40 mm for articaine with 1:200,000 epinephrine. Martin et al. (74) administered 1.8 mL of 4% articaine with 1:100,000 epinephrine as a primary buccal infiltration injection adjacent to the mandibular first molar. The mean pain rating for needle placement was

39 mm. These studies reported means in the “mild” category on the VAS, which is comparable to the results in the current study. Differences in needle placement pain ratings should not depend on which anesthetic is to be used if anesthetic solution is not deposited as the needle is guided through the tissues. Differences in reported pain ratings could be explained by gender differences of the operator and subject, operator skill, needle type (bevel design), speed at which the needle is guided through the tissues, and whether or not bone was sounded (contacted) during needle placement. As discussed earlier, Lehtinen and Oksala reported that bevel type (angle profile of the bevel) had a significant effect on pain of needle insertion (120). Further research on the impact of these factors on needle placement is required for this injection.

Other studies (1, 4, 5) have investigated the pain ratings when articaine is given as a primary buccal infiltration injection adjacent to the mandibular first molar. As previously discussed, these studies did not use topical anesthetic and did not break down

81 the injection by stage (needle insertion, needle placement, and solution deposition), therefore the mean pain ratings are reported for the injection as a whole. These studies also used a 100 mm VAS. Kanaa et al. (1) reported a mean of 20.9 mm, which corresponds to 35.5 mm on a 170 mm VAS when 1.8 mL of 4% articaine with 1:100,000 epinephrine was injected with a 30-gauge needle (1). Corbett et al. (4) reported a mean of 20.9 mm for 1.8 mL of 4% articaine with 1:100,000 epinephrine using a 30-gauge needle, which corresponds to 35.5 mm on a 170 mm VAS (4). Abdulwahab et al. (5) reported a mean of 26.2 mm for 0.9 mL of 4% articaine with 1:100,000 epinephrine, which corresponds to 44.5 mm on a 170 mm VAS; and a mean of 24.1 mm for 0.9 mL of

4% articaine with 1:200,000 epinephrine, which corresponds to 41 mm on a 170 mm

VAS. They used a 30-gauge needle (5). These studies (1, 4, 5) all had pain ratings in the

“mild” category, which was similar to the results of our study. Dressman et al. (76) administered 1.8 mL of 4% articaine with 1:100,000 epinephrine in the area of the mental foramen and had a mean pain rating of 25.7 mm for needle placement on a 170 mm VAS.

A 27-gauge needle was used. Although the injections were given in the area of the mental foramen, this is in the general anatomic region where the injections were given in our study.

Abdulwahab et al. (5) is only study to date to report injection pain using 0.9 mL of 4% prilocaine with 1:200,000 epinephrine given as a primary buccal infiltration injection adjacent to the mandibular first molar with a 30-gauge needle. No topical anesthetic was used in the study. The author did not break down the injection by stage

(needle insertion, needle placement, or solution deposition). Subjects reported a mean

pain rating of 21 mm on a 100 mm VAS (5), which corresponds to 35.7 mm on a 170 mm

VAS, which is considered “mild” pain on a VAS. This result is similar to our study.

Needle placement pain for 2% lidocaine with 1:100:000 epinephrine when given as a primary buccal infiltration injection adjacent to the mandibular first molar was recorded by Robertson et al. (2), who reported a mean pain rating of 32 mm on a 170 mm

VAS when using a 27-gauge needle. This was considered “mild” pain. Kanaa et al. (1) administered 1.8 mL of 2% lidocaine with 1:100,000 epinephrine with a 30-gauge needle

and recorded pain on a 100 mm VAS from the injection as a whole, not separated into

three phases (needle insertion, needle placement, or solution deposition). The mean pain

rating for lidocaine was 17.8 mm on a 100 mm VAS, which corresponds to 30.3 mm on a

170 mm VAS, which would be categorized as “mild” pain and is similar to the results of

our study (1). Abdulwahab et al. (5) administered 0.9 mL of 2% lidocaine with

1:100,000 epinephrine given as a primary buccal infiltration injection adjacent to the

mandibular first molar and had a mean pain rating of 27.6 mm on a 100 mm VAS, which

corresponds to 46.9 mm on a 170 mm VAS. This would be considered “mild” pain and

is similar to the results of our study. Both Kanaa (1) and Abdulwahab (5) did not use

topical anesthetic and used 30-gauge needles, and did not break down the pain of the

injection by injection stage, rather rated the pain of the injection as a whole. Both of the

studies showed pain ratings in the “mild” category, but as previously discussed, it is

difficult to compare the pain ratings of our study to their studies due the fact that one is

unable to distinguish the amount of pain recorded due to needle insertion, needle

placement, or solution deposition.

As previously discussed, anesthetic solution should not influence needle

placement because no anesthetic was given as the needle moved through the tissues. This

is consistent with the results of the current study as there was no significant difference

between the three solutions for needle placement. Therefore, the pain may be due to

trauma to the tissues from the needle as it is guided through the tissue.

Some studies have looked at depositing approximately 0.4 mL of anesthetic

solution as the needle was guided through the tissue for an IANB (121, 122), while other

studies have given IANB without depositing anesthetic solution during the needle

placement phase. Steinkruger et al. investigated the effect of administering 0.4 mL of

anesthetic during the needle placement phase and reported that administering solution

during this phase did not significantly reduce the pain from needle placement for an

IANB (121). McCartney et al. confirmed this when administering 0.2-0.4 mL of

anesthetic solution during the needle placement stage of an IANB (122). This could be due to the fact that the port where the anesthetic exits the needle is not at the tip, it is on the side of the bevel, so the tip of the needle is moving through the tissue ahead of the anesthetic. That is, even if local anesthetic is expressed ahead of the needle’s path, its effect may not be quick enough to overcome the speed of the needle passing through the tissue. As a result of these studies, no anesthetic was deposited during the needle placement stage.

The technique of administering a small amount of anesthetic during needle placement is different from two-stage injections, where a small amount of anesthetic is deposited just under the mucosa (usually a ¼ of a cartridge of anesthetic) prior to the

main injection. In the two-stage injection, after waiting several minutes, to allow the

mucosa to be anesthetized, the needle is inserted and guided to its destination and the rest

of the cartridge of anesthetic is administered. Nusstein et al. (121) found that females

reported significantly less pain when a two-stage injection was given for needle

placement pain. There was no significant difference for men with the two-stage

injection.

Overall, 84.4% of subjects reported none-to-mild pain for needle placement with a mean VAS ranging from 33.0 mm to 34.3 mm which is in the “mild” category. The results of the current study are similar to the results of other studies where needle placement pain is reported (2, 67, 73, 74, 76). As shown in the current study, the type of

anesthetic used did not affect needle placement pain, as no solution was deposited during

this phase of the injection.

Pain on Solution Deposition

The mean VAS pain ratings for solution deposition for the anesthetics were as

follows: articaine 52.3±29.6 mm, lidocaine 50.4±25.1 mm, and prilocaine 40.7±25.0 mm

(Table 2). There was no significant difference between solution deposition pain among any of the anesthetics (p>0.05). The means for all three anesthetics fell into the “mild” pain category on the VAS, although the articaine group was on the verge of falling in the

“moderate” pain category (≥54mm). Table 6 shows the summary of pain ratings for solution deposition for each anesthetic. For articaine, 38 subjects (63.3%) reported none-to-mild pain and 22 subjects (36.7%) reported moderate-to-severe pain. For

lidocaine, 44 subjects (73.3%) reported none-to-mild pain and 16 subjects (26.7%) reported moderate-to-severe pain. For prilocaine, 45 subjects (75.0%) reported none-to-

mild pain and 15 subjects (25.0%) reported moderate-to-severe pain (Table 6).

Articaine solution deposition was significantly more painful than needle insertion

and needle placement (p=0.0003 and p=0.0008, respectively). Lidocaine solution

deposition was significantly more painful than needle insertion and needle placement

(p=0.0008 and p=0.0040, respectively). There was no significant difference between any

stage of the prilocaine injection (p>0.05), however, the pain rating for solution deposition

was higher than needle insertion and needle placement.

There was no significant difference between males and females for solution

deposition; however, females did report a higher mean pain rating for each solution

(Table 3). Females reported a mean pain rating of 61.6±26.4 mm for articaine, 54.9±22.9

mm for lidocaine, and 49.8±22.6 mm for prilocaine. Males reported a mean pain rating

of 43.1±30.1 mm for articaine, 46.0±26.7 mm for lidocaine, 31.5±24.2 mm for prilocaine.

For each anesthetic solution, males reported a mean pain rating in the “mild” category on

the VAS. For articaine and lidocaine, females reported a mean pain rating greater than

54 mm on the VAS, which is considered “moderate” pain.

Table 6 shows the summary of pain ratings for solution deposition using a

numerical scale. For solution deposition overall, regardless of the anesthetic used,

females reported none-to-mild pain 60.0% of the time, and reported moderate-to-severe

pain 40.0% of the time. Males reported none-to-mild pain 81.1% of the time, and

reported moderate-to-severe pain 18.9% of the time. These results are consistent with

86 other studies (1, 2, 67, 73, 74, 76) where females reported more pain than males and where solution deposition pain was higher than needle placement and needle insertion pain.

Solution deposition pain ratings for articaine from this study can be compared to studies which also investigated articaine given at the same injection site and using a 170 mm VAS. Robertson et al. (2) administered 1.8 mL of 4% articaine with 1:100,000 epinephrine as a primary buccal infiltration injection adjacent to the mandibular molar.

They reported a mean of 36 mm for solution deposition pain for articaine. Pabst et al.

(67) administered 1.8 mL of 4% articaine with 1:100,000 epinephrine as a primary buccal infiltration injection adjacent to the mandibular first molar, followed by an additional infiltration injection with the same solution at the same site. They reported 34 mm for the initial solution deposition. McEntire et al. (73) administered 1.8 mL of 4% articaine with 1:100,000 and 1.8 mL of 4% articaine with 1:200,000 epinephrine as primary buccal infiltration injections adjacent to the mandibular first molar. The mean pain rating for solution deposition for both solutions was 30 mm. Martin et al. (74) administered 1.8 mL and 3.6 mL of 4% articaine with 1:100,000 epinephrine as a primary buccal infiltration injection adjacent to the mandibular first molar at two separate appointments. The mean pain ratings for solution deposition for the 1.8 mL solution, which was deposited at a rate of 1.8 mL/minutes, was 36.9 mm for males and 36.6 mm for females, which was not significantly different. The mean pain ratings for solution deposition for the 3.6 mL solution, which was deposited at a rate of 1.8 mL/minute, was 41.7 mm for males and

31.9 mm for females, which was not significantly different. There was no significant

87 difference between the pain ratings for the 1.8 and 3.6 mL solutions. A 27-gauge needle was used for all the listed studies. These studies all recorded solution deposition pain in the “mild” category on a 170 mm VAS. The mean pain rating for solution deposition in the current study was higher at 52.3 mm, but was still in the “mild” pain category on the

VAS.

Dressman et al. (76) administered 1.8 mL of 4% articaine with 1:100,000 epinephrine in the area of the mental foramen and had a mean pain rating of 32.4 mm for solution deposition on a 170 mm VAS. Although the injections were given in the area of the mental foramen, this is in the general anatomic region where the injections were given in our study, and the results were slightly lower than the results of the current study, which were in the “mild” range.

As previously discussed, Kanaa et al. (1), Corbett et al. (4), and Abdulwahab et al.

(5) all administered articaine as a primary buccal infiltration injection adjacent to the mandibular first molar. They did not break down the injection by stage and used a 100 mm VAS. Kanaa et al. (1) reported a mean pain rating of 20.9 mm (35.5 mm on a 170 mm VAS). Corbett et al. (4) reported a mean pain rating of 20.9 mm (35.5 mm on a 170 mm VAS). Abdulwahab et al. (5) reported a mean pain rating of 26.2 mm (44.5 mm on a

170 mm VAS) for articaine with 1:100,000 epinephrine and 24.1 mm (41 mm on a 170 mm VAS) for articaine with 1:200,000. Although the injections were not broken down by stage (needle insertion, needle placement, or solution deposition), all of the means were in the “mild” category on a VAS. The mean pain ratings of these studies could be a result of solution deposition pain. As previously discussed, Robertson et al. (2) showed,

and as shown in the current study, solution deposition to elicit more pain than needle

insertion and needle placement. However, Pabst et al. (67), McEntire et al. (73), and

Martin et al. (74) showed no significant difference between solution deposition and

needle placement. Pabst et al. (67) showed that solution deposition pain was greater

when an initial and repeat injection of articaine was given. When only the initial, plus mock repeat injection was given, needle placement was more painful, but not significantly. Pabst et al. (67) and Martin et al. (74) both showed that needle placement was more painful than solution deposition, but the differences were not significant. So when the injection is not broken down into three stages, the pain rated is the most pain felt at any point during the injection, which in some studies has been shown to be solution deposition, whereas in other studies it has been shown to be needle placement.

Mader et al. (123) looked at skin infiltration injections of the arm and Ram et al.

(124) looked at intraoral infiltration injections in pediatric patients and both studies warmed the anesthetic solutions above room temperature in an attempt to reduce solution deposition pain. Both studies found no significant difference between the test solutions for injection pain. Another possible influence on the pain of the solution deposition stage is the pH of the solutions. Malamed et al. (125) reported that when an anesthetic solution is alkalinized close to physiologic pH, the pain of the injection is decreased. Kashyap et al. (126) also confirmed that alkalinizing anesthetics produced significantly less pain for inferior alveolar nerve blocks, lingual and long buccal injections. However, Whitcomb et al. (127) reported that there were no significant differences between buffered and nonbuffered anesthetic solutions for pain of injection for an inferior alveolar nerve block.

With contradicting results on buffering of anesthetics, it is possible that solution pH may

affect solution deposition pain. Further research is needed in this area. The pHs of the

solutions used in this study will be explained later in the discussion.

Abdulwahab et al. (5) is the only study to date to report injection pain using 0.9

mL if 4% prilocaine with 1:200,000 epinephrine given as a primary buccal infiltration

injection adjacent to the mandibular first molar. The author did not break down the

injection by stage (needle insertion, needle placement, or solution deposition). Subjects

reported a mean pain rating of 21 mm on a 100 mm VAS, which corresponds to 35.7 mm

on a 170 mm VAS, which is considered “mild” pain on a VAS. This result is similar to

the results of the current study (5).

Solution deposition pain for 2% lidocaine with 1:100:000 epinephrine when given

as a primary buccal infiltration injection adjacent to the mandibular first molar was

recorded by Robertson et al. (2), who reported a mean pain rating of 37 mm on a 170 mm

VAS, which was considered “mild” pain. Although the concentration (2%) was half the concentration used in the current study (4%), the results are similar. As previously discussed, both Kanaa (1) and Abdulwahab (5) did not break down the pain of the injection by injection stage, rather rated the pain of the injection as a whole. Kanaa et al.

(1) gave 1.8 mL of 2% lidocaine with 1:100,000 epinephrine and Abdulwahab et al. (5) gave 0.9 mL of 2% lidocaine with 1:100,000 epinephrine as primary buccal infiltration injections adjacent to the mandibular first molar. Both Kanaa et al. (1) and Abdulwahab et al. (5) showed pain ratings in the “mild” category (30.3 mm and 46.9 mm, respectively, on a 170 mm VAS). As previously discussed, it is difficult to compare the pain ratings of

90 the current study to the studies discussed due the fact that one is unable to distinguish the amount of pain recorded due to needle insertion, needle placement, or solution deposition; however, the pain ratings from studies where the injection was not separated into stages (1, 4, 5) is most likely indicative of needle placement or solution deposition pain as those have been shown to be the most painful parts of the injection (2, 67, 73, 74).

Solution deposition speed could affect the pain associated with solution deposition. In the current study, a rate of 1.8 mL/min was used to deposit the solution.

Robertson et al. (2), Abdulwahab et al. (5), Pabst et al. (67), McEntire et al. (73), and

Martin et al. (74) all used the same rate of solution deposition. Kanaa et al. (1) and

Corbett et al. (4) used a rate of 1.8 mL/30 secs. Hochman et al. (128) reported that anesthetic solutions administered at a slower injection speed (0.005 mL/sec) significantly reduced the pain of the injection. Kudo et al. (129) confirmed this and reported that injecting anesthetics with lower pressures (30 or 160 s/mL) significantly reduced the pain of the injection. Furthermore, Kanaa et al. (130) reported that a slow injection (2.0 mL/60 seconds) was less painful than a fast injection (15 seconds) for an inferior alveolar nerve block in asymptomatic subjects.

One other possible factor, as mentioned earlier, why solution deposition may be the most painful stage of the injection could be due to the pH of the anesthetic solutions.

An analysis of the pH of the study solutions was done by taking 3 different readings of the three solutions spaced 1 week apart. Cartridges of anesthetic were randomly sampled for articaine and prilocaine. Lidocaine (4%) and the epinephrine (1:1000) used in this study were sampled separately three times, then as a proportionately mixed solution. The

91 mean pH for each of the solutions was as follows: 4% articaine with 1:100,000 epinephrine - 3.3, 4% prilocaine with 1:200,000 epinephrine- 4.0, 4% lidocaine plain –

6.2, 1:1000 epinephrine – 2.6, and 4% lidocaine with 1:100,000 epinephrine combination

- 6.1 (Table 17). All of the injected solutions were significantly different (p<0.0001). As noted earlier, the mean pain ratings on the VAS were all “mild” for each solution and there were no significant differences in pain of solution deposition; however, articaine

(52.3 mm) had the highest mean pain rating, which was close to being “moderate” on the

VAS (Table 2). Although the mean pain ratings for solution deposition were not significantly different, the pH readings for the solutions were significantly different.

Articaine had the highest pain rating for solution deposition and had the lowest pH (3.3).

This could explain why articaine was the most painful anesthetic in terms of solution deposition. However this does not explain why lidocaine, which was the most basic (pH

– 6.1), was more painful for solution deposition than prilocaine (pH - 4.0). Adding the epinephrine to the 4% lidocaine did not change the pH very much. Prilocaine had the lowest mean pain rating for solution deposition, but was almost as acidic as the articaine solution. The argument could be made that even though lidocaine approached physiologic pH (7.4), this does not necessarily mean less pain on solution deposition.

There may be other factors involved.

McKay et al. (131) compared the pain of intradermal skin infiltration injections of different formulations of lidocaine, epinephrine, and sodium bicarbonate. The authors showed that when the pH of the lidocaine solution was higher, less pain was produced.

Plain lidocaine with sodium bicarbonate, which had the highest pH (7.38), produced the

92 least amount of pain, while lidocaine with epinephrine, which had the lowest pH (4.05), produced the most amount of pain. They concluded that pH may be a factor in injection pain, but that there may also be other intrinsic properties of the local anesthetics, besides the pH, which could play a role in the pain response elicited by different anesthetics.

Morris et al. (132) compared the pain of intradermal and subcutaneous infiltration injections with different 1% anesthetic solutions. Mepivacaine, lidocaine, and etidocaine were the 1% concentration anesthetics used. The results showed that 1% etidocaine was significantly more painful than mepivacaine (p=0.00005) and lidocaine (p=0.00001).

Mepivacaine was significantly more painful than lidocaine (p=0.012). The authors concluded that the concentration (which was constant at 1%) was not the factor that caused one anesthetic to be more painful than another and that it may be something intrinsic within the chemical structure of the anesthetic.

Another possible factor that could affect the pain of solution deposition is the place where the solution is deposited. If the solution is deposited in the buccal space of the mandible, there is sufficient soft tissue into which the anesthetic solution can diffuse.

Whereas in a maxillary palatal injection, which are very painful injections, there is less space for solution diffusion. Therefore, a possible conclusion could be made that something inherent in the chemical structures of the anesthetics is what causes one anesthetic to be more painful than another. Articaine and prilocaine have the same chemical formula for the hydrophilic terminus (propylamino) while lidocaine has a diethylamino hydrophilic terminus. This difference between articaine and all other anesthetics, as described earlier, is the thiophene ring that allows articaine to collapse due

to hydrogen bond formation once the molecule contacts the lipid membrane (45).

Lidocaine has an acetoxylidide hydrochloride for its lipohillic terminus and prilocaine

has a propionotoluidide hydrochloride liphophillic terminus (17). Perhaps the molecular

structure of these anesthetics is the cause for pain. More research is needed on this topic.

Overall, 84.5% of subjects reported none-to-mild pain for solution deposition with a mean VAS ranging from 40.7 mm to 52.3 mm which is in the “mild” category. The results of the current study are similar to the results of other studies where needle insertion pain is reported (2, 67, 73, 74, 76). As shown in the current study, there were no significant differences between anesthetics for solution deposition. There were also no significant differences between stages of the injection for prilocaine. Articaine solution deposition was significantly more painful than articaine needle insertion

(p=0.0003). Lidocaine solution deposition was significantly more painful than lidocaine needle insertion (p=0.0008) and lidocaine needle placement (p=0.0040).

Anesthetic Success Definition

Before each injection, at all three appointments, the experimental teeth and the

contralateral canine (control tooth) were tested 2 times with the electric pulp tester (EPT)

to ensure tooth vitality and obtain baseline information. McDaniel and coauthors

investigated the tissue response to an EPT and concluded that there was no evidence of

soft-tissue damage in mice when the maximum current stimulation from the EPT was

delivered for 3 continuous hours (133). Therefore, using the EPT to test the vitality of

teeth every 3 minutes, for an hour would not cause soft-tissue damage.

An electric pulp tester (EPT) was chosen to test pulpal anesthesia. Certosimo et

al. reported that the results of the EPT is a valuable instrument for predicting pulpal

anesthesia (134). Dreven et al. also showed that the EPT was effective for evaluating

pulpal anesthesia for normal and asymptomatic teeth (135). Since all teeth in the current

study were vital and asymptomatic, the EPT was used to test pulpal anesthesia.

The definition of pulpal anesthetic success in the current study was achieving 2

consecutive readings at the maximum output (80/80 reading) on the EPT at any time

during the testing period. Many studies (1, 2, 4, 5, 67, 73, 74, 76) have used this same

definition to describe anesthetic success. The test teeth were tested every three minutes,

starting 1 minute after the solution deposition phase was completed. Three minutes was

used as the interval because that amount of time was needed to test all the teeth in

sequence. The average time to test a single tooth was approximately 30 seconds. Testing

4 teeth and allowing for recording of data and reapplying conducting medium took

almost 3 minutes per cycle. The mandibular molars and premolars were tested for pulpal

anesthesia for 60 minutes because it has been shown (1, 2, 4, 5, 67, 73, 74, 76) that peak

pulpal anesthesia can be expected at about 20-30 minutes post-injection but then gradually decreases. Anterior teeth were not tested because a mandibular buccal infiltration injection would not be given in this location in an attempt to anesthetize anterior teeth. The contralateral canine was tested as well to serve as a control to ensure the reliability of the subjects. The definition used shows that enough anesthetic solution was available to properly anesthetize the pulps of the teeth. A limitation of this definition is that the minimum qualifier of two consecutive readings (which could be duration of

just over three minutes) would not be sufficient time to complete any procedures in

dentistry. Also, there is no defined time when these two consecutive readings could

occur. Therefore the two consecutive readings could occur immediately after the

injection or 5-10 minutes later. Clinically this would make treatment difficult for the

dentist since they would not know onset or duration. However, there has been no better

clinical definition brought forward for this injection technique.

Robertson et al. (2), Pabst et al. (67), McEntire et al. (73), and Martin et al. (74)

showed that pulpal anesthesia was at its highest from 20-30 minutes following a mandibular buccal infiltration injection, and then decreased steadily for 20-30 minutes.

Martin et al. (74) showed that less than 10% of subjects had pulpal anesthesia for the

molars at 60 minutes. Kanaa et al. also showed a similar distribution, although their

study only tested the teeth for 30 minutes (1). Abdulwahab et al. tested the anesthetic

solutions in their study for 20 minutes (5). Since 4% lidocaine with 1:100,000

epinephrine has not been studied as a primary mandibular buccal infiltration injection, 60

minutes was used to see if it, or prilocaine could possibly produce anesthetic duration

longer than articaine.

Articaine Success

A summary of anesthetic success broken down by tooth can be seen in Table 7.

Articaine was more successful than lidocaine and prilocaine for each tooth tested. There

was no significant difference for pulpal anesthesia between lidocaine and prilocaine for

all teeth tested. For the first molar, articaine (55.0%) was significantly more successful

than lidocaine (33.3%) and prilocaine (31.7%) (p=0.0024 and p=0.0094, respectively).

The adjusted p-values were (p=0.0259 and p=0.0842, respectively). For the second molar, articaine (61.7%) was significantly more successful than lidocaine (45.0%) and

prilocaine (36.7%) (p=0.0309 and p=0.0015, respectively). The adjusted p-values were

(p=0.1862 and p=0.0179, respectively). For the second premolar, articaine (58.2%) was significantly more successful than lidocaine (38.2%) and prilocaine (30.9%) (p=0.0266 and p=0.0026, respectively). The adjusted p-values were (p=0.1862 and p=0.0260, respectively). For the first premolar, articaine (50.0%) was significantly more successful than prilocaine (31.0%) (p=0.0127, p-value=0.1018). There was no significant difference between articaine (50.0%) and lidocaine (41.4%) and between lidocaine (41.4%) and prilocaine (31.0%).

Tables 8-11 and Figures 3-6 demonstrate that the peak anesthetic success of articaine was between 25 and 28 minutes then began to gradually decrease for the tested teeth. This is clinically important because it shows that, for subjects who achieved pulpal anesthesia, approximately 20-30 minutes of working time is available when articaine is given as a primary mandibular buccal infiltration injection.

Kanaa et al. (1) and Robertson et al. (2) both administered 1.8 mL of 4% articaine with 1:100,000 epinephrine adjacent to the mandibular first molar, and using the same definition of success, the first molar achieved pulpal anesthesia 64.5%, and 87.0%, respectively. Kanaa et al. had a sample size of 31 patients and tested the teeth for 30 minutes and found a similar result to the current study, though it was almost 10% higher for the first molar and almost 20% higher than the second molar (1). Robertson et al. had

a sample size of 60 patients and tested the teeth for 60 minutes and reported the success

rates for the second molar (75.0%), second premolar (92.0%), and the first premolar

(86.0%) (2). These results were much higher than the results of the current study and

most other reported studies. Reasons for this could be related to the sample size, operator

differences (different interpretations the location of the first molar apices), reliability of

the pulp testers, and differences in patient population.

Jung et al. administered 1.7 mL of 4% articaine with 1:100,000 epinephrine

adjacent to the mandibular first molar utilizing the same definition of success, and

reported that the first molar achieved successful pulpal anesthesia 54% of the time (3).

Twenty-five subjects participated in this study and the teeth were tested for 30 minutes.

These results were similar to the current study (55%).

Corbett et al. (4) compared a buccal infiltration of 1.8 mL of 4% articaine with

1:100,000 epinephrine to 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 adjacent to the mandibular first molar and tested the teeth for 30 minutes.

Using the same definition of success, the buccal infiltration alone was successful 64.5%,

which was higher than the result of the current study. This showed higher success rates

with less volume of anesthetic. Success rate for the buccal plus lingual infiltrations was

67.7%. Thirty-one subjects participated in this study.

Pabst et al. reported the following success rates when 1.8 mL of 4% articaine with

1:100,000 epinephrine was administered adjacent to the mandibular first molar: 69.8% for the second molar, 66.3% for the first molar, 78.8% for the 2nd premolar, and 80.7%

for the first premolar (67). These results are somewhat higher, but close to the current

study for the molars. However the results for the premolars are much higher than the

results of the premolars for the current study. Eight-six subjects participated in this study.

Meechan et al. (71) compared success rates of buccal versus lingual infiltration of

1.8 mL of 4% articaine with 1:100,000 epinephrine administered adjacent to the mandibular first molar. The same definition of success was used as in the current study.

The buccal infiltration achieved successful pulpal anesthesia of 65% for the mandibular first molar and 90% for the premolar. The lingual infiltration achieved successful pulpal anesthesia of 10% for the first molar and 15% for the premolar. The results of the buccal infiltration of the first molar were again, 10% higher versus the results of the current study, while the results of premolar were much higher than the results of the current study. Meechan et al. (71), however, only had twenty subjects participate in their study.

McEntire et al. (73) investigated the anesthetic efficacy of 1.8 mL of 4% articaine with 1:100,000 epinephrine and 1.8 mL of 4% articaine with 1:200,000 epinephrine and had somewhat higher success rates to the current study when 1.8 mL of 4% articaine with

1:100,000 epinephrine was administered adjacent to the mandibular first molar. The results showed the following success rates for the solution of articaine with 1:100,000 epinephrine: 59.3% for the 2nd molar, 67.4% for the 1st molar, 84.9% for the 2nd premolar, and 73.8% for the 1st premolar. The results of articaine with 1:200,000 epinephrine was 59.3% for the 2nd molar, 59.3% for the 1st molar, 79.1% for the 2nd premolar, and 75.0% for the 1st premolar. The success rates of the second molar of their

study were similar to the current study; however the success rates of the first molar and

premolars were higher than the current study. McEntire and coworkers showed that concentration of epinephrine had no significant difference in success rates. Eighty-six

subjects participated in their study.

Martin et al. (74) compared the success rates of 1.8 ml versus 3.6 mL of 4%

articaine with 1:100,000 epinephrine when administered adjacent to the mandibular first

molar. The results with the 1.8 mL solution showed success rates of: 48.8% for the 2nd

molar, 52.3% for the 1st molar, 87.1% for the 2nd premolar, and 81.4% for the 1st

premolar. Results for the 3.6 mL solution were as follows: 65.1% for the 2nd molar,

75.6% for the 1st molar, 92.9% for the 2nd premolar, and 91.9% for the 1st premolar.

Martin reported a significant difference between the 1.8 mL and 3.6 mL solutions. When

comparing the results of the 1.8 mL solution, the results of the molars were similar to the

results of the current study, while the results of the premolars were much higher than the

results of the current study. Eighty-six subjects participated in their study.

Dressman et al. (76) administered 1.8 mL of 4% articaine with 1:100,000

epinephrine in the area of the mental foramen, and showed success rates of 60.0% for the

1st molar, 81.8% for the 2nd premolar, and 90.5% for the 1st premolar. It is difficult to

compare the success rates between this study and the current study because of where the

injection was given, but the results of the first molar were similar to the current study.

As stated earlier, reasons as to why the results of the current study were lower

than in some studies, could be due to operator differences, subject population, age of

subjects, and sample size. However the subject population and age of subjects were

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similar to the studies completed at The Ohio State University College of Dentistry (2, 67,

73, 74, 76). A possible reason for differences between this study and others is operator

differences, specifically injection technique (depth and location of the injection). This

would explain the relatively high success of the second molars and low success of the

premolars in the current study because the anesthetic solution would have a greater

distance to diffuse to reach the apices of the premolars. Needle depth was not measured

in the current study, rather approximated to be at the depth of the mandibular first molar

apices. It is possible that the depth of needle placement of the current study varied from

the depths of needle placement in other studies, and that may have influenced anesthetic

diffusion into the bone.

Currie et al. (137) evaluated the anesthetic efficacy of mandibular molar buccal

infiltrations compared to a mental/incisive nerve block. Twenty-two subjects received

1.8 mL of 4% articaine with 1:100,000 epinephrine as a primary buccal infiltration injection at the mandibular canine, first molar, or second molar. The same definition of success was used as in the current study. The success of the first molar was highest when the injection was administered adjacent to the mandibular first molar (72.7%). When the injection was administered adjacent to the canine, the success of the first molar was

40.9% and when the injection was adjacent to the second molar the success of the first molar was 31.8%. The authors concluded that anesthesia was significantly more successful when the injections were administered adjacent to the tested tooth.

As reported in the results section, articaine was successful 55% of the time for the mandibular first molar. Haase et al. (6) showed that when articaine was given as a

101 supplemental buccal infiltration injection adjacent to the mandibular first molar following an IANB, the success rate for pulpal anesthesia was 88%. Kanaa et al. (7) showed a similar success rate of 91.7% with the same sequence of injections as Haase et al. (6).

These studies show that articaine is useful in enhancing pulpal anesthesia of the mandibular first molar following and IANB.

Prilocaine Success

Tables 8-11 and Figures 3-6 demonstrate that the peak anesthetic success of prilocaine was between 25 and 28 minutes then began to gradually decrease over the remaining test period for all the tested teeth. However with the poor success rate of prilocaine (Table 7), it cannot be considered reliable as a primary injection and a clinician could not expect consistent pulpal anesthesia using prilocaine as a primary mandibular buccal infiltration injection.

Prilocaine was less successful than articaine and lidocaine for each tooth tested.

For the first molar, articaine (55.0%) was significantly more successful than and prilocaine (31.7%) (p=0.0094, adjusted p=0.0842). For the second molar, articaine

(61.7%) was significantly more successful than prilocaine (36.7%) (p=0.0015, adjusted p=0.0179). For the second premolar, articaine (58.2%) was significantly more successful than prilocaine (30.9%) (p=0.0026, adjusted p=0.0260). For the first premolar, articaine

(50.0%) was significantly more successful than prilocaine (31.0%) (p=0.0127, adjusted p- value=0.1018). There was no significant difference between lidocaine (41.4%) and prilocaine (31.0%) (p>0.05).

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Only 3 published studies have looked at prilocaine as a primary buccal infiltration

injection (5, 64, 65), however, all three of the studies used different amounts of

prilocaine. Haas et al. (65) administered 1.5 mL of 4% prilocaine with 1:200,000

epinephrine adjacent to the mandibular second molar and mandibular canine. Pulpal

anesthesia was considered successful if the subject did not respond to the maximum

output (80/80) on the EPT at any time during the test period, which lasted for 25 minutes.

Using 20 patients, the results for successful pulpal anesthesia were as follows: 53% for

the 2nd molar and 50% for the canine. These results were much better than the results of

the current study; however, this can be expected because the definition of success was

stricter in the current study and the injection location used by Haas was directly over the

tested teeth. This could be significant as the anesthetic did not need to diffuse through

soft tissues to reach the target test tooth. It is interesting to note their results were much better for the second molar compared to the results of the current study. When one considers the thickness of bone over the second molar (136) compared to other mandibular teeth, one may have expected less success. However the fact that the inferior

alveolar nerve generally traverses more buccal to the apices of the second molar as

compared to the first molar (136), this may explain why a bolus of anesthetic over the

second molar may be more successful than an injection over the first molar. Another

explanation may simply be the need for diffusion of the anesthetic distally in our study

compared to Haas et al. (64).

Abdulwahab et al. (5) administered 0.9 mL of 4% prilocaine with 1:200,000

epinephrine adjacent the mandibular first molar. The definition of success was getting a

103 single maximum reading (80/80) on the EPT at any time during the test period, which was 20 minutes. Using 18 patients, the first molar achieved successful anesthesia 22.2% of the time, which was much lower than the results of the current study. This result might be expected because the volume given in their study was half the amount of anesthetic given in the current study. However, with a definition of success in

Abdulwahab’s study being not as strict as the definition of success in the current study, one would expect a higher success rate of pulpal anesthesia in their study.

Haas et al. (64) administered 1.5 mL of 4% prilocaine with 1:200,000 epinephrine adjacent to the mandibular canine. The definition of success was getting a single maximum reading (80/80) on the EPT at any time during the test period, which was 23 minutes. Using 20 patients, the mandibular canine achieved successful pulpal anesthesia

50% of the time. The current study did not test canines, but did test the premolars. The success rate of the first premolar in the current study was 31%. This is much lower than

Haas et al. reported for the mandibular canine; however, the definition of success was not as strict as it was in the current study and the anesthetic solutions were deposited in different locations.

A possible explanation of why prilocaine is not as successful as other anesthetics

(articaine), is that the concentration of epinephrine is half that of other anesthetic solutions tested. However, studies have shown (5, 73) that no significant differences were found between articaine solutions of 1:100,000 epinephrine and 1:200,000 epinephrine when given as primary buccal infiltration injections in the posterior mandible. This suggests that the lower epinephrine content in 4% prilocaine should not

104 affect its anesthetic efficacy. So with the epinephrine concentration not being a factor in anesthetic success, and the concentration of the prilocaine being constant (4%), the probable explanation why prilocaine is not successful is the anesthetic itself. This topic will be explained later.

Lidocaine Success

The results for anesthetic success for the lidocaine solution can be seen in Table

7. The results were as follows for lidocaine: 45.0% for the 2nd molar, 33.3% for the 1st molar, 38.2% for the 2nd premolar, and 41.4% for the 1st premolar. Lidocaine was significantly less successful than articaine for the 1st molar (p=0.0024, adjusted p=0.0259). Lidocaine was significantly less successful than articaine for the second molar (p=0.0309, adjusted p=0.1862). For the 2nd premolar lidocaine was significantly less successful than articaine (p=0.0266, adjusted p=0.1862). There was no significant difference between lidocaine and articaine for the 1st premolar (p=0.3593, adjusted p=1.000), although the success rates for articaine were always higher. There was no significant difference between lidocaine and prilocaine for all tested teeth (p>0.05).

Lidocaine had a higher success rate for all test teeth versus prilocaine.

Tables 8-11 and Figures 3-6 demonstrate that the peak anesthetic success of lidocaine was between 25 and 28 minutes then began to gradually decrease. However with the poor success rate of lidocaine (compared to articaine), it is not reliable as a primary injection and a clinician could not expect consistent pulpal anesthesia using lidocaine as a primary mandibular buccal infiltration injection.

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No published studies have been performed utilizing 4% lidocaine given as a primary buccal infiltration injection of the mandibular first molar. However, Vreeland et al. (53) evaluated the anesthetic efficacy of 1.8 mL of 4% lidocaine with 1:100,000 epinephrine compared to 1.8 mL of 2% lidocaine with 1:100,000 epinephrine, and 3.6 mL of 2% lidocaine with 1:200,000 epinephrine given as an inferior alveolar nerve block

(IANB). There were no significant differences reported between the three anesthetics

(p>0.05). The increase in lidocaine concentration did not improve IANB success.

Kanaa et al. (1) administered 1.8 mL of 2% lidocaine with 1:100,000 epinephrine adjacent to the mandibular first molar. With the same definition of success as the current study, the first molar achieved pulpal anesthesia 38.7% of the time. Although the lidocaine solution was only a 2% concentration, which is half the concentration of the current study, their results were similar to the results of the current study, which were both poor results.

Robertson et al. (2) administered 1.8 mL of 2% lidocaine with 1:100,000 epinephrine adjacent to the mandibular first molar. The same definition of success was used. Using 60 patients, the results for lidocaine were as follows: 45% for the 2nd molar,

57% for the 1st molar, 67% for the 2nd premolar, and 61% for the 1st premolar. The lidocaine solution was also only a 2% concentration; however, these results were much higher for the 1st molar and premolars than the results of the current study. Possible explanations why Robertson had higher success rates than the current study are: operator differences, depth of needle penetration, injection location, and differences in sample

106 population. The results of their study were much higher than all other reported studies looking at this injection technique.

Abdulwahab et al. (5) administered 0.9 mL of 2% lidocaine with 1:100,000 epinephrine adjacent to the mandibular first molar. Success was defined as achieving an

80/80 reading on the EPT at any time during the test period. Success for the first molar was 16.7%. Half the amount of lidocaine (0.9 versus 1.8 mL), with half the concentration

(2% versus 4%) was given to 18 patients. The result was much lower than the result of the current study.

As seen in the results of the current study, the increase of the number of lidocaine molecules (concentration) did not appear to increase the success rate of lidocaine when given as a primary mandibular buccal infiltration injection. Although the current study did not compare 2% and 4% lidocaine solutions, the 4% solution was not better when comparing our results to the results of studies where 2% lidocaine was evaluated.

The theory for the current study was to evaluate the effect of anesthetic concentration (especially for lidocaine) for buccal infiltration injections. We also wanted to compare 4% prilocaine with 4% articaine and 4% lidocaine because there are no studies that have compared these solutions. The thought was that if the concentration of lidocaine (2%) in the standard cartridge was doubled (4%), the efficacy of lidocaine may increase because double the number of lidocaine molecules would be available to diffuse through the bone to the teeth. However, according to the success rates of the current study compared to the studies looking at 2% lidocaine, the results were similar and the

4% lidocaine solution did not increase pulpal anesthesia. Prilocaine had the lowest

107 success rate and is a 4% solution as well. The higher success of articaine appears to be due to the better ability of articaine to penetrate bone compared to other anesthetics (45,

47). As discussed in the literature review section, the ability of articaine to traverse bone and tissue compared to other anesthetics has traditionally been ascribed to the presence of a thiophene ring within the structure of articaine (45, 47). Recently, however, one study

(46) suggested that it is the intramolecular hydrogen bond that gives articaine its favorable properties. Skjevik et al. demonstrated what happens as the articaine molecule is exposed to a lipid membrane. An internal hydrogen bond forms at the same time as articaine enters the membrane. This hydrogen bond is formed between the amine nitrogen and ester carbonyl oxygen groups within the molecule. Trajectory analyses show the intramolecular distances “pre” and “post” hydrogen bond formation. “Pre” hydrogen bond formation, the intramolecular distance is 5.06 Å, while the “post” hydrogen bond formation intramolecular distance is 3.11 Å. Essentially, after the hydrogen bond forms within articaine, the molecule folds over on itself (45). Lidocaine and prilocaine are both classified as amide local anesthetics and are both metabolized by the liver. Neither lidocaine nor prilocaine contain the thiophene ring, which is unique to articaine, thus lack the ability to collapse like articaine (12). Thus, the chemical make-up of the anesthetic, and not the concentration of the anesthetic solution, appears to affect the anesthetic diffusion ability and thus anesthetic efficacy of each solution. Buccal infiltration studies between 2% articaine and 4% articaine may be useful to see if this is in fact the case. Further research would be beneficial to study what changes occur, if

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any, to other anesthetics such as lidocaine and prilocaine when they come in contact with

a lipid membrane.

Most local anesthetics are weak bases and with acid ionization constants (pKa)

ranging from 7.5 to 9.0 (17). According to Yagiela and coauthors (12), local anesthetics,

which are acidic, are quickly neutralized by tissue fluid buffers, and a portion of the

cationic form is converted to the nonionized base. The amount of the drug that is

converted to nonionized base form is determined by the Henderson-Hasselbalch equation,

which is:

- [pH = pKa + log ([A ]/[HA])].

It is dependent on the local anesthetic pKa and the tissue pH. Articaine, lidocaine, and

prilocaine all have a pKa of 7.8 (12). This shows that pKa of each solution would not affect the onset or success of the drug. As stated earlier, it is the chemical structure of articaine that makes it superior for mandibular buccal infiltration injections. As discussed earlier, articaine had the lowest pH (3.3), followed by prilocaine (4.0), then lidocaine (6.1). This showed that the pH of the solution did not impact success.

According the Henderson-Hasselbalch equation the more acidic the solution, the faster the solution is neutralized by tissue buffers (12). This may not be the case as articaine was the most acidic, but was the most successful. As previously discussed, buffering an anesthetic has been thought to improve success. However Whitcomb et al. (127) showed that buffering did not improve anesthetic success of the inferior alveolar nerve block.

Therefore, pH is not really a factor for this injection.

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Overall, articaine was significantly more successful by 10-22% than lidocaine and prilocaine for all teeth. There were no significant differences in success between lidocaine and prilocaine for all tested teeth.

Onset/Duration/Failure of Anesthesia

Onset of pulpal anesthesia was defined as the time at which the first of two

consecutive 80/80 (maximum) readings on the EPT were recorded. The mean onset time

(minutes) can be seen in Table 12. Readings for each tooth were recorded every 3

minutes, so the results are not representative of the exact times of onset. Without

monitoring the teeth continually for pulpal anesthesia, the exact onset times for each

solution cannot be known. The results can be accurate up to 3 minutes in either direction.

Onset time could only be calculated for those teeth that attained pulpal anesthesia and in

order to effectively compare the solutions and the teeth, the number of samples had to be

the same for each group (Table 12). As shown in the results section and in Table 12, the

number of samples for each tooth was the same. Not all teeth attained pulpal anesthesia

equally. Anesthesia onset could only be calculated for those teeth that attained anesthesia

and that is why the sample numbers (Table 12) are different for each tooth but the same

for each tooth-type across the anesthetic group. However, when comparing which

anesthetic had faster onset times, the sample numbers were made the same, so that the

groups could be effectively analyzed. Articaine generally had a faster onset than

lidocaine and prilocaine, and prilocaine was generally faster than lidocaine. The

exception was the first molar, where prilocaine had the quickest onset. As discussed

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earlier, articaine has the unique ability to penetrate the tissues better than other local

anesthetics (45). The premolars had a quicker onset than the molars for all solutions. A

possible explanation for this could be the fact that buccal cortical plate is thinner than in the area of the molars, or that the mental foramen is anatomically located in the area of the root apices of the premolars. Pabst et al. suggested that the anesthetic solution, when deposited as a mandibular buccal infiltration injection, would diffuse anteriorly from the site of solution deposition (76). If this was the case, more solution would be available near the apices of the premolars, or even diffuse through the mental foramen. This could possibly explain why the premolars were more successful in their study. The results of the current study, however, showed that the molars were more successful than the premolars.

Anesthetic duration was not recorded in the current study because the test period ended at 60 minutes and there were some trials where the patient was numb for the duration of the test period. Therefore we could not accurately say how long the duration of anesthesia was for those patients (Appendix I). In the current study, there were many subjects who never achieved successful pulpal anesthesia. If two consecutive 80/80 readings on the EPT were not obtained during the test period, this was considered a failure to obtain pulpal anesthesia. For the second molar, there were 23 of subjects who did not achieve success with articaine, 33 for lidocaine, and 38 for prilocaine. For the first molar, the number of failures was 27 for articaine, 40 for lidocaine, and 41 for prilocaine. For the second premolar, the number of failures was 23 for articaine, 34 for lidocaine, and 38 for prilocaine. For the first premolar, the number of failures was 29 for

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articaine, 34 for lidocaine, and 40 for prilocaine. There were also many subjects who

maintained successful pulpal anesthesia longer than the test period. Articaine maintained

pulpal anesthesia at 60 minutes in 10-17.2% of subjects, depending on tooth type.

Lidocaine maintained pulpal anesthesia at 60 minutes in 1.7-12.1% of subjects,

depending on tooth type. Prilocaine maintained pulpal anesthesia at 60 minutes in 1.7%

of patients for the molars and premolars.

Tables 8-11 and Figures 3-6 show the percentage of 80/80 EPT readings for all

three anesthetics for the test teeth. For the second and first molars, pulpal anesthesia

generally peaked between 25 and 28 minutes, and then gradually began to drop-off. For

the second and first premolars, pulpal anesthesia also peaked around 28 minutes, and then

began to drop-off; however, the drop-off was much more gradual than the molars. This

trend of peak anesthesia is consistent with the findings of many of the studies reviewed in

this section (2-4, 67, 73, 74, 77). As explained previously, articaine generally had a

faster onset times (5.8-11.6 minutes) than lidocaine (6.0-13.9 minutes) and prilocaine

(7.0-8.5). The exception to this was the first molar where articaine had a slower onset time than lidocaine and prilocaine. Clinically this is important in that articaine, lidocaine, and prilocaine, if successful, will give approximately 20-25 minutes of pulpal anesthesia.

Pabst et al. (67) evaluated the efficacy of a repeated buccal infiltration of articaine

in prolonging duration of pulpal anesthesia in the mandibular first molar. Following the

first buccal infiltration injection of 1.8 mL of 4% articaine with 1:100,000 epinephrine

adjacent to the mandibular first molar, the duration of the first molar was 28 minutes.

The repeated injection increased the duration to 109 minutes. The results for the initial

112 injection of this study was similar to the results of the current study. Dressman et al. (76) evaluated the anesthetic efficacy of a primary articaine infiltration of 1.8 mL of 4% articaine with 1:100,000 epinephrine and a repeat articaine infiltration in the incisive/mental nerve region of mandibular premolars. The repeat injection of articaine increased the duration of pulpal anesthesia of the mandibular first molar from 28 to 96 minutes.

Postoperative Pain

Postoperative pain was rated using a 170 mm VAS (Appendix H). Subjects were asked to rate their pain the day of the injection when the anesthesia wore off (Day 0) and the next three consecutive mornings (Day 1, Day 2, and Day 3, respectively). Mean postoperative pain ratings can be seen in Table 13 and were recorded to see if any of the anesthetics produced more postoperative pain. The mean VAS pain ratings for Day 0 for the three anesthetic groups were as follows: articaine 37.4±27.4 mm, lidocaine 23.0±19.1 mm, and prilocaine 21.9±19.9 mm. Articaine resulted in significantly more pain than lidocaine and prilocaine at Day 0 (p=0.0038 and p=0.0011, respectively). There were no significant differences between the anesthetic groups on postoperative Day 1, Day 2, and

Day 3. Mean pain ratings for each anesthetic group fell into the “mild” category on the

VAS, with articaine having the highest mean, followed by lidocaine then prilocaine

(Table 13). Pain ratings decreased each day for all three anesthetic groups (Table 13,

Figure 7).

113

A summary of pain ratings for postoperative pain by day and anesthetic group

utilizing a numerical scale can be seen in Table 14. Articaine had more incidences

(21.7%) of moderate-to-severe pain than lidocaine (8.3%) and prilocaine (3.3%) for Day

0. For Days 1, 2, and 3 articaine, lidocaine, and prilocaine had similar numbers of

subjects who reported moderate-to-severe pain. On Day 1, subjects reported none-to- mild pain 91.7% of the time for articaine, 95.0% for lidocaine, and 93.3% for prilocaine.

On Day 2, subjects reported none-to-mild pain 95.0% of the time for articaine, 96.7% for lidocaine, and 95.0% for prilocaine. On Day 3, subjects reported none-to-mild pain

95.0% of the time for articaine, 98.3% for lidocaine, and 98.3% for prilocaine. A summary of mean postoperative pain by postoperative day, anesthetic group, and gender can be seen in Table 15. For Day 0, females reported significantly more pain than males for articaine (p=0.0186), while for lidocaine and prilocaine there was no significant difference (p=0.9985, and p=1.0000, respectively). For Day 1, there was no significant difference between males and females for articaine, lidocaine, or prilocaine (p=0.2033, p=0.9516, and p=0.9986, respectively). For Day 2, there was no significant difference between males and females for articaine, lidocaine, and prilocaine (p=0.5200, p=1.0000, and p=1.0000, respectively). For Day 3, there was no significant difference between males and females for articaine, lidocaine, and prilocaine (p=1.0000, p=1.0000, and p=1.0000, respectively). While females reported more pain for each day and for each anesthetic group, all mean pain ratings for males and females were between none-to-mild on the VAS.

114

A summary of postoperative complications by anesthetic for each postoperative

day can be seen in Table 16. Tenderness to palpation (also considered bruising) and

swelling were the most common postoperative complication for each anesthetic, followed

by pain on opening, prolonged numbness, headache, light-headedness, and nausea. The

number of subjects who experienced tenderness to palpation with articaine was 11.7% on

Day 0, 16.7% on Day 1, 5.0% on Day 2, and no incidences on Day 3. The number of subjects who experienced tenderness to palpation with lidocaine was 8.3% on Day 0,

16.7% on Day 1, 8.3% on Day 2, and 8.3% on Day 3. The number of subjects who experienced tenderness to palpation with prilocaine was 3.3% on Day 0, 10.0% on Day 1,

10.0% on Day 2, and 8.3% on Day 3. Although articaine had the highest pain ratings on solution deposition, it had the lowest overall pain ratings for tenderness to palpation. It is also important to note that for each anesthetic group, more accounts of tenderness to palpation were noted on Day 1 than Day 0. This could be due to residual soft tissue numbness on Day 0. The subjects were asked to rate their pain and note any comments

as soon as the numbing wore off. Tenderness to palpation, or bruising, is likely to occur

some time after the injection.

Subjective swelling was reported to occur most frequently with articaine. The number of subjects who reported swelling with articaine was 10.0% on Day 0, 3.3% on

Days 1 and 2, and no incidences on Day 3. The number of subjects who experienced swelling with lidocaine was 5.0% on Day 0, and no incidences on Days 1, 2, or 3. The number of subjects who experienced swelling with prilocaine was 1.7% for Days 0 and 1 and no incidences for Days 2 and 3. Each anesthetic had an incidence of 3.3% of

115 prolonged numbness on Day 0. Prolonged numbness was not defined as any certain amount of time, but upon questioning the subjects, the responses were usually numbness that lasted for more than 3 to 4 hours after the injection was given. There were no cases of paresthesia for any anesthetic.

Robertson et al. (2) reported similar mean postoperative pain ratings as the current study. The definitions of postoperative days were the same as the current study. The mean pain rating of 1.8 mL of 4% articaine with 1:100,000 epinephrine was 20±23 mm for Day 0, 15±24 mm for Day 1, 11±22 mm for Day 2, and 6±18 mm for Day 3. The mean pain rating of 1.8 mL of 2% lidocaine with 1:100,000 epinephrine was 18±25 mm for Day 0, 12±24 mm for Day 1, 9±20 mm for Day 2, and 5±15 mm for Day 3. These results are lower than the results of the current study. A reason why lidocaine had higher postoperative pain ratings in the current study could be due to the fact that solution used in the current study was a 4% solution. The only reported postinjection complications were bruising and slight swelling in the area of the injection. For articaine, 4% of subjects reported swelling and no subjects reported any bruising. For lidocaine, 5% of subjects reported swelling and 2% of subjects reported bruising. These results are lower than the current study.

Pabst et al. (67) compared the postoperative pain ratings for repeated buccal infiltration injections of 1.8 mL of 4% articaine with 1:100,000 epinephrine adjacent to the mandibular first molar. The mean pain ratings for the mock infiltration were as follows: 28±27 mm on Day 0, 19±21 mm on Day 1, 14±20 mm on Day 2, and 8±15 mm on Day 3. The mean pain ratings for the repeated infiltration were as follows: 40±32 mm

116 on Day 0, 33±25 mm on Day 1, 23±23 mm on Day 2, and 14±20 mm. These results were similar to the results of the current study. For the mock and repeated infiltrations, 22% of subjects reported tenderness at the site of the injection. Sixteen percent reported slight swelling with the repeated infiltration, and 9% reported slight swelling with the mock infiltration. These results were higher than the current study, which could be due to the fact that 2 injections per appointment were given at the same site, as opposed to one injection per appointment in the current study.

McEntire et al. (73) compared postoperative pain ratings between 1.8 mL of 4% articaine with 1:100,000 epinephrine and 1:200,000 epinephrine when given as a primary buccal infiltration injection adjacent to the mandibular first molar. The mean pain ratings for the epinephrine 1:100,000 group were as follows: 20±22 mm on Day 0, 13±19 mm on

Day 1, 8±14 mm on Day 2, and 5±13 mm on Day 3. The mean pain ratings for the epinephrine 1:200,000 group were as follows: 23±26 mm on Day 0, 15±21 mm on Day 1,

10±19 mm on Day 2, and 6±16 mm on Day 3. These results were similar to the current study. They also reported the most frequent postoperative complication was tenderness

5%-7%, followed by bruising (1%-4%) and swelling (1%-2%). These results were also similar to the current study. It is interesting to note that the mean pain ratings of the

1:200,000 epinephrine group were higher than that of the 1:100,000 epinephrine group, but the differences were not significant. This shows that epinephrine content may not contribute to postinjection pain as much as previously thought.

Martin et al. (74) compared the postoperative pain ratings and complications between 1.8 mL and 3.6 mL of 4% articaine with 1:100,000 epinephrine given as a

117

primary buccal infiltration injection adjacent to the mandibular first molar. The mean

pain ratings for the 1.8 mL solution were as follows: 24±24 mm on Day 0, 17±20 mm on

Day 1, 13±21 mm on Day 2, and 9±18 mm on Day 3. The mean pain ratings for the 3.6

mL solution were as follows: 36±29 mm on Day 0, 31±28 on Day 1, 25±28 mm on Day

2, and 18±26 mm on Day 3. These results were similar to the current study. The

postoperative complications reported were initial tenderness (6%-13%) and slight subjective swelling (4%-9%). These results were also similar to the results of the current

study. The higher pain ratings for the 3.6 mL solution is likely due to the fact that twice

the amount of anesthetic was given in the buccal vestibule.

Dressman et al. (76) compared the postoperative pain ratings of initial and

repeated buccal infiltrations injections of 1.8 mL of 4% articaine with 1:100,000

epinephrine given in the area of the mental foramen, which is in the area of the root

apices of the mandibular premolars. The postoperative mean pain ratings of the repeated

injections group were as follows: 31.8±27.2 mm on Day 0, 22.8±22.4 mm on Day 1,

18.1±22.2 mm on Day 2, and 10.2±18.4 mm on Day 3. The mean pain ratings for the

initial and mock injection group were as follows: 14.9±15.5 mm on Day 0, 8.7±12.1 mm

on Day 1, 4.1±8.4 mm on Day 2, and 1.8±4.8 mm on Day 3. The postoperative

complications most commonly reported were tenderness to palpation which was 22.0%

for the initial and repeated infiltrations and 16.0% for the initial and mock infiltrations;

and injection site swelling which was 9.0% for the initial and repeated infiltrations and

4.0% for the initial and mock infiltrations (76). Even though the injection was in the area

of the mental foramen, the study showed similar results to the current study in

118

postoperative complications. However, the mean postoperative pain ratings were lower than the current study. This could be related to the injection site.

Overall, 78.3% of subjects reported none-to-mild pain on postoperative Day 0 for articaine, 91.7% for lidocaine, and 96.7% for prilocaine. Articaine mean pain ratings on postoperative Day 0 were 37.4±27.4, 23.0±19.1 for lidocaine, and 21.9±19.9 for prilocaine. As shown in the current study, articaine had more subjects who reported more than mild pain, followed by lidocaine then prilocaine. No subjects reported severe pain for any postoperative day for any anesthetic solution. It is possible that something within the articaine molecule makes it a more painful solution for postoperative pain, which was greatest for articaine. However, pain ratings decreased for Days 1-3 and were similar to the other solutions.

119

Chapter 6

Summary and Conclusions

The purpose of this prospective, randomized, double-blind, crossover study was to compare the degree of pulpal anesthesia obtained with 4% articaine with 1:100,000 epinephrine, 4% prilocaine with 1:200,000 epinephrine, and 4% lidocaine with

1:100,000 epinephrine as a primary buccal infiltration injection of the mandibular first molar.

Sixty healthy adult subjects participated in this study, thirty males and thirty females. All teeth that were tested were asymptomatic. A topical anesthetic (0.2 mL of

20% benzocaine) was applied at the injection site for one minute. All subjects received three injections consisting of a single, primary mandibular first molar buccal infiltration injection of 1.8 mL of 4% articaine with 1:100,000 epinephrine, 1.8 mL of 4% lidocaine with 1:100,000 epinephrine, and 1.8 mL of 4% prilocaine with 1:200,000 epinephrine in three separate appointments. The mandibular molars and premolars were tested every 3 minutes for pulpal anesthesia using an electric pulp tester (EPT). The contralateral canine was tested as a control. The test period lasted for 60 minutes. All subjects rated the pain of the injection, which was separated into three stages: needle insertion, needle placement, and solution deposition.

120 Postoperative pain was recorded for each anesthetic solution immediately after the numbness wore-off and again each morning for the next three days. Subjects were

asked to rate any discomfort, soreness, or pain at the area of the injection.

There were no significant differences in mean pain ratings between anesthetics

for needle insertion, needle placement, or solution deposition. All mean pain ratings for

each anesthetic for needle insertion, needle placement, and solution deposition fell into

the category of “mild” pain. Solution deposition had the highest pain ratings compared

to both needle insertion and needle placement ratings for all anesthetic groups.

Females reported more pain than males for each anesthetic and for each stage of

the injection. For articaine and lidocaine solution deposition, females rated the pain in

the “moderate” category, but in the “mild” category for prilocaine. There were no

significant differences between males and females for any stage of the injection stages

or between anesthetic groups.

Anesthetic success was defined as achieving 80/80 (maximum reading)

with the EPT for two consecutive test periods at any time during the 60-minute testing

period. For the second molar, articaine was significantly more successful than lidocaine

(p=0.0309, adjusted p=0.1862) and prilocaine (p=0.0015, adjusted p=0.0179). There

was no significant difference between lidocaine and prilocaine. For the first molar,

articaine was significantly more successful than lidocaine (p=0.0024, adjusted

p=0.0259) and prilocaine (p=0.0094, adjusted p=0.0842). The was no significant

difference between lidocaine and prilocaine. For the second premolar, articaine was

significantly more successful than lidocaine (p=0.0266, adjusted p=0.1862) and

prilocaine (p=0.0026, adjusted p=0.0260). There was no significant difference between

121 lidocaine and prilocaine. For the first premolar, articaine was significantly more

successful than prilocaine (p=0.0127, adjusted p=0.1018). There was no significant

difference between articaine to lidocaine and lidocaine to prilocaine. Articaine was

more succesful than lidocaine and prilocaine for all teeth.

Onset of pulpal anesthesia was defined as the time at which the first of two consecutive 80/80 (maximum) readings on the EPT were recorded. Articaine onset times ranged from 5.8 minutes (first premolar) to 11.6 minutes (first molar). Lidocaine onset times ranged from 6.0 minutes (second premolar) to 13.8 minutes (second molar).

Prilocaine onset times ranged from 7.0 minutes (first premolar) to 8.5 minutes (second molar). The first premolar generally achieved successful pulpal anesthesia the fastest, followed by the second premolar, the first molar, and the second molar.

Subjects were asked to rate their pain the day of the injection when anesthesia wore-off and the next consecutive three mornings immediately after waking up. The day of the injection, when anesthesia wore-off, articaine produced significantly more pain than lidocaine and prilocaine. Females reported significantly more pain than males for articaine on the first day. For the remaining three days, there was no significant difference between males and females for pain ratings. There were no significant differences between the anesthetic groups for the remaining 3 days. Mean pain ratings for all three anesthetics fell into the “mild” category. Pain gradually decreased for all three anesthetics each postoperative day.

No statistical analysis was performed on postoperative complications. Tenderness to palpation was the most common complication, followed by subjective swelling at the

122 site of injection. It did not appear that any anesthetic solution produced significantly more postoperative complications.

We concluded that 1.8 mL of 4% articaine with 1:100,000 epinephrine was more successful for all teeth than 1.8 mL of 4% lidocaine with 1:100,000 epinephrine and 1.8 mL of 4% prilocaine with 1:200,000 epinephrine. The increased concentration of lidocaine from a 2% solution to a 4% solution did not appear to improve its anesthetic success. We also concluded that it is the chemical structure of articaine, not the concentration, which makes it a more successful anesthetic for mandibular buccal infiltration injections.

The results of this study show that for the mandibular first molar, successful pulpal anesthesia can be expected 55% of the time. This shows that predictable pulpal anesthesia cannot be expected.

123

APPENDIX A

TABLES

124

# of Subjects Age Range Mean Age Standard (years) (years) Deviation

Males 30 23-31 26.1 ±2.0 Females 30 20-38 25.5 ±2.9 Totals 60 20-38 25.8 ±2.5

Table 1. Biographical data for all subjects.

125 Variable Articaine* Lidocaine† Prilocaine‡ (N=60) (N=60) (N=60)

Insertion 32.2±22.3 31.2±20.1 32.5±21.5

Placement 33.1±28.0 33.0±28.2 34.3±30.4

Deposition 52.3±29.6†† 50.4±25.1** 40.7±25.0

* Articaine = 1.8 mL 4% Articaine with 1:100,000 epinephrine. † Lidocaine = 1.8 mL 4% Lidocaine with 1:100,000 epinephrine. ‡ Prilocaine = 1.8 mL 4% Prilocaine with 1:200,000 epinephrine.

There was no significant difference between insertion and placement pain for all solutions (p>0.05). ††There was a significant difference between articaine insertion and articaine deposition (p=0.0003). There was a significant difference between articaine placement and articaine deposition (p=0.0008). **There was a significant difference between lidocaine insertion and lidocaine deposition (p=0.0008). There was a significant difference between lidocaine placement and lidocaine deposition (p=0.0040). There was no significant difference among anesthetics for deposition pain.

Table 2. Mean VAS Values (mm) of Injection Pain Ratings for Buccal Infiltration.

126 Variable Males Females p-value (N=30) (N=30) Insertion Articaine* 27.9±20.3 36.6±23.8 0.9968 Lidocaine† 25.0±15.8 37.4±22.3 0.8931 Prilocaine‡ 30.3±18.1 34.8±24.6 1.0000

Placement Articaine 22.8±19.5 43.3±31.7 0.1179 Lidocaine 29.2±25.1 36.8±31.0 0.9993 Prilocaine 27.7±22.0 40.8±36.1 0.8461

Deposition Articaine 43.1±30.1 61.6±26.4 0.2553 Lidocaine 46.0±26.7 54.9±22.9 0.9955 Prilocaine 31.5±24.2 49.8±22.6 0.2763

* Articaine = 1.8 mL 4% Articaine with 1:100,000 epinephrine. †Lidocaine = 1.8 mL 4% Lidocaine with 1:100,000 epinephrine. ‡Prilocaine = 1.8 mL 4% Prilocaine with 1:200,000 epinephrine.

Table 3. Mean VAS Values (mm) of Injection Pain Ratings for Buccal Infiltration of Three Different Anesthetic Solutions by Gender.

127 N None Mild Moderate Severe

Total 180 13 (7.2%) 142 (78.9%) 25 (13.9%) 0 (0%)

Articaine* 60 2 (3.3%) 49 (81.7%) 9 (15.0%) 0 (0%)

Lidocaine† 60 5 (8.3%) 48 (80.0%) 7 (11.7%) 0 (0%)

Prilocaine‡ 60 6 (10.0%) 45 (75.0%) 9 (15.0%) 0 (0%)

Male 90 6 (6.7%) 75 (83.3%) 9 (10%) 0 (0%)

Female 90 7 (7.8%) 67 (74.4%) 16 (17.8%) 0 (0%)

* 1.8 mL 4% Articaine with 1:100,000 epinephrine. † 1.8 mL 4% Lidocaine with 1:100,000 epinephrine. ‡ 1.8 mL 4% Prilocaine with 1:200,000 epinephrine.

Table 4. Summary of Pain Ratings for Needle Insertion Utilizing a Descriptive Scale.

128 N None Mild Moderate Severe

Total 180 23 (12.8%) 129 (71.7%) 23 (12.8%) 5 (2.8%)

Articaine* 60 7 (11.7%) 42 (70.0%) 10 (16.7%) 1 (1.7%)

Lidocaine† 60 8 (13.3%) 46 (76.7%) 4 (6.7%) 2 (3.3%)

Prilocaine‡ 60 8 (13.3%) 41 (68.3%) 9 (15.0%) 2 (3.3%)

Male 90 11 (12.2%) 72 (80.0%) 6 (6.7%) 1 (1.1%)

Female 90 12 (13.3%) 57 (63.3%) 17 (18.9%) 4 (4.4%)

* Articaine = 1.8 mL 4% Articaine with 1:100,000 epinephrine. † Lidocaine = 1.8 mL 4% Lidocaine with 1:100,000 epinephrine. ‡ Prilocaine = 1.8 mL 4% Prilocaine with 1:200,000 epinephrine.

Table 5. Summary of Pain Ratings for Needle Placement Utilizing a Descriptive Scale.

129 N None Mild Moderate Severe

Total 180 23 (12.8%) 129 (71.7%) 23 (12.8%) 5 (2.8%)

Articaine* 60 2 (3.3%) 36 (60.0%) 21 (35.0%) 1 (1.7%)

Lidocaine† 60 0 (0%) 44 (73.3%) 14 (23.3%) 2 (3.3%)

Prilocaine‡ 60 5 (8.3%) 40 (66.7%) 15 (25.0%) 0 (0%)

Male 90 7 (7.8%) 66 (73.3%) 16 (16.7%) 2 (2.2%)

Female 90 0 (0%) 54 (60%) 35 (38.9%) 1 (1.7%)

* Articaine = 1.8 mL 4% Articaine with 1:100,000 epinephrine. † Lidocaine = 1.8 mL 4% Lidocaine with 1:100,000 epinephrine. ‡ Prilocaine = 1.8 mL 4% Prilocaine with 1:200,000 epinephrine.

Table 6. Summary of Pain Ratings for Solution Deposition Utilizing a Descriptive Scale.

130 Tooth Articaine† Lidocaine‡ Prilocaine**

Second Molar N=60 37 (61.7%) 27 (45.0%) 22 (36.7%)

First Molar N=60 33 (55.0%) 20 (33.3%) 19 (31.7%)

Second Premolar N=60 32 (58.2%) 21 (38.2%) 17 (30.9%)

First Premolar N=60 29 (50.0%) 24 (41.4%) 18 (31.0%)

† 1.8 mL 4% Articaine with 1:100,000 epinephrine ‡ 1.8 mL 4% Lidocaine with 1:100,000 epinephrine ** 1.8 mL 4% Prilocaine with 1:200,000 epinephrine

Table 7: Anesthetic Success.

131

Post-injection Articaine* Lidocaine† Prilocaine‡ Time (min) (%) (%) (%)

1 18.3% 10.0% 18.3% 4 33.3% 23.3% 13.3% 7 40.4% 25.0% 20.0% 10 36.7% 26.7% 26.7% 13 45.0% 26.7% 26.7% 16 43.3% 33.3% 23.3% 19 45.0% 30.0% 21.7% 22 43.3% 25.0% 18.3% 25 46.7% 21.7% 16.7% 28 38.3% 30.3% 21.7% 31 33.3% 23.3% 15.0% 34 33.3% 16.7% 13.3% 37 30.0% 15.0% 10.0% 40 31.7% 11.7% 5.0% 43 18.3% 16.7% 3.3% 46 18.3% 11.7% 6.7% 49 20.0% 10.0% 5.0% 52 20.0% 13.3% 11.7% 55 11.7% 11.7% 8.3% 58 13.3% 10.0% 3.3%

* 1.8 mL 4% Articaine with 1:100,000 epinephrine. † 1.8 mL 4% Lidocaine with 1:100,000 epinephrine. ‡ 1.8 mL 4% Prilocaine with 1:200,000 epinephrine.

Table 8: Second Molar 80/80 Pulp Tester Readings for all Three Anesthetic Groups.

132 Post-injection Articaine* Lidocaine† Prilocaine‡ Time (min) (%) (%) (%)

1 3.3% 1.7% 6.7% 4 18.3% 5.0% 11.7% 7 25.0% 18.3% 20.0% 10 30.0% 25.0% 21.7% 13 40.0% 23.3% 23.3% 16 40.0% 26.7% 18.3% 19 41.7% 26.7% 16.7% 22 40.0% 25.0% 11.7% 25 46.7% 20.0% 18.3% 28 35.0% 16.7% 21.7% 31 28.3% 20.0% 6.7% 34 30.0% 18.3% 5.0% 37 23.3% 15.0% 3.3% 40 28.3% 11.7% 3.3% 43 20.0% 5.0% 1.7% 46 15.0% 5.0% 5.0% 49 11.7% 6.7% 1.7% 52 13.3% 1.7% 1.7% 55 8.3% 6.7% 0.0% 58 10.0% 3.3% 3.3%

* 1.8 mL 4% Articaine with 1:100,000 epinephrine. † 1.8 mL 4% Lidocaine with 1:100,000 epinephrine. ‡ 1.8 mL 4% Prilocaine with 1:200,000 epinephrine.

Table 9: First Molar 80/80 Pulp Tester Readings for all Three Anesthetic Groups.

133

Post-injection Articaine* Lidocaine† Prilocaine‡ Time (min) (%) (%) (%)

1 14.5% 3.6% 1.8% 4 27.3% 18.2% 16.4% 7 47.3% 27.3% 27.3% 10 47.3% 36.4% 27.3% 13 56.4% 30.9% 29.1% 16 54.5% 32.7% 25.5% 19 50.9% 29.1% 23.6% 22 45.5% 27.3% 20.0% 25 52.7% 25.5% 21.8% 28 45.5% 21.8% 16.4% 31 38.2% 25.5% 12.7% 34 43.6% 21.8% 7.3% 37 36.4% 21.8% 9.1% 40 27.3% 20.0% 5.5% 43 23.6% 12.7% 5.5% 46 25.5% 12.7% 5.5% 49 21.8% 12.7% 5.5% 52 21.8% 10.9% 5.5% 55 20.0% 10.9% 3.6% 58 21.8% 9.1% 3.6%

* 1.8 mL 4% Articaine with 1:100,000 epinephrine. † 1.8 mL 4% Lidocaine with 1:100,000 epinephrine. ‡ 1.8 mL 4% Prilocaine with 1:200,000 epinephrine.

Table 10: Second Premolar 80/80 Pulp Tester Readings for all Three Anesthetic Groups.

134 Post-injection Articaine* Lidocaine† Prilocaine‡ Time (min) (%) (%) (%)

1 8.6% 6.9% 6.9% 4 25.9% 17.2% 15.5% 7 36.2% 27.6% 19.0% 10 43.1% 32.8% 32.8% 13 39.7% 32.8% 32.8% 16 36.2% 31.0% 29.3% 19 48.3% 29.3% 25.9% 22 43.1% 24.1% 20.7% 25 48.3% 25.9% 19.0% 28 41.4% 25.9% 15.5% 31 39.7% 22.4% 10.3% 34 36.2% 22.4% 10.3% 37 25.9% 22.4% 12.1% 40 22.4% 17.2% 6.9% 43 20.7% 10.3% 6.9% 46 22.4% 13.8% 5.2% 49 19.0% 6.9% 3.4% 52 17.2% 3.4% 3.4% 55 15.5% 3.4% 3.4% 58 12.1% 3.4% 5.2%

* 1.8 mL 4% Articaine with 1:100,000 epinephrine. † 1.8 mL 4% Lidocaine with 1:100,000 epinephrine. ‡ 1.8 mL 4% Prilocaine with 1:200,000 epinephrine.

Table 11: First Premolar 80/80 Pulp Tester Readings for all Three Anesthetic Groups.

135

Solution Tooth N** Mean Onset S.D. (Minutes) (Minutes)

Articaine* Second Molar 42 7.0 ±6.2 First Molar 33 11.6 ±11.4 Second Premolar 18 8.3 ±5.8 First Premolar 36 5.8 ±2.2

Lidocaine† Second Molar 42 13.9 ±13.4 First Molar 33 10.8 ±7.8 Second Premolar 18 6.0 ±3.9 First Premolar 36 6.8 ±5.8

Prilocaine‡ Second Molar 42 8.5 ±9.1 First Molar 33 8.4 ±6.4 Second Premolar 18 7.0 ±3.1 First Premolar 36 7.0 ±3.1

* 1.8 mL 4% Articaine with 1:100,000 epinephrine. † 1.8 mL 4% Lidocaine with 1:100,000 epinephrine. ‡ 1.8 mL 4% Prilocaine with 1:200,000 epinephrine. ** Number of subjects that experienced two consecutive 80/80 readings.

Anesthesia onset was defined as the time at which the first of two consecutive 80/80 readings were recorded.

Table 12: Mean Anesthesia Onset Time for each Anesthetic Group by Tooth.

136

Variable Articaine* Lidocaine† Prilocaine‡

Post-op Day 0 37.4±27.4ab 23.0±19.1a 21.9±19.9b

Post-op Day 1 26.9±24.3 20.3±22.5 18.3±21.3

Post-op Day 2 17.9±19.6 14.6±19.5 12.3±19.4

Post-op Day 3 10.4±16.1 8.7±17.1 7.8±14.4

N=60 * 1.8 mL 4% Articaine with 1:100,000 epinephrine. † 1.8 mL 4% Lidocaine with 1:100,000 epinephrine. ‡ 1.8 mL 4% Prilocaine with 1:200,000 epinephrine. a = Articaine was significantly more painful than lidocaine at post-op day 0 (0.0038) b= Articaine was significantly more painful than prilocaine at post-op day 0 (0.0011) Table 13. Mean VAS Values (mm) of Postoperative Pain Ratings.

137

N None Mild Moderate Severe

Articaine* 60 Day 0 6 (10.0%) 41 (68.3%) 13 (21.7%) 0 (0%) Day 1 16 (26.7%) 39 (65.0%) 5 (8.3%) 0 (0%) Day 2 24 (40.0%) 33 (55.0%) 3 (5.0%) 0 (0%) Day 3 31 (51.7%) 26 (43.3%) 3 (5.0%) 0 (0%)

Lidocaine† 60 Day 0 12 (20.0%) 43 (71.7%) 5 (8.3%) 0 (0%) Day 1 22 (36.7%) 35 (58.3%) 3 (5.0%) 0 (0%) Day 2 26 (43.3%) 32 (53.3%) 2 (3.3%) 0 (0%) Day 3 32 (53.3%) 27 (45.0%) 1 (1.7%) 0 (0%)

Prilocaine‡ 60 Day 0 15 (25.0%) 43 (71.7%) 2 (3.3%) 0 (0%) Day 1 22 (36.7%) 34 (56.7%) 4 (6.7%) 0 (0%) Day 2 32 (52.3%) 25 (41.7%) 3 (5.0%) 0 (0%) Day 3 33 (55.0%) 26 (43.3%) 1 (1.7%) 0 (0%)

* Articaine = 1.8 mL 4% Articaine with 1:100,000 epinephrine. † Lidocaine = 1.8 mL 4% Lidocaine with 1:100,000 epinephrine. ‡ Prilocaine = 1.8 mL 4% Prilocaine with 1:200,000 epinephrine.

Table 14. Summary of Pain Ratings for Postoperative Pain by Day and Anesthetic Utilizing a Numerical Scale.

138 Anesthetic Period Gender N Mean S.D. Min Max p-value (mm) (±mm) (mm) (mm) Articaine* Day 0 Male 30 27.4 ±20.9 0 91 Female 30 47.3 ±29.6 0 112 0.0186 Day 1 Male 30 18.9 ±19.5 0 82 Female 30 34.9 ±26.2 0 112 0.2033 Day 2 Male 30 11.0 ±13.3 0 36 Female 30 24.7 ±22.5 0 83 0.5200 Day 3 Male 30 9.1 ±14.2 0 58 Female 30 11.6 ±17.9 0 69 1.0000 Lidocaine† Day 0 Male 30 19.2 ±17.5 0 82 Female 30 26.8 ±20.2 0 71 0.9985 Day 1 Male 30 15.3 ±17.2 0 54 Female 30 25.3 ±26.2 0 90 0.9516 Day 2 Male 30 12.3 ±15.6 0 54 Female 30 16.8 ±22.8 0 89 1.0000 Day 3 Male 30 7.8 ±13.6 0 54 Female 30 9.7 ±20.2 0 87 1.0000 Prilocaine‡ Day 0 Male 30 19.7 ±16.9 0 52 Female 30 24.2 ±22.6 0 83 1.0000 Day 1 Male 30 14.5 ±15.6 0 52 Female 30 22.1 ±25.6 0 82 0.9986 Day 2 Male 30 11.2 ±18.1 0 65 Female 30 13.4 ±20.9 0 71 1.0000 Day 3 Male 30 7.0 ±13.6 0 54 Female 30 8.6 ±15.2 0 62 1.0000 N=60

* 1.8 mL 4% articaine with 1:100,000 epinephrine † 1.8 mL 4% lidocaine with 1:100,000 epinephrine ‡ 1.8 mL 4% prilocaine with 1:200,000 epinephrine

Table 15: Summary of Mean Postoperative Pain by Postoperative Day and Gender.

139 Post-op Day Post-op Day Post-op Day 2 Post-op Day 0 1 3 (%) (%) (%) (%) Tender to Palpation Articaine* 7 (11.7%) 10 (16.7%) 3 (5.0%) 0 (0%) Lidocaine† 5 (8.3%) 10 (16.7%) 5 (8.3%) 5 (8.3%) Prilocaine‡ 2 (3.3%) 6 (10.0%) 6 (10.0%) 5 (8.3%) Subjective Swelling Articaine 6 (10.0%) 2 (3.3%) 2 (3.3%) 0 (0%) Lidocaine 3 (5.0%) 0 (0%) 0 (0%) 0 (0%) Prilocaine 1 (1.7%) 1 (1.7%) 0 (0%) 0 (0%) Pain on Opening Articaine 2 (3.3%) 1 (1.7%) 0 (0%) 0 (0%) Lidocaine 0 (0%) 0 (0%) 1 (1.7%) 0 (0%) Prilocaine 0 (0%) 0 (0%) 1 (1.7%) 0 (0%) Prolonged Numbness Articaine 2 (3.3%) 0 (0%) 0 (0%) 0 (0%) Lidocaine 2 (3.3%) 0 (0%) 0 (0%) 0 (0%) Prilocaine 2 (3.3%) 0 (0%) 0 (0%) 0 (0%) Headache Articaine 1 (1.7%) 0 (0%) 0 (0%) 0 (0%) Lidocaine 1 (1.7%) 0 (0%) 0 (0%) 0 (0%) Prilocaine 0 (0%) 0 (0%) 0 (0%) 0 (0%) Light-headed Articaine 1 (1.7%) 0 (0%) 0 (0%) 0 (0%) Lidocaine 0 (0%) 0 (0%) 0 (0%) 0 (0%) Prilocaine 0 (0%) 0 (0%) 0 (0%) 0 (0%) Nauseated Articaine 0 (0%) 0 (0%) 0 (0%) 0 (0%) Lidocaine 0 (0%) 1 (1.7%) 0 (0%) 0 (0%) Prilocaine 0 (0%) 0 (0%) 0 (0%) 0 (0%)

* 1.8 mL 4% articaine with 1:100,000 epinephrine † 1.8 mL 4% lidocaine with 1:100,000 epinephrine ‡ 1.8 mL 4% prilocaine with 1:200,000 epinephrine

Table 16: Frequency of Subject-reported Postoperative Complications by Day.

140 Solution Mean pH S.D. Minimum Maximum 4% Articaine 3.297 0.034 3.260 3.350 with 1:100,000 epinephrine 4% Prilocaine 3.972 0.065 3.860 4.050 with 1:200,000 epinephrine 4% Lidocaine 6.162 0.042 6.110 6.220 Epinephrine 2.615 0.023 2.570 2.660 1:1000 4% Lidocaine 6.097 0.056 5.980 6.160 with 1:100,000 epinephrine

Solution Mean pH p-value 4% Articaine with 3.297 1:100,000 epinephrine 4% Prilocaine with 3.972 P<0.0001 1:200,000 epinephrine

Solution Mean pH p-value 4% Articaine with 3.297 1:100,000 epinephrine 4% Lidocaine with 6.097 P<0.0001 1:100,000 epinephrine

Solution Mean pH p-value 4% Prilocaine with 3.972 1:200,000 epinephrine 4% Lidocaine with 6.097 P<0.0001 1:100,000 epinephrine

Table 17: pH of Anesthetic Solutions.

141

APPENDIX B

FIGURES

142 70 60

50 40 30 20 10 0 Males Females Articaine Lidocaine Mean MM VAS Pain MeanVAS MM Articaine Prilocaine Lidocaine Prilocaine Articaine

Insertion Lidocaine Placement Prilocaine Deposition Injection Type

Figure 1: Summary of Injection Pain by Solution, Type, and Gender.

143 100

50 Articaine

% Success Lidocaine Prilocaine

0 2nd Molar 1st Molar 2nd Premolar 1st Premolar Tooth Type

Figure 2: Overall Anesthetic Success.

144 100

50 Arti Lido

% Anesthesia Pril

0 0 15 30 45 60 Minutes

Figure 3: Percent of Pulpal Anesthesia for the First Molar.

145 100

50 Arti Lido

% Anesthesia Pril 25

0 0 15 30 45 60 Minutes

Figure 4: Percent Pulpal Anesthesia for the Second Molar.

146 100

50 Arti Lido

% Anesthesia Pril

0 0 15 30 45 60 Minutes

Figure 5: Percent Pulpal Anesthesia for the First Premolar.

147 100

50 Arti Lido

% Anesthesia Pril

0 0 15 30 45 60 Minutes

Figure 6: Percent Pulpal Anesthesia for the Second Premolar.

148 50

10 Males Mean MM VAS Pain MeanVAS MM 0 Females Articaine Lidocaine Articaine Prilocaine Lidocaine Articaine Prilocaine Lidocaine Articaine Day 0 Prilocaine Lidocaine

Day 1 Prilocaine Day 2 Day 3 Post-operative Day

Figure 7: Summary of Post-operative Pain by Day.

149

APPENDIX C

BIOGRAPHICAL DATA

150 BIOGRAPHICAL DATA

SUBJECT 6-Digit ID AGE SEX SUBJECT 6-Digit ID AGE SEX 1 382985 25 female 31 276956 27 male 2 349175 26 male 32 955730 24 male 3 950234 29 male 33 766726 24 female 4 952149 25 female 34 686959 29 male 5 111173 23 female 35 618584 28 male 6 317625 23 female 36 981968 27 male 7 282284 24 female 37 955873 26 female 8 726248 25 female 38 276896 26 female 9 670812 25 male 39 125699 28 female 10 283330 23 female 40 456093 24 male 11 519077 29 male 41 430391 28 female 12 469015 26 male 42 211252 25 female 13 103606 23 male 43 522107 23 male 14 535402 24 female 44 197812 25 male 15 603918 26 female 45 283376 31 male 16 906941 27 male 46 830214 26 male 17 834521 28 male 47 452838 25 female 18 462988 25 male 48 104096 24 female 19 950932 25 male 49 118637 24 female 20 990449 26 male 50 875755 26 female 21 998782 27 female 51 830285 24 male 22 296243 26 female 52 146915 38 female 23 190786 26 female 53 400386 25 male 24 946811 28 male 54 302414 24 male 25 925096 28 male 55 723292 25 male 26 439565 27 male 56 587571 28 female 27 420000 26 female 57 505678 27 female 28 920009 24 male 58 276155 20 female 29 142718 25 female 59 834661 25 female 30 800941 23 female 60 301970 25 male

151

APPENDIX D

MEIDCAL HISTORY FORM

152

THE OHIO STATE UNIVERSITY Patient ID# ______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

153 10. Have you consumed alcohol within the last 48 hrs? NO YES

11. Are you currently taking any drugs or medications (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

154

APPENDIX E

CONSENT

155 The Ohio State University Consent to Participate in Research

Anesthetic efficacy of 4% articaine with 1:100,000 epinephrine, 4% prilocaine with 1:200,000 epinephrine, and Study Title: 4% lidocaine with 1:100,000 epinephrine as a primary buccal infiltration in the mandibular first molar. Principal John Nusstein Investigator:

Sponsor: None

• 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?

The purpose of this study is to compare three different numbing solutions and see which numbing solution works best when injected next to the lower first molar.

2. How many people will take part in this study?

Sixty-five (65) people will take part in this study.

3. What will happen if I take part in this study?

156 I will receive three different injections (shots). The shots will be articaine, lidocaine, and prilocaine (numbing solutions like “novocaine”), all with epinephrine next to the lower jaw first molar. The articaine, lidocaine, and prilocaine numbing solutions are not experimental. They are routine anesthetics and all have been approved by the FDA 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 solutions. 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 (are alive). This will take about 6 minutes. I will have three appointments spaced at least one week apart. I will receive one injection at each appointment. After topical numbing anesthetic has been applied to the injection (shot) site for one minute (to numb the gums), I will receive 1.8 ml (one anesthetic cartridge) of either 4% articaine with 1:100,000 epinephrine, 4% lidocaine with 1:100,000 epinephrine, or 4% prilocaine with 1:200,000 epinephrine. My numb tooth and the adjacent teeth (in front and behind this tooth) will then be pulp tested every 3 minutes for 60 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 not know which injection, using either the articaine, lidocaine, or prilocaine numbing solution, I will receive at each session. The doctor will not know which injection I receive either. An assistant will help prepare the solutions and will know which anesthetic solution I will receive. 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 three appointments. Each will last approximately 70 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 60 minutes. The post-injection 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 envelope or personally deliver them to the endodontic clinic front office. This will take about five minutes.

5. Can I stop being in the study?

157 You may leave the study at any time. If you decide to stop participating in the study, there will be no penalty to you, and you will not lose any benefits to which you are otherwise entitled. Your decision will not affect your future relationship with The Ohio State University.

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 (1%.) I may experience a feeling of anxiety, lightheadedness or fainting (3.2%), and/or a temporary increase in my heart rate (1%.) 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, 1%) 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 (1%) that may last up to a few weeks.

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 group 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, lidocaine, and prilocaine in pregnant women. This pregnancy test will be paid for by the study.

7. What benefits can I expect from being in the study?

I will not directly benefit from this study. Society may benefit if one of the anesthetics (numbing solutions) works better at anesthetizing (numbing) the teeth than others.

8. What other choices do I have if I do not take part in the study?

You may choose not to participate without penalty or loss of benefits to which you are otherwise entitled. No dental treatment will be done, so no other choices are available.

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 158 information regarding your participation in this study may be disclosed if required by 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;

You may also be asked to sign a separate Health Insurance Portability and Accountability Act (HIPAA) research authorization form if the study involves the use of your protected health information.

10. What are the costs of taking part in this study?

The study will pay for the cost of the study drugs (articaine, lidocaine, and prilocaine) and urine pregnancy test. You may need to pay for parking while participating in the study.

11. Will I be paid for taking part in this study?

Yes, I will be paid $90 for my participation. I will receive $90.00 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 $25.00 per session and an additional pro-rated $5.00 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 you suffer an injury from participating in this study, you should notify the researcher or study doctor immediately, who will determine if you should obtain medical treatment at The Ohio State University Medical Center.

The cost for this treatment will be billed to you or your medical or hospital insurance. The Ohio State University has no funds set aside for the payment of health care expenses for this study.

159 13. What are my rights if I take part in this study?

If you choose to participate in the study, you may discontinue participation at any time without penalty or loss of benefits. By signing this form, you do not give up any personal legal rights you may have as a participant in this study.

You will be provided with any new information that develops during the course of the research that may affect your decision whether or not to continue participation in the study.

You may refuse to participate in this study without penalty or loss of benefits to which you are 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. Brett Nydegger 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. Brett Nydegger at (614) 292- 5399.

160 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 Signature of person authorized to consent for subject 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

161

APPENDIX F

HIPAA FORMS

162 THE OHIO STATE UNIVERSITY AUTHORIZATION TO USE PERSONAL HEALTH INFORMATION IN RESEARCH

OSU Protocol Number:

Principal Investigator: Dr. John Nusstein, DDS, MS

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: ______163

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. Authorized Ohio State University staff not involved in the study may be aware that you are participating in a research study and have access to your information. If this study is related to your medical care, your study-related information may be placed in your permanent hospital, clinic or physician’s office records. • 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 Job and Family 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______

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 164 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 43210 or Dr. Henry Fischbach at the College of Dentistry, 305 W. 12th Avenue, The Ohio State University, Columbus, Ohio 43210 • 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. Henry Fischbach at the College of Dentistry, 305 W. 12th Avenue, The Ohio State University, Columbus, Ohio 43210 • 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 43210

165 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

166

APPENDIX G

INJECTION VAS FORM AND RAW VAS PAIN SCORE DATA

167 Code #: ______

Treatment Pain Sheet

Incision

1. Please place an “X” on the line below to rank the level of pain felt during the incision procedure.

None Faint Weak Mild Moderate Strong Intense Maximum Possible

Drainage

2. Please place an “X” on the line below to rank the level of pain felt during the drainage procedure.

None Faint Weak Mild Moderate Strong Intense Maximum Possible

Dissection

3. Please place an “X” on the line below to rank the level of pain felt during the dissection procedure.

None Faint Weak Mild Moderate Strong Intense Maximum Possible

Note: Visual Analog Scales here are for representation purposes only and are not drawn to scale.

168 SUB 6-DIGIT AGE SEX SIDE AINS APLC ADEP # # yrs 0=Female 0=Right VAS VAS VAS 1=Male 1=Left SCORE SCORE SCORE

1 382985 25 0 0 36 13 90 2 349175 26 1 1 21 21 21 3 950234 29 1 1 36 0 54 4 952149 25 0 1 61 43 82 5 111173 23 0 0 113 142 102 6 317625 23 0 0 21 36 36 7 282284 24 0 0 21 95 112 8 726248 25 0 1 83 71 83 9 670812 25 1 1 21 10 36 10 283330 23 0 0 26 25 90 11 519077 29 1 1 1 12 36 12 469015 26 1 1 43 4 65 13 103606 23 1 1 21 53 54 14 535402 24 0 0 53 36 53 15 603918 26 0 0 21 36 82 16 906941 27 1 1 36 36 21 17 834521 28 1 0 36 36 53 18 462988 25 1 1 5 5 29 19 950932 25 1 1 18 62 39 20 990449 26 1 1 41 29 60 21 998782 27 0 1 55 55 83 22 296243 26 0 1 39 39 82 23 190786 26 0 1 60 50 78 24 946811 28 1 0 21 11 45 25 925096 28 1 0 0 36 53 26 439565 27 1 0 7 8 21 27 420000 26 0 1 13 95 66 28 920009 24 1 0 21 36 82 29 142718 25 0 1 2 2 21 30 800941 23 0 1 21 0 54 31 276956 27 1 0 36 21 1 32 955730 24 1 1 21 0 0 33 776726 24 0 1 54 21 82 34 686959 29 1 0 72 72 51 35 618584 28 1 1 1 0 12 36 981968 27 1 0 57 36 82

169

SUB LINS LPLC LDEP PINS PPLC PDEP APOST1 APOST2 APOST3 # VAS VAS VAS VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE SCORE SCORE SCORE

1 36 21 54 9 29 29 41 36 35 2 21 21 21 21 21 36 0 0 0 3 21 21 21 51 15 81 54 54 0 4 25 25 58 43 27 24 36 36 25 5 21 141 118 83 142 54 21 0 0 6 21 21 36 36 36 54 20 36 0 7 54 54 54 21 21 55 82 54 54 8 54 18 29 68 53 50 83 68 50 9 54 9 36 9 2 21 1 7 21 10 59 58 57 44 120 77 72 42 25 11 21 36 54 19 31 47 37 29 19 12 19 2 61 60 13 36 18 27 28 13 36 2 36 21 36 54 21 20 21 14 36 36 21 21 0 36 54 54 36 15 54 54 82 54 82 82 36 54 21 16 21 36 36 0 21 0 36 36 36 17 19 0 36 36 36 36 52 36 36 18 15 25 45 30 8 28 29 29 10 19 32 50 71 23 24 31 59 40 33 20 42 60 42 52 30 54 21 0 0 21 82 54 54 54 83 82 83 54 36 22 48 5 41 57 9 45 91 43 42 23 88 100 106 69 40 89 59 42 35 24 19 35 44 17 16 50 15 0 0 25 21 54 83 0 36 21 54 21 21 26 29 29 49 61 61 59 18 27 10 27 45 46 70 3 29 60 61 70 67 28 36 48 21 36 54 4 45 25 0 29 6 4 26 0 0 20 15 34 25 30 0 0 54 21 82 36 0 0 0 31 36 36 53 21 53 21 21 0 0 32 0 31 21 21 0 0 21 21 0 33 54 0 54 82 0 71 21 36 21 34 58 39 46 48 24 19 10 1 2 35 19 0 21 22 1 0 36 21 21 36 36 20 141 54 36 54 36 0 0 170

SUB APOST4 LPOST1 LPOST2 LPOST3 LPOST4 PPOST1 PPOST2 PPOST3 PPOST4 # VAS VAS VAS VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE SCORE SCORE SCORE

1 25 28 33 32 18 21 17 5 0 2 0 10 0 0 0 0 0 0 0 3 0 0 0 0 0 0 0 0 0 4 17 18 17 18 3 19 19 7 3 5 0 4 0 0 0 0 0 0 0 6 0 20 0 0 0 21 36 0 0 7 21 36 54 21 21 21 21 10 1 8 5 36 53 53 54 53 70 54 36 9 9 11 21 41 21 6 21 36 21 10 8 51 18 19 20 9 50 25 24 11 17 21 22 9 21 45 32 31 3 12 21 15 48 34 3 29 52 65 33 13 20 23 22 21 2 52 36 54 54 14 0 21 0 0 0 0 0 0 0 15 0 36 36 36 0 54 82 54 36 16 21 36 36 36 36 21 0 0 0 17 58 36 54 36 36 52 38 38 38 18 29 1 2 1 1 30 30 15 2 19 34 24 9 19 1 12 1 0 0 20 0 36 21 2 2 21 15 0 0 21 36 55 0 0 0 83 0 0 0 22 10 60 28 0 0 35 2 2 2 23 7 24 18 10 10 26 17 3 3 24 0 0 0 0 0 21 20 0 0 25 21 36 21 21 21 36 36 21 21 26 0 25 25 29 4 18 8 4 2 27 69 70 81 89 87 72 81 61 62 28 0 0 0 0 0 43 21 0 0 29 2 26 26 4 4 21 21 11 2 30 0 21 36 21 0 0 21 21 21 31 0 21 0 0 0 36 0 0 0 32 0 36 36 21 0 0 36 36 21 33 9 0 0 0 0 21 0 0 0 34 1 14 3 5 5 13 4 3 2 35 0 35 21 0 0 20 0 0 0 36 0 82 54 54 54 36 21 0 0

171

SUB 6-DIGIT AGE SEX SIDE AINS APLC ADEP # # yrs 0=Female 0=Right VAS VAS VAS 1=Male 1=Left SCORE SCORE SCORE

37 955873 26 0 1 52 40 40 38 276896 26 0 1 34 54 83 39 125699 28 0 0 35 18 52 40 456093 24 1 1 54 21 112 41 430391 28 0 1 21 65 21 42 211252 25 0 1 36 35 20 43 522107 23 1 0 40 10 51 44 197812 25 1 0 21 0 54 45 283376 31 1 0 3 15 2 46 830214 26 1 0 42 18 50 47 452838 25 0 0 60 64 91 48 104096 24 0 0 36 0 21 49 118637 24 0 0 36 58 57 50 875755 26 0 0 21 21 36 51 830257 24 1 0 18 14 29 52 146915 38 0 1 21 36 36 53 400386 25 1 0 36 41 53 54 302414 24 1 1 8 0 8 55 723292 25 1 0 21 29 0 56 587571 28 0 0 24 10 49 57 505678 27 0 1 21 36 55 58 276155 20 0 0 21 82 54 59 834661 25 0 1 0 21 36 60 301970 25 1 0 79 48 118

172

SUB LINS LPLC LDEP PINS PPLC PDEP APOST1 APOST2 APOST3 # VAS VAS VAS VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE SCORE SCORE SCORE

37 25 25 39 24 19 40 33 33 33 38 0 21 83 20 20 83 112 112 83 39 21 0 36 21 36 36 57 32 21 40 0 54 54 59 60 87 0 0 0 41 65 21 82 54 66 67 21 0 0 42 52 36 36 0 0 21 36 0 0 43 9 10 21 21 53 36 42 36 19 44 40 32 62 36 54 21 91 82 36 45 1 19 16 5 2 2 16 1 0 46 27 1 15 35 4 12 18 0 0 47 58 38 51 47 41 15 103 67 61 48 21 0 36 54 0 36 36 21 0 49 36 34 35 31 57 51 53 21 19 50 21 36 54 21 36 54 36 36 21 51 0 0 16 33 24 41 0 0 0 52 21 36 54 0 0 36 0 0 0 53 18 54 62 17 10 36 31 21 18 54 21 36 53 21 0 0 0 0 0 55 21 0 54 21 21 0 21 21 0 56 23 49 83 31 87 17 68 29 9 57 21 54 54 0 36 71 15 0 0 58 54 36 36 54 36 82 21 0 0 59 21 82 54 21 36 21 54 36 21 60 58 116 88 58 86 59 20 11 0

173

SUB APOST4 LPOST1 LPOST2 LPOST3 LPOST4 PPOST1 PPOST2 PPOST3 PPOST4 # VAS VAS VAS VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE SCORE SCORE SCORE

37 17 33 55 35 2 42 41 33 12 38 57 21 0 0 0 0 0 0 0 39 21 21 21 0 0 18 0 0 0 40 0 21 0 0 0 2 2 0 0 41 0 0 0 0 0 21 0 0 0 42 0 0 0 0 0 0 0 0 0 43 0 19 4 0 0 36 27 5 3 44 21 0 0 0 0 0 0 0 0 45 0 13 0 0 0 27 24 19 4 46 0 21 0 0 0 10 0 0 0 47 41 71 90 76 49 41 60 71 29 48 0 36 54 21 0 21 21 0 0 49 2 19 4 4 2 2 0 0 0 50 0 36 36 21 21 36 36 21 21 51 0 0 0 0 0 0 0 0 0 52 0 0 0 0 0 0 0 0 0 53 21 0 30 11 2 21 0 0 0 54 0 0 0 0 0 0 0 0 0 55 0 21 21 21 11 0 7 10 5 56 2 5 45 23 0 53 32 25 6 57 0 0 0 0 0 0 0 0 0 58 0 21 0 0 0 0 0 0 0 59 0 36 54 21 0 36 36 0 0 60 0 20 9 8 13 3 5 0 0

174

APPENDIX H

EPT DATA COLLECTION FORMS AND RAW EPT DATA

175

EPT Values

Date______Patient #______Code #______Appointment # ______Side______

nd st nd st 2 1 2 1 Contra- lateral premolar premolar molar molar canine Min. Pre-test Min. Pre-test Base-line

* indicates tooth will be tested with a mock electrode nd st nd st 2 1 2 1 Contra- lateral premolar premolar molar molar canine 1

9 *

nd st nd st 2 1 2 1 Contra- lateral premolar premolar molar molar canine

176

18 *

27 *

36 *

177

45 *

54 *

178

179

SUB 6-DIGIT AGE SEX SIDE AINS APLC ADEP # # yrs 0=Female 0=Right VAS VAS VAS 1=Male 1=Left SCORE SCORE SCORE

1 382985 25 0 0 36 13 90 1 382985 25 0 0 36 13 90 1 382985 25 0 0 36 13 90 1 382985 25 0 0 36 13 90 2 349175 26 1 1 21 21 21 2 349175 26 1 1 21 21 21 2 349175 26 1 1 21 21 21 2 349175 26 1 1 21 21 21 3 950234 29 1 1 36 0 54 3 950234 29 1 1 36 0 54 3 950234 29 1 1 36 0 54 3 950234 29 1 1 36 0 54 4 952149 25 0 1 61 43 82 4 952149 25 0 1 61 43 82 4 952149 25 0 1 61 43 82 4 952149 25 0 1 61 43 82 5 111173 23 0 0 113 142 102 5 111173 23 0 0 113 142 102 5 111173 23 0 0 113 142 102 5 111173 23 0 0 113 142 102 6 317625 23 0 0 21 36 36 6 317625 23 0 0 21 36 36 6 317625 23 0 0 21 36 36 6 317625 23 0 0 21 36 36 7 282284 24 0 0 21 95 112 7 282284 24 0 0 21 95 112 7 282284 24 0 0 21 95 112 7 282284 24 0 0 21 95 112 8 726248 25 0 1 83 71 83 8 726248 25 0 1 83 71 83 8 726248 25 0 1 83 71 83 8 726248 25 0 1 83 71 83 9 670812 25 1 1 21 10 36 9 670812 25 1 1 21 10 36 9 670812 25 1 1 21 10 36 9 670812 25 1 1 21 10 36 10 283330 23 0 0 26 25 90 10 283330 23 0 0 26 25 90 10 283330 23 0 0 26 25 90 10 283330 23 0 0 26 25 90 11 519077 29 1 1 1 12 36 11 519077 29 1 1 1 12 36 11 519077 29 1 1 1 12 36 11 519077 29 1 1 1 12 36

180 SUB 6-DIGIT AGE SEX SIDE AINS APLC ADEP # # yrs 0=Female 0=Right VAS VAS VAS 1=Male 1=Left SCORE SCORE SCORE

12 469015 26 1 1 43 4 65 12 469015 26 1 1 43 4 65 12 469015 26 1 1 43 4 65 12 469015 26 1 1 43 4 65 13 103606 23 1 1 21 53 54 13 103606 23 1 1 21 53 54 13 103606 23 1 1 21 53 54 13 103606 23 1 1 21 53 54 14 535402 24 0 0 53 36 53 14 535402 24 0 0 53 36 53 14 535402 24 0 0 53 36 53 14 535402 24 0 0 53 36 53 15 603918 26 0 0 21 36 82 15 603918 26 0 0 21 36 82 15 603918 26 0 0 21 36 82 15 603918 26 0 0 21 36 82 16 906941 27 1 1 36 36 21 16 906941 27 1 1 36 36 21 16 906941 27 1 1 36 36 21 16 906941 27 1 1 36 36 21 17 834521 28 1 0 36 36 53 17 834521 28 1 0 36 36 53 17 834521 28 1 0 36 36 53 17 834521 28 1 0 36 36 53 18 462988 25 1 1 5 5 29 18 462988 25 1 1 5 5 29 18 462988 25 1 1 5 5 29 18 462988 25 1 1 5 5 29 19 950932 25 1 1 18 62 39 19 950932 25 1 1 18 62 39 19 950932 25 1 1 18 62 39 19 950932 25 1 1 18 62 39 20 990449 26 1 1 41 29 60 20 990449 26 1 1 41 29 60 20 990449 26 1 1 41 29 60 20 990449 26 1 1 41 29 60 21 998782 27 0 1 55 55 83 21 998782 27 0 1 55 55 83 21 998782 27 0 1 55 55 83 21 998782 27 0 1 55 55 83 22 296243 26 0 1 39 39 82 22 296243 26 0 1 39 39 82 22 296243 26 0 1 39 39 82 22 296243 26 0 1 39 39 82

181 SUB 6-DIGIT AGE SEX SIDE AINS APLC ADEP # # yrs 0=Female 0=Right VAS VAS VAS 1=Male 1=Left SCORE SCORE SCORE

23 190786 26 0 1 60 50 78 23 190786 26 0 1 60 50 78 23 190786 26 0 1 60 50 78 23 190786 26 0 1 60 50 78 24 946811 28 1 0 21 11 45 24 946811 28 1 0 21 11 45 24 946811 28 1 0 21 11 45 24 946811 28 1 0 21 11 45 25 925096 28 1 0 0 36 53 25 925096 28 1 0 0 36 53 25 925096 28 1 0 0 36 53 25 925096 28 1 0 0 36 53 26 439565 27 1 0 7 8 21 26 439565 27 1 0 7 8 21 26 439565 27 1 0 7 8 21 26 439565 27 1 0 7 8 21 27 420000 26 0 1 13 95 66 27 420000 26 0 1 13 95 66 27 420000 26 0 1 13 95 66 27 420000 26 0 1 13 95 66 28 920009 24 1 0 21 36 82 28 920009 24 1 0 21 36 82 28 920009 24 1 0 21 36 82 28 920009 24 1 0 21 36 82 29 142718 25 0 1 2 2 21 29 142718 25 0 1 2 2 21 29 142718 25 0 1 2 2 21 29 142718 25 0 1 2 2 21 30 800941 23 0 1 21 0 54 30 800941 23 0 1 21 0 54 30 800941 23 0 1 21 0 54 30 800941 23 0 1 21 0 54 31 276956 27 1 0 36 21 1 31 276956 27 1 0 36 21 1 31 276956 27 1 0 36 21 1 31 276956 27 1 0 36 21 1 32 955730 24 1 1 21 0 0 32 955730 24 1 1 21 0 0 32 955730 24 1 1 21 0 0 32 955730 24 1 1 21 0 0 33 766726 24 0 1 54 21 82 33 776726 24 0 1 54 21 82 33 776726 24 0 1 54 21 82 33 776726 24 0 1 54 21 82

182 SUB 6-DIGIT AGE SEX SIDE AINS APLC ADEP # # yrs 0=Female 0=Right VAS VAS VAS 1=Male 1=Left SCORE SCORE SCORE

34 686959 29 1 0 72 72 51 34 686959 29 1 0 72 72 51 34 686959 29 1 0 72 72 51 34 686959 29 1 0 72 72 51 35 618584 28 1 1 1 0 12 35 618584 28 1 1 1 0 12 35 618584 28 1 1 1 0 12 35 618584 28 1 1 1 0 12 36 981968 27 1 0 57 36 82 36 981968 27 1 0 57 36 82 36 981968 27 1 0 57 36 82 36 981968 27 1 0 57 36 82 37 955873 26 0 1 52 40 40 37 955873 26 0 1 52 40 40 37 955873 26 0 1 52 40 40 37 955873 26 0 1 52 40 40 38 276896 26 0 1 34 54 83 38 276896 26 0 1 34 54 83 38 276896 26 0 1 34 54 83 38 276896 26 0 1 34 54 83 39 125699 28 0 0 35 18 52 39 125699 28 0 0 35 18 52 39 125699 28 0 0 35 18 52 39 125699 28 0 0 35 18 52 40 456093 24 1 1 54 21 112 40 456093 24 1 1 54 21 112 40 456093 24 1 1 54 21 112 40 456093 24 1 1 54 21 112 41 430391 28 0 1 21 65 21 41 430391 28 0 1 21 65 21 41 430391 28 0 1 21 65 21 41 430391 28 0 1 21 65 21 42 211252 25 0 1 36 35 20 42 211252 25 0 1 36 35 20 42 211252 25 0 1 36 35 20 42 211252 25 0 1 36 35 20 43 522107 23 1 0 40 10 51 43 522107 23 1 0 40 10 51 43 522107 23 1 0 40 10 51 43 522107 23 1 0 40 10 51 44 197812 25 1 0 21 0 54 44 197812 25 1 0 21 0 54 44 197812 25 1 0 21 0 54 44 197812 25 1 0 21 0 54

183 SUB 6-DIGIT AGE SEX SIDE AINS APLC ADEP # # yrs 0=Female 0=Right VAS VAS VAS 1=Male 1=Left SCORE SCORE SCORE

45 283376 31 1 0 3 15 2 45 283376 31 1 0 3 15 2 45 283376 31 1 0 3 15 2 45 283376 31 1 0 3 15 2 46 830214 26 1 0 42 18 50 46 830214 26 1 0 42 18 50 46 830214 26 1 0 42 18 50 46 830214 26 1 0 42 18 50 47 452838 25 0 0 60 64 91 47 452838 25 0 0 60 64 91 47 452838 25 0 0 60 64 91 47 452838 25 0 0 60 64 91 48 104096 24 0 0 36 0 21 48 104096 24 0 0 36 0 21 48 104096 24 0 0 36 0 21 48 104096 24 0 0 36 0 21 49 118637 24 0 0 36 58 57 49 118637 24 0 0 36 58 57 49 118637 24 0 0 36 58 57 49 118637 24 0 0 36 58 57 50 875755 26 0 0 21 21 36 50 875755 26 0 0 21 21 36 50 875755 26 0 0 21 21 36 50 875755 26 0 0 21 21 36 51 830285 24 1 0 18 14 29 51 830257 24 1 0 18 14 29 51 830257 24 1 0 18 14 29 51 830257 24 1 0 18 14 29 52 146915 38 0 1 21 36 36 52 146915 38 0 1 21 36 36 52 146915 38 0 1 21 36 36 52 146915 38 0 1 21 36 36 53 400386 25 1 0 36 41 53 53 400386 25 1 0 36 41 53 53 400386 25 1 0 36 41 53 53 400386 25 1 0 36 41 53 54 302414 24 1 1 8 0 8 54 302414 24 1 1 8 0 8 54 302414 24 1 1 8 0 8 54 302414 24 1 1 8 0 8 55 723292 25 1 0 21 29 0 55 723292 25 1 0 21 29 0 55 723292 25 1 0 21 29 0 55 723292 25 1 0 21 29 0

184 SUB 6-DIGIT AGE SEX SIDE AINS APLC ADEP # # yrs 0=Female 0=Right VAS VAS VAS 1=Male 1=Left SCORE SCORE SCORE

56 587571 28 0 0 24 10 49 56 587571 28 0 0 24 10 49 56 587571 28 0 0 24 10 49 56 587571 28 0 0 24 10 49 57 505678 27 0 1 21 36 55 57 505678 27 0 1 21 36 55 57 505678 27 0 1 21 36 55 57 505678 27 0 1 21 36 55 58 276155 20 0 0 21 82 54 58 276155 20 0 0 21 82 54 58 276155 20 0 0 21 82 54 58 276155 20 0 0 21 82 54 59 834661 25 0 1 0 21 36 59 834661 25 0 1 0 21 36 59 834661 25 0 1 0 21 36 59 834661 25 0 1 0 21 36 60 301970 25 1 0 79 48 118 60 301970 25 1 0 79 48 118 60 301970 25 1 0 79 48 118 60 301970 25 1 0 79 48 118

185 SUB 6-DIGIT LINS LPLC LDEP PINS PPLC PDEP # # VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE

1 382985 36 21 54 9 29 29 1 382985 36 21 54 9 29 29 1 382985 36 21 54 9 29 29 1 382985 36 21 54 9 29 29 2 349175 21 21 21 21 21 36 2 349175 21 21 21 21 21 36 2 349175 21 21 21 21 21 36 2 349175 21 21 21 21 21 36 3 950234 21 21 21 51 15 81 3 950234 21 21 21 51 15 81 3 950234 21 21 21 51 15 81 3 950234 21 21 21 51 15 81 4 952149 25 25 58 43 27 24 4 952149 25 25 58 43 27 24 4 952149 25 25 58 43 27 24 4 952149 25 25 58 43 27 24 5 111173 21 141 118 83 142 54 5 111173 21 141 118 83 142 54 5 111173 21 141 118 83 142 54 5 111173 21 141 118 83 142 54 6 317625 21 21 36 36 36 54 6 317625 21 21 36 36 36 54 6 317625 21 21 36 36 36 54 6 317625 21 21 36 36 36 54 7 282284 54 54 54 21 21 55 7 282284 54 54 54 21 21 55 7 282284 54 54 54 21 21 55 7 282284 54 54 54 21 21 55 8 726248 54 18 29 68 53 50 8 726248 54 18 29 68 53 50 8 726248 54 18 29 68 53 50 8 726248 54 18 29 68 53 50 9 670812 54 9 36 9 2 21 9 670812 54 9 36 9 2 21 9 670812 54 9 36 9 2 21 9 670812 54 9 36 9 2 21 10 283330 59 58 57 44 120 77 10 283330 59 58 57 44 120 77 10 283330 59 58 57 44 120 77 10 283330 59 58 57 44 120 77 11 519077 21 36 54 19 31 47 11 519077 21 36 54 19 31 47 11 519077 21 36 54 19 31 47 11 519077 21 36 54 19 31 47

186 SUB 6-DIGIT LINS LPLC LDEP PINS PPLC PDEP # # VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE

12 469015 19 2 61 60 13 36 12 469015 19 2 61 60 13 36 12 469015 19 2 61 60 13 36 12 469015 19 2 61 60 13 36 13 103606 36 2 36 21 36 54 13 103606 36 2 36 21 36 54 13 103606 36 2 36 21 36 54 13 103606 36 2 36 21 36 54 14 535402 36 36 21 21 0 36 14 535402 36 36 21 21 0 36 14 535402 36 36 21 21 0 36 14 535402 36 36 21 21 0 36 15 603918 54 54 82 54 82 82 15 603918 54 54 82 54 82 82 15 603918 54 54 82 54 82 82 15 603918 54 54 82 54 82 82 16 906941 21 36 36 0 21 0 16 906941 21 36 36 0 21 0 16 906941 21 36 36 0 21 0 16 906941 21 36 36 0 21 0 17 834521 19 0 36 36 36 36 17 834521 19 0 36 36 36 36 17 834521 19 0 36 36 36 36 17 834521 19 0 36 36 36 36 18 462988 15 25 45 30 8 28 18 462988 15 25 45 30 8 28 18 462988 15 25 45 30 8 28 18 462988 15 25 45 30 8 28 19 950932 32 50 71 23 24 31 19 950932 32 50 71 23 24 31 19 950932 32 50 71 23 24 31 19 950932 32 50 71 23 24 31 20 990449 42 60 42 52 30 54 20 990449 42 60 42 52 30 54 20 990449 42 60 42 52 30 54 20 990449 42 60 42 52 30 54 21 998782 82 54 54 54 83 82 21 998782 82 54 54 54 83 82 21 998782 82 54 54 54 83 82 21 998782 82 54 54 54 83 82 22 296243 48 5 41 57 9 45 22 296243 48 5 41 57 9 45 22 296243 48 5 41 57 9 45 22 296243 48 5 41 57 9 45

187 SUB 6-DIGIT LINS LPLC LDEP PINS PPLC PDEP # # VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE

23 190786 88 100 106 69 40 89 23 190786 88 100 106 69 40 89 23 190786 88 100 106 69 40 89 23 190786 88 100 106 69 40 89 24 946811 19 35 44 17 16 50 24 946811 19 35 44 17 16 50 24 946811 19 35 44 17 16 50 24 946811 19 35 44 17 16 50 25 925096 21 54 83 0 36 21 25 925096 21 54 83 0 36 21 25 925096 21 54 83 0 36 21 25 925096 21 54 83 0 36 21 26 439565 29 29 49 61 61 59 26 439565 29 29 49 61 61 59 26 439565 29 29 49 61 61 59 26 439565 29 29 49 61 61 59 27 420000 45 46 70 3 29 60 27 420000 45 46 70 3 29 60 27 420000 45 46 70 3 29 60 27 420000 45 46 70 3 29 60 28 920009 36 48 21 36 54 4 28 920009 36 48 21 36 54 4 28 920009 36 48 21 36 54 4 28 920009 36 48 21 36 54 4 29 142718 6 4 26 0 0 20 29 142718 6 4 26 0 0 20 29 142718 6 4 26 0 0 20 29 142718 6 4 26 0 0 20 30 800941 0 0 54 21 82 36 30 800941 0 0 54 21 82 36 30 800941 0 0 54 21 82 36 30 800941 0 0 54 21 82 36 31 276956 36 36 53 21 53 21 31 276956 36 36 53 21 53 21 31 276956 36 36 53 21 53 21 31 276956 36 36 53 21 53 21 32 955730 0 31 21 21 0 0 32 955730 0 31 21 21 0 0 32 955730 0 31 21 21 0 0 32 955730 0 31 21 21 0 0 33 766726 54 0 54 82 0 71 33 776726 54 0 54 82 0 71 33 776726 54 0 54 82 0 71 33 776726 54 0 54 82 0 71

188 SUB 6-DIGIT LINS LPLC LDEP PINS PPLC PDEP # # VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE

34 686959 58 39 46 48 24 19 34 686959 58 39 46 48 24 19 34 686959 58 39 46 48 24 19 34 686959 58 39 46 48 24 19 35 618584 19 0 21 22 1 0 35 618584 19 0 21 22 1 0 35 618584 19 0 21 22 1 0 35 618584 19 0 21 22 1 0 36 981968 36 20 141 54 36 54 36 981968 36 20 141 54 36 54 36 981968 36 20 141 54 36 54 36 981968 36 20 141 54 36 54 37 955873 25 25 39 24 19 40 37 955873 25 25 39 24 19 40 37 955873 25 25 39 24 19 40 37 955873 25 25 39 24 19 40 38 276896 0 21 83 20 20 83 38 276896 0 21 83 20 20 83 38 276896 0 21 83 20 20 83 38 276896 0 21 83 20 20 83 39 125699 21 0 36 21 36 36 39 125699 21 0 36 21 36 36 39 125699 21 0 36 21 36 36 39 125699 21 0 36 21 36 36 40 456093 0 54 54 59 60 87 40 456093 0 54 54 59 60 87 40 456093 0 54 54 59 60 87 40 456093 0 54 54 59 60 87 41 430391 65 21 82 54 66 67 41 430391 65 21 82 54 66 67 41 430391 65 21 82 54 66 67 41 430391 65 21 82 54 66 67 42 211252 52 36 36 0 0 21 42 211252 52 36 36 0 0 21 42 211252 52 36 36 0 0 21 42 211252 52 36 36 0 0 21 43 522107 9 10 21 21 53 36 43 522107 9 10 21 21 53 36 43 522107 9 10 21 21 53 36 43 522107 9 10 21 21 53 36 44 197812 40 32 62 36 54 21 44 197812 40 32 62 36 54 21 44 197812 40 32 62 36 54 21 44 197812 40 32 62 36 54 21

189 SUB 6-DIGIT LINS LPLC LDEP PINS PPLC PDEP # # VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE

45 283376 1 19 16 5 2 2 45 283376 1 19 16 5 2 2 45 283376 1 19 16 5 2 2 45 283376 1 19 16 5 2 2 46 830214 27 1 15 35 4 12 46 830214 27 1 15 35 4 12 46 830214 27 1 15 35 4 12 46 830214 27 1 15 35 4 12 47 452838 58 38 51 47 41 15 47 452838 58 38 51 47 41 15 47 452838 58 38 51 47 41 15 47 452838 58 38 51 47 41 15 48 104096 21 0 36 54 0 36 48 104096 21 0 36 54 0 36 48 104096 21 0 36 54 0 36 48 104096 21 0 36 54 0 36 49 118637 36 34 35 31 57 51 49 118637 36 34 35 31 57 51 49 118637 36 34 35 31 57 51 49 118637 36 34 35 31 57 51 50 875755 21 36 54 21 36 54 50 875755 21 36 54 21 36 54 50 875755 21 36 54 21 36 54 50 875755 21 36 54 21 36 54 51 830285 0 0 16 33 24 41 51 830257 0 0 16 33 24 41 51 830257 0 0 16 33 24 41 51 830257 0 0 16 33 24 41 52 146915 21 36 54 0 0 36 52 146915 21 36 54 0 0 36 52 146915 21 36 54 0 0 36 52 146915 21 36 54 0 0 36 53 400386 18 54 62 17 10 36 53 400386 18 54 62 17 10 36 53 400386 18 54 62 17 10 36 53 400386 18 54 62 17 10 36 54 302414 21 36 53 21 0 0 54 302414 21 36 53 21 0 0 54 302414 21 36 53 21 0 0 54 302414 21 36 53 21 0 0 55 723292 21 0 54 21 21 0 55 723292 21 0 54 21 21 0 55 723292 21 0 54 21 21 0 55 723292 21 0 54 21 21 0

190 SUB 6-DIGIT LINS LPLC LDEP PINS PPLC PDEP # # VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE

56 587571 23 49 83 31 87 17 56 587571 23 49 83 31 87 17 56 587571 23 49 83 31 87 17 56 587571 23 49 83 31 87 17 57 505678 21 54 54 0 36 71 57 505678 21 54 54 0 36 71 57 505678 21 54 54 0 36 71 57 505678 21 54 54 0 36 71 58 276155 54 36 36 54 36 82 58 276155 54 36 36 54 36 82 58 276155 54 36 36 54 36 82 58 276155 54 36 36 54 36 82 59 834661 21 82 54 21 36 21 59 834661 21 82 54 21 36 21 59 834661 21 82 54 21 36 21 59 834661 21 82 54 21 36 21 60 301970 58 116 88 58 86 59 60 301970 58 116 88 58 86 59 60 301970 58 116 88 58 86 59 60 301970 58 116 88 58 86 59

191 SUB 6-DIGIT APOST1 APOST2 APOST3 APOST4 LPOST1 LPOST2 # # VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE

1 382985 41 36 35 25 28 33 1 382985 41 36 35 25 28 33 1 382985 41 36 35 25 28 33 1 382985 41 36 35 25 28 33 2 349175 0 0 0 0 10 0 2 349175 0 0 0 0 10 0 2 349175 0 0 0 0 10 0 2 349175 0 0 0 0 10 0 3 950234 54 54 0 0 0 0 3 950234 54 54 0 0 0 0 3 950234 54 54 0 0 0 0 3 950234 54 54 0 0 0 0 4 952149 36 36 25 17 18 17 4 952149 36 36 25 17 18 17 4 952149 36 36 25 17 18 17 4 952149 36 36 25 17 18 17 5 111173 21 0 0 0 4 0 5 111173 21 0 0 0 4 0 5 111173 21 0 0 0 4 0 5 111173 21 0 0 0 4 0 6 317625 20 36 0 0 20 0 6 317625 20 36 0 0 20 0 6 317625 20 36 0 0 20 0 6 317625 20 36 0 0 20 0 7 282284 82 54 54 21 36 54 7 282284 82 54 54 21 36 54 7 282284 82 54 54 21 36 54 7 282284 82 54 54 21 36 54 8 726248 83 68 50 5 36 53 8 726248 83 68 50 5 36 53 8 726248 83 68 50 5 36 53 8 726248 83 68 50 5 36 53 9 670812 1 7 21 9 11 21 9 670812 1 7 21 9 11 21 9 670812 1 7 21 9 11 21 9 670812 1 7 21 9 11 21 10 283330 72 42 25 8 51 18 10 283330 72 42 25 8 51 18 10 283330 72 42 25 8 51 18 10 283330 72 42 25 8 51 18 11 519077 37 29 19 17 21 22 11 519077 37 29 19 17 21 22 11 519077 37 29 19 17 21 22 11 519077 37 29 19 17 21 22

192 SUB 6-DIGIT APOST1 APOST2 APOST3 APOST4 LPOST1 LPOST2 # # VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE

12 469015 18 27 28 21 15 48 12 469015 18 27 28 21 15 48 12 469015 18 27 28 21 15 48 12 469015 18 27 28 21 15 48 13 103606 21 20 21 20 23 22 13 103606 21 20 21 20 23 22 13 103606 21 20 21 20 23 22 13 103606 21 20 21 20 23 22 14 535402 54 54 36 0 21 0 14 535402 54 54 36 0 21 0 14 535402 54 54 36 0 21 0 14 535402 54 54 36 0 21 0 15 603918 36 54 21 0 36 36 15 603918 36 54 21 0 36 36 15 603918 36 54 21 0 36 36 15 603918 36 54 21 0 36 36 16 906941 36 36 36 21 36 36 16 906941 36 36 36 21 36 36 16 906941 36 36 36 21 36 36 16 906941 36 36 36 21 36 36 17 834521 52 36 36 58 36 54 17 834521 52 36 36 58 36 54 17 834521 52 36 36 58 36 54 17 834521 52 36 36 58 36 54 18 462988 29 29 10 29 1 2 18 462988 29 29 10 29 1 2 18 462988 29 29 10 29 1 2 18 462988 29 29 10 29 1 2 19 950932 59 40 33 34 24 9 19 950932 59 40 33 34 24 9 19 950932 59 40 33 34 24 9 19 950932 59 40 33 34 24 9 20 990449 21 0 0 0 36 21 20 990449 21 0 0 0 36 21 20 990449 21 0 0 0 36 21 20 990449 21 0 0 0 36 21 21 998782 83 54 36 36 55 0 21 998782 83 54 36 36 55 0 21 998782 83 54 36 36 55 0 21 998782 83 54 36 36 55 0 22 296243 91 43 42 10 60 28 22 296243 91 43 42 10 60 28 22 296243 91 43 42 10 60 28 22 296243 91 43 42 10 60 28

193 SUB 6-DIGIT APOST1 APOST2 APOST3 APOST4 LPOST1 LPOST2 # # VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE

23 190786 59 42 35 7 24 18 23 190786 59 42 35 7 24 18 23 190786 59 42 35 7 24 18 23 190786 59 42 35 7 24 18 24 946811 15 0 0 0 0 0 24 946811 15 0 0 0 0 0 24 946811 15 0 0 0 0 0 24 946811 15 0 0 0 0 0 25 925096 54 21 21 21 36 21 25 925096 54 21 21 21 36 21 25 925096 54 21 21 21 36 21 25 925096 54 21 21 21 36 21 26 439565 18 27 10 0 25 25 26 439565 18 27 10 0 25 25 26 439565 18 27 10 0 25 25 26 439565 18 27 10 0 25 25 27 420000 61 70 67 69 70 81 27 420000 61 70 67 69 70 81 27 420000 61 70 67 69 70 81 27 420000 61 70 67 69 70 81 28 920009 45 25 0 0 0 0 28 920009 45 25 0 0 0 0 28 920009 45 25 0 0 0 0 28 920009 45 25 0 0 0 0 29 142718 15 34 25 2 26 26 29 142718 15 34 25 2 26 26 29 142718 15 34 25 2 26 26 29 142718 15 34 25 2 26 26 30 800941 0 0 0 0 21 36 30 800941 0 0 0 0 21 36 30 800941 0 0 0 0 21 36 30 800941 0 0 0 0 21 36 31 276956 21 0 0 0 21 0 31 276956 21 0 0 0 21 0 31 276956 21 0 0 0 21 0 31 276956 21 0 0 0 21 0 32 955730 21 21 0 0 36 36 32 955730 21 21 0 0 36 36 32 955730 21 21 0 0 36 36 32 955730 21 21 0 0 36 36 33 766726 21 36 21 9 0 0 33 776726 21 36 21 9 0 0 33 776726 21 36 21 9 0 0 33 776726 21 36 21 9 0 0

194 SUB 6-DIGIT APOST1 APOST2 APOST3 APOST4 LPOST1 LPOST2 # # VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE

34 686959 10 1 2 1 14 3 34 686959 10 1 2 1 14 3 34 686959 10 1 2 1 14 3 34 686959 10 1 2 1 14 3 35 618584 36 21 21 0 35 21 35 618584 36 21 21 0 35 21 35 618584 36 21 21 0 35 21 35 618584 36 21 21 0 35 21 36 981968 36 0 0 0 82 54 36 981968 36 0 0 0 82 54 36 981968 36 0 0 0 82 54 36 981968 36 0 0 0 82 54 37 955873 33 33 33 17 33 55 37 955873 33 33 33 17 33 55 37 955873 33 33 33 17 33 55 37 955873 33 33 33 17 33 55 38 276896 112 112 83 57 21 0 38 276896 112 112 83 57 21 0 38 276896 112 112 83 57 21 0 38 276896 112 112 83 57 21 0 39 125699 57 32 21 21 21 21 39 125699 57 32 21 21 21 21 39 125699 57 32 21 21 21 21 39 125699 57 32 21 21 21 21 40 456093 0 0 0 0 21 0 40 456093 0 0 0 0 21 0 40 456093 0 0 0 0 21 0 40 456093 0 0 0 0 21 0 41 430391 21 0 0 0 0 0 41 430391 21 0 0 0 0 0 41 430391 21 0 0 0 0 0 41 430391 21 0 0 0 0 0 42 211252 36 0 0 0 0 0 42 211252 36 0 0 0 0 0 42 211252 36 0 0 0 0 0 42 211252 36 0 0 0 0 0 43 522107 42 36 19 0 19 4 43 522107 42 36 19 0 19 4 43 522107 42 36 19 0 19 4 43 522107 42 36 19 0 19 4 44 197812 91 82 36 21 0 0 44 197812 91 82 36 21 0 0 44 197812 91 82 36 21 0 0 44 197812 91 82 36 21 0 0

195 SUB 6-DIGIT APOST1 APOST2 APOST3 APOST4 LPOST1 LPOST2 # # VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE

45 283376 16 1 0 0 13 0 45 283376 16 1 0 0 13 0 45 283376 16 1 0 0 13 0 45 283376 16 1 0 0 13 0 46 830214 18 0 0 0 21 0 46 830214 18 0 0 0 21 0 46 830214 18 0 0 0 21 0 46 830214 18 0 0 0 21 0 47 452838 103 67 61 41 71 90 47 452838 103 67 61 41 71 90 47 452838 103 67 61 41 71 90 47 452838 103 67 61 41 71 90 48 104096 36 21 0 0 36 54 48 104096 36 21 0 0 36 54 48 104096 36 21 0 0 36 54 48 104096 36 21 0 0 36 54 49 118637 53 21 19 2 19 4 49 118637 53 21 19 2 19 4 49 118637 53 21 19 2 19 4 49 118637 53 21 19 2 19 4 50 875755 36 36 21 0 36 36 50 875755 36 36 21 0 36 36 50 875755 36 36 21 0 36 36 50 875755 36 36 21 0 36 36 51 830285 0 0 0 0 0 0 51 830257 0 0 0 0 0 0 51 830257 0 0 0 0 0 0 51 830257 0 0 0 0 0 0 52 146915 0 0 0 0 0 0 52 146915 0 0 0 0 0 0 52 146915 0 0 0 0 0 0 52 146915 0 0 0 0 0 0 53 400386 31 21 18 21 0 30 53 400386 31 21 18 21 0 30 53 400386 31 21 18 21 0 30 53 400386 31 21 18 21 0 30 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 55 723292 21 21 0 0 21 21 55 723292 21 21 0 0 21 21 55 723292 21 21 0 0 21 21 55 723292 21 21 0 0 21 21

196 SUB 6-DIGIT APOST1 APOST2 APOST3 APOST4 LPOST1 LPOST2 # # VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE

56 587571 68 29 9 2 5 45 56 587571 68 29 9 2 5 45 56 587571 68 29 9 2 5 45 56 587571 68 29 9 2 5 45 57 505678 15 0 0 0 0 0 57 505678 15 0 0 0 0 0 57 505678 15 0 0 0 0 0 57 505678 15 0 0 0 0 0 58 276155 21 0 0 0 21 0 58 276155 21 0 0 0 21 0 58 276155 21 0 0 0 21 0 58 276155 21 0 0 0 21 0 59 834661 54 36 21 0 36 54 59 834661 54 36 21 0 36 54 59 834661 54 36 21 0 36 54 59 834661 54 36 21 0 36 54 60 301970 20 11 0 0 20 9 60 301970 20 11 0 0 20 9 60 301970 20 11 0 0 20 9 60 301970 20 11 0 0 20 9

197 SUB 6-DIGIT LPOST3 LPOST4 PPOST1 PPOST2 PPOST3 PPOST4 # # VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE

1 382985 32 18 21 17 5 0 1 382985 32 18 21 17 5 0 1 382985 32 18 21 17 5 0 1 382985 32 18 21 17 5 0 2 349175 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 3 950234 0 0 0 0 0 0 3 950234 0 0 0 0 0 0 3 950234 0 0 0 0 0 0 3 950234 0 0 0 0 0 0 4 952149 18 3 19 19 7 3 4 952149 18 3 19 19 7 3 4 952149 18 3 19 19 7 3 4 952149 18 3 19 19 7 3 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 6 317625 0 0 21 36 0 0 6 317625 0 0 21 36 0 0 6 317625 0 0 21 36 0 0 6 317625 0 0 21 36 0 0 7 282284 21 21 21 21 10 1 7 282284 21 21 21 21 10 1 7 282284 21 21 21 21 10 1 7 282284 21 21 21 21 10 1 8 726248 53 54 53 70 54 36 8 726248 53 54 53 70 54 36 8 726248 53 54 53 70 54 36 8 726248 53 54 53 70 54 36 9 670812 41 21 6 21 36 21 9 670812 41 21 6 21 36 21 9 670812 41 21 6 21 36 21 9 670812 41 21 6 21 36 21 10 283330 19 20 9 50 25 24 10 283330 19 20 9 50 25 24 10 283330 19 20 9 50 25 24 10 283330 19 20 9 50 25 24 11 519077 9 21 45 32 31 3 11 519077 9 21 45 32 31 3 11 519077 9 21 45 32 31 3 11 519077 9 21 45 32 31 3

198 SUB 6-DIGIT LPOST3 LPOST4 PPOST1 PPOST2 PPOST3 PPOST4 # # VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE

12 469015 34 3 29 52 65 33 12 469015 34 3 29 52 65 33 12 469015 34 3 29 52 65 33 12 469015 34 3 29 52 65 33 13 103606 21 2 52 36 54 54 13 103606 21 2 52 36 54 54 13 103606 21 2 52 36 54 54 13 103606 21 2 52 36 54 54 14 535402 0 0 0 0 0 0 14 535402 0 0 0 0 0 0 14 535402 0 0 0 0 0 0 14 535402 0 0 0 0 0 0 15 603918 36 0 54 82 54 36 15 603918 36 0 54 82 54 36 15 603918 36 0 54 82 54 36 15 603918 36 0 54 82 54 36 16 906941 36 36 21 0 0 0 16 906941 36 36 21 0 0 0 16 906941 36 36 21 0 0 0 16 906941 36 36 21 0 0 0 17 834521 36 36 52 38 38 38 17 834521 36 36 52 38 38 38 17 834521 36 36 52 38 38 38 17 834521 36 36 52 38 38 38 18 462988 1 1 30 30 15 2 18 462988 1 1 30 30 15 2 18 462988 1 1 30 30 15 2 18 462988 1 1 30 30 15 2 19 950932 19 1 12 1 0 0 19 950932 19 1 12 1 0 0 19 950932 19 1 12 1 0 0 19 950932 19 1 12 1 0 0 20 990449 2 2 21 15 0 0 20 990449 2 2 21 15 0 0 20 990449 2 2 21 15 0 0 20 990449 2 2 21 15 0 0 21 998782 0 0 83 0 0 0 21 998782 0 0 83 0 0 0 21 998782 0 0 83 0 0 0 21 998782 0 0 83 0 0 0 22 296243 0 0 35 2 2 2 22 296243 0 0 35 2 2 2 22 296243 0 0 35 2 2 2 22 296243 0 0 35 2 2 2

199 SUB 6-DIGIT LPOST3 LPOST4 PPOST1 PPOST2 PPOST3 PPOST4 # # VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE

23 190786 10 10 26 17 3 3 23 190786 10 10 26 17 3 3 23 190786 10 10 26 17 3 3 23 190786 10 10 26 17 3 3 24 946811 0 0 21 20 0 0 24 946811 0 0 21 20 0 0 24 946811 0 0 21 20 0 0 24 946811 0 0 21 20 0 0 25 925096 21 21 36 36 21 21 25 925096 21 21 36 36 21 21 25 925096 21 21 36 36 21 21 25 925096 21 21 36 36 21 21 26 439565 29 4 18 8 4 2 26 439565 29 4 18 8 4 2 26 439565 29 4 18 8 4 2 26 439565 29 4 18 8 4 2 27 420000 89 87 72 81 61 62 27 420000 89 87 72 81 61 62 27 420000 89 87 72 81 61 62 27 420000 89 87 72 81 61 62 28 920009 0 0 43 21 0 0 28 920009 0 0 43 21 0 0 28 920009 0 0 43 21 0 0 28 920009 0 0 43 21 0 0 29 142718 4 4 21 21 11 2 29 142718 4 4 21 21 11 2 29 142718 4 4 21 21 11 2 29 142718 4 4 21 21 11 2 30 800941 21 0 0 21 21 21 30 800941 21 0 0 21 21 21 30 800941 21 0 0 21 21 21 30 800941 21 0 0 21 21 21 31 276956 0 0 36 0 0 0 31 276956 0 0 36 0 0 0 31 276956 0 0 36 0 0 0 31 276956 0 0 36 0 0 0 32 955730 21 0 0 36 36 21 32 955730 21 0 0 36 36 21 32 955730 21 0 0 36 36 21 32 955730 21 0 0 36 36 21 33 766726 0 0 21 0 0 0 33 776726 0 0 21 0 0 0 33 776726 0 0 21 0 0 0 33 776726 0 0 21 0 0 0

200 SUB 6-DIGIT LPOST3 LPOST4 PPOST1 PPOST2 PPOST3 PPOST4 # # VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE

34 686959 5 5 13 4 3 2 34 686959 5 5 13 4 3 2 34 686959 5 5 13 4 3 2 34 686959 5 5 13 4 3 2 35 618584 0 0 20 0 0 0 35 618584 0 0 20 0 0 0 35 618584 0 0 20 0 0 0 35 618584 0 0 20 0 0 0 36 981968 54 54 36 21 0 0 36 981968 54 54 36 21 0 0 36 981968 54 54 36 21 0 0 36 981968 54 54 36 21 0 0 37 955873 35 2 42 41 33 12 37 955873 35 2 42 41 33 12 37 955873 35 2 42 41 33 12 37 955873 35 2 42 41 33 12 38 276896 0 0 0 0 0 0 38 276896 0 0 0 0 0 0 38 276896 0 0 0 0 0 0 38 276896 0 0 0 0 0 0 39 125699 0 0 18 0 0 0 39 125699 0 0 18 0 0 0 39 125699 0 0 18 0 0 0 39 125699 0 0 18 0 0 0 40 456093 0 0 2 2 0 0 40 456093 0 0 2 2 0 0 40 456093 0 0 2 2 0 0 40 456093 0 0 2 2 0 0 41 430391 0 0 21 0 0 0 41 430391 0 0 21 0 0 0 41 430391 0 0 21 0 0 0 41 430391 0 0 21 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 43 522107 0 0 36 27 5 3 43 522107 0 0 36 27 5 3 43 522107 0 0 36 27 5 3 43 522107 0 0 36 27 5 3 44 197812 0 0 0 0 0 0 44 197812 0 0 0 0 0 0 44 197812 0 0 0 0 0 0 44 197812 0 0 0 0 0 0

201 SUB 6-DIGIT LPOST3 LPOST4 PPOST1 PPOST2 PPOST3 PPOST4 # # VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE

45 283376 0 0 27 24 19 4 45 283376 0 0 27 24 19 4 45 283376 0 0 27 24 19 4 45 283376 0 0 27 24 19 4 46 830214 0 0 10 0 0 0 46 830214 0 0 10 0 0 0 46 830214 0 0 10 0 0 0 46 830214 0 0 10 0 0 0 47 452838 76 49 41 60 71 29 47 452838 76 49 41 60 71 29 47 452838 76 49 41 60 71 29 47 452838 76 49 41 60 71 29 48 104096 21 0 21 21 0 0 48 104096 21 0 21 21 0 0 48 104096 21 0 21 21 0 0 48 104096 21 0 21 21 0 0 49 118637 4 2 2 0 0 0 49 118637 4 2 2 0 0 0 49 118637 4 2 2 0 0 0 49 118637 4 2 2 0 0 0 50 875755 21 21 36 36 21 21 50 875755 21 21 36 36 21 21 50 875755 21 21 36 36 21 21 50 875755 21 21 36 36 21 21 51 830285 0 0 0 0 0 0 51 830257 0 0 0 0 0 0 51 830257 0 0 0 0 0 0 51 830257 0 0 0 0 0 0 52 146915 0 0 0 0 0 0 52 146915 0 0 0 0 0 0 52 146915 0 0 0 0 0 0 52 146915 0 0 0 0 0 0 53 400386 11 2 21 0 0 0 53 400386 11 2 21 0 0 0 53 400386 11 2 21 0 0 0 53 400386 11 2 21 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 55 723292 21 11 0 7 10 5 55 723292 21 11 0 7 10 5 55 723292 21 11 0 7 10 5 55 723292 21 11 0 7 10 5

202 SUB 6-DIGIT LPOST3 LPOST4 PPOST1 PPOST2 PPOST3 PPOST4 # # VAS VAS VAS VAS VAS VAS SCORE SCORE SCORE SCORE SCORE SCORE

56 587571 23 0 53 32 25 6 56 587571 23 0 53 32 25 6 56 587571 23 0 53 32 25 6 56 587571 23 0 53 32 25 6 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 59 834661 21 0 36 36 0 0 59 834661 21 0 36 36 0 0 59 834661 21 0 36 36 0 0 59 834661 21 0 36 36 0 0 60 301970 8 13 3 5 0 0 60 301970 8 13 3 5 0 0 60 301970 8 13 3 5 0 0 60 301970 8 13 3 5 0 0

203 SUB 6-DIGIT TOOTH AONSET LONSET PONSET ADURAT1 LDURAT1 # # 1=2M MIN MIN MIN MIN MIN 2=1M 3=2PM 4=1PM 1 382985 1 7 . . 7 0 1 382985 2 16 . . 10 0 1 382985 3 2 . . 36 0 1 382985 4 5 . . 43 0 2 349175 1 . . . 0 0 2 349175 2 13 . . 7 0 2 349175 3 5 . . 37 0 2 349175 4 5 8 8 52 4 3 950234 1 4 4 28 28 19 3 950234 2 4 7 7 13 21 3 950234 3 7 5 5 16 56 3 950234 4 8 8 11 34 13 4 952149 1 19 4 7 7 19 4 952149 2 . . . 0 0 4 952149 3 8 5 8 31 37 4 952149 4 5 2 5 34 46 5 111173 1 10 . . 1 0 5 111173 2 . . . 0 0 5 111173 3 . . . 0 0 5 111173 4 23 . . 7 0 6 317625 1 13 . 31 4 0 6 317625 2 . . . 0 0 6 317625 3 11 . 5 22 0 6 317625 4 5 2 2 31 25 7 282284 1 . 7 . 0 4 7 282284 2 . . . 0 0 7 282284 3 . 14 26 0 43 7 282284 4 . 38 17 0 4 8 726248 1 . . . 0 0 8 726248 2 . . . 0 0 8 726248 3 . . . 0 0 8 726248 4 . . . 0 0 9 670812 1 1 4 . 60 24 9 670812 2 19 4 10 16 15 9 670812 3 5 5 0 24 6 9 670812 4 5 5 11 30 15 10 283330 1 . . . 0 0 10 283330 2 . 7 4 0 16 10 283330 3 . . . 0 0 10 283330 4 5 2 2 10 19 11 519077 1 . 13 . 0 4 11 519077 2 . . . 0 0 11 519077 3 . 2 5 0 59 11 519077 ......

204 SUB 6-DIGIT TOOTH AONSET LONSET PONSET ADURAT1 LDURAT1 # # 1=2M MIN MIN MIN MIN MIN 2=1M 3=2PM 4=1PM 12 469015 1 1 37 . 7 4 12 469015 2 19 . . 7 0 12 469015 3 14 8 . 4 7 12 469015 4 . . . 0 0 13 103606 1 13 7 . 4 4 13 103606 2 22 16 . 4 16 13 103606 ...... 13 103606 4 17 14 . 4 4 14 535402 1 . 1 . 0 37 14 535402 2 13 7 13 28 34 14 535402 3 14 2 8 7 10 14 535402 4 . 8 . 0 13 15 603918 1 1 . . 7 0 15 603918 2 37 . . 4 0 15 603918 3 8 . . 4 0 15 603918 4 . . . 0 0 16 906941 1 13 43 . 10 4 16 906941 2 4 . . 22 0 16 906941 3 5 5 . 15 10 16 906941 4 5 11 . 4 13 17 834521 1 . . . 0 0 17 834521 2 10 . . 13 0 17 834521 3 8 . . 13 0 17 834521 4 . . . 0 0 18 462988 1 13 4 16 25 19 18 462988 2 28 10 . 13 4 18 462988 3 . 8 8 0 16 18 462988 4 . 8 . 0 7 19 950932 1 7 13 . 7 4 19 950932 2 . . . 0 0 19 950932 3 8 17 . 13 10 19 950932 4 . . 11 0 0 20 990449 1 . . . 0 0 20 990449 2 . . . 0 0 20 990449 3 5 . . 43 0 20 990449 4 . . . 0 0 21 998782 1 1 1 1 43 43 21 998782 2 . . . 0 0 21 998782 3 8 . . 28 0 21 998782 4 8 . . 24 0 22 296243 1 . 10 7 0 4 22 296243 2 43 7 1 4 10 22 296243 3 . 14 8 0 4 22 296243 4 . . . 0 0

205 SUB 6-DIGIT TOOTH AONSET LONSET PONSET ADURAT1 LDURAT1 # # 1=2M MIN MIN MIN MIN MIN 2=1M 3=2PM 4=1PM 23 190786 1 4 7 . 31 28 23 190786 2 10 7 . 19 24 23 190786 3 11 17 . 42 7 23 190786 4 . 23 . 0 4 24 946811 1 7 . . 4 0 24 946811 2 7 . . 16 0 24 946811 3 23 . . 7 0 24 946811 4 . . . 0 0 25 925096 1 1 . 22 20 0 25 925096 2 13 . . 7 0 25 925096 3 5 . . 16 0 25 925096 4 8 . . 53 0 26 439565 1 16 . 4 13 0 26 439565 2 7 13 4 43 22 26 439565 ...... 26 439565 4 8 5 5 53 43 27 420000 1 . . . 0 0 27 420000 2 22 . . 4 0 27 420000 ...... 27 420000 4 5 . . 46 0 28 920009 1 4 . . 7 0 28 920009 2 . 10 16 0 7 28 920009 3 . . . 0 0 28 920009 4 20 . . 16 0 29 142718 1 . . . 0 0 29 142718 2 . . . 0 0 29 142718 3 . . . 0 0 29 142718 4 . . . 0 0 30 800941 1 . . . 0 0 30 800941 2 . . . 0 0 30 800941 3 . . . 0 0 30 800941 4 . . . 0 0 31 276956 1 16 . . 28 0 31 276956 2 16 19 10 33 4 31 276956 3 17 14 8 21 19 31 276956 4 . 14 11 0 4 32 955730 1 1 4 1 4 4 32 955730 2 . . . 0 0 32 955730 3 . . . 0 0 32 955730 4 . . . 0 0 33 766726 1 . . . 0 0 33 776726 2 . . . 0 0 33 776726 3 . . . 0 0 33 776726 4 . . . 0 0

206 SUB 6-DIGIT TOOTH AONSET LONSET PONSET ADURAT1 LDURAT1 # # 1=2M MIN MIN MIN MIN MIN 2=1M 3=2PM 4=1PM 34 686959 1 4 28 1 13 7 34 686959 2 1 4 1 20 31 34 686959 3 5 . 4 19 0 34 686959 4 5 . 5 7 0 35 618584 1 . . . 0 0 35 618584 2 16 . . 37 0 35 618584 3 . . . 0 0 35 618584 4 . . . 0 0 36 981968 1 4 28 7 37 7 36 981968 2 4 . 10 25 0 36 981968 3 11 . 14 37 0 36 981968 4 11 . . 16 0 37 955873 1 22 . 13 7 0 37 955873 2 22 . 28 10 0 37 955873 ...... 37 955873 4 . . . 0 0 38 276896 1 13 16 10 28 4 38 276896 2 13 19 . 7 4 38 276896 3 . . . 0 0 38 276896 4 8 23 8 7 4 39 125699 1 . . . 0 0 39 125699 2 10 7 25 4 31 39 125699 3 . 29 . 0 4 39 125699 4 . . . 0 0 40 456093 1 . . . 0 0 40 456093 2 . . 25 0 0 40 456093 3 . . . 0 0 40 456093 4 . . . 0 0 41 430391 1 . . . 0 0 41 430391 2 . . . 0 0 41 430391 3 . . . 0 0 41 430391 ...... 42 211252 1 . . . 0 0 42 211252 2 . . . 0 0 42 211252 3 . . . 0 0 42 211252 4 . . . 0 0 43 522107 1 4 1 28 13 4 43 522107 2 . . . 0 0 43 522107 3 . . . 0 0 43 522107 4 . . 0 0 44 197812 1 10 . . 10 0 44 197812 2 10 . . 19 0 44 197812 3 2 11 . 59 31 44 197812 4 2 5 . 59 46

207 SUB 6-DIGIT TOOTH AONSET LONSET PONSET ADURAT1 LDURAT1 # # 1=2M MIN MIN MIN MIN MIN 2=1M 3=2PM 4=1PM 45 283376 1 . . 7 0 0 45 283376 2 . . 22 0 0 45 283376 3 . . . 0 0 45 283376 4 . 32 . 0 4 46 830214 1 4 13 4 49 7 46 830214 2 4 31 7 4 4 46 830214 3 5 . 8 21 0 46 830214 4 11 . . 21 0 47 452838 1 4 7 . 25 25 47 452838 2 4 7 . 31 34 47 452838 3 14 8 . 4 13 47 452838 4 . 8 . 0 7 48 104096 1 1 1 . 60 4 48 104096 2 4 7 7 56 7 48 104096 3 2 5 . 59 22 48 104096 4 2 5 . 59 56 49 118637 1 4 1 1 55 4 49 118637 2 4 22 . 43 4 49 118637 3 2 5 . 58 55 49 118637 4 5 5 . 55 55 50 875755 1 7 . . 4 0 50 875755 2 37 . . 7 0 50 875755 3 2 5 5 59 21 50 875755 4 2 5 8 51 6 51 830285 1 . . 7 0 0 51 830257 2 . . . 0 0 51 830257 3 5 . 14 55 0 51 830257 4 5 . 10 55 0 52 146915 1 13 4 . 10 16 52 146915 2 10 16 . 7 7 52 146915 ...... 52 146915 4 8 8 5 28 34 53 400386 1 7 22 7 28 10 53 400386 2 7 13 7 28 7 53 400386 3 8 8 . 31 52 53 400386 4 8 11 11 19 40 54 302414 1 . . . 0 0 54 302414 2 . . . 0 0 54 302414 3 . . . 0 0 54 302414 4 26 . . 4 0 55 723292 1 4 . 10 4 0 55 723292 2 4 . . 4 0 55 723292 3 2 5 8 37 13 55 723292 4 2 2 8 34 28

208 SUB 6-DIGIT TOOTH AONSET LONSET PONSET ADURAT1 LDURAT1 # # 1=2M MIN MIN MIN MIN MIN 2=1M 3=2PM 4=1PM 56 587571 1 19 46 1 4 7 56 587571 2 . . 1 0 0 56 587571 3 8 . 11 28 0 56 587571 4 . . . 0 0 57 505678 1 . . . 0 0 57 505678 2 . . . 0 0 57 505678 3 . . . 0 0 57 505678 4 . . . 0 0 58 276155 1 1 . . 10 0 58 276155 2 . . . 0 0 58 276155 3 . . . 0 0 58 276155 4 . . . 0 0 59 834661 1 . . . 0 0 59 834661 2 . . . 0 0 59 834661 3 16 . . 4 0 59 834661 4 . . . 0 0 60 301970 1 1 22 7 4 21 60 301970 2 . . 1 0 0 60 301970 3 17 . 2 12 0 60 301970 4 20 . 2 16 0

209 SUB 6-DIGIT PDURAT1 ASUC1 LSUC1 PSUC1 A1 A2 # # MIN 0=no suc 0=no suc 0=no suc 0=NO 80/800=NO 80/80 1=suc 1=suc 1=suc 1=80/80 1=80/80 Articaine Articaine 1 min 4 min 1 382985 0 1 0 0 0 0 1 382985 0 1 0 0 0 1 1 382985 0 1 0 0 1 1 1 382985 0 1 0 0 0 1 2 349175 0 0 0 0 0 0 2 349175 0 1 0 0 0 0 2 349175 . 1 0 0 0 1 2 349175 7 1 1 1 0 1 3 950234 4 1 1 1 0 1 3 950234 22 1 1 1 0 1 3 950234 28 1 1 1 0 0 3 950234 19 1 1 1 0 0 4 952149 34 1 1 1 0 0 4 952149 0 0 0 0 0 0 4 952149 53 1 1 1 1 0 4 952149 46 1 1 1 0 1 5 111173 0 1 0 0 0 0 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 5 111173 0 1 0 0 0 0 6 317625 3 1 0 1 0 1 6 317625 0 0 0 0 0 0 6 317625 15 1 0 1 0 0 6 317625 15 1 1 1 0 1 7 282284 0 0 1 0 0 0 7 282284 0 0 0 0 0 0 7 282284 4 0 1 1 0 0 7 282284 4 0 1 1 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 9 670812 0 1 1 0 1 1 9 670812 13 1 1 1 1 0 9 670812 0 1 1 0 0 1 9 670812 13 1 1 1 0 1 10 283330 0 0 0 0 0 0 10 283330 4 0 1 1 0 0 10 283330 0 0 0 0 0 0 10 283330 4 1 1 1 0 1 11 519077 0 0 1 0 0 0 11 519077 0 0 0 0 0 0 11 519077 24 0 1 1 0 1 11 519077 ......

210 SUB 6-DIGIT PDURAT1 ASUC1 LSUC1 PSUC1 A1 A2 # # MIN 0=no suc 0=no suc 0=no suc 0=NO 80/800=NO 80/80 1=suc 1=suc 1=suc 1=80/80 1=80/80 Articaine Articaine 1 min 4 min 12 469015 0 1 1 0 1 1 12 469015 0 1 0 0 0 0 12 469015 0 1 1 0 0 0 12 469015 0 0 0 0 0 0 13 103606 0 1 1 0 0 0 13 103606 0 1 1 0 0 0 13 103606 ...... 13 103606 0 1 1 0 0 0 14 535402 0 0 1 0 0 0 14 535402 7 1 1 1 0 0 14 535402 7 1 1 1 0 0 14 535402 0 0 1 0 0 0 15 603918 0 1 0 0 1 1 15 603918 0 1 0 0 0 0 15 603918 0 1 0 0 1 0 15 603918 0 0 0 0 0 0 16 906941 0 1 1 0 0 0 16 906941 0 1 0 0 0 1 16 906941 0 1 1 0 0 1 16 906941 0 1 1 0 0 1 17 834521 0 0 0 0 0 0 17 834521 0 1 0 0 0 0 17 834521 0 1 0 0 0 0 17 834521 0 0 0 0 0 0 18 462988 7 1 1 1 0 0 18 462988 0 1 1 0 0 0 18 462988 7 0 1 1 0 0 18 462988 0 0 1 0 0 0 19 950932 0 1 1 0 0 0 19 950932 0 0 0 0 0 0 19 950932 0 1 1 0 0 0 19 950932 7 0 0 1 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 1 0 0 0 1 20 990449 0 0 0 0 0 0 21 998782 4 1 1 1 1 1 21 998782 0 0 0 0 0 0 21 998782 0 1 0 0 0 0 21 998782 0 1 0 0 0 0 22 296243 19 0 1 1 0 0 22 296243 31 1 1 1 0 0 22 296243 10 0 1 1 0 0 22 296243 0 0 0 0 1 0

211 SUB 6-DIGIT PDURAT1 ASUC1 LSUC1 PSUC1 A1 A2 # # MIN 0=no suc 0=no suc 0=no suc 0=NO 80/800=NO 80/80 1=suc 1=suc 1=suc 1=80/80 1=80/80 Articaine Articaine 1 min 4 min 23 190786 0 1 1 0 0 1 23 190786 0 1 1 0 0 0 23 190786 0 1 1 0 0 0 23 190786 0 0 1 0 0 0 24 946811 0 1 0 0 0 0 24 946811 0 1 0 0 0 0 24 946811 0 1 0 0 0 0 24 946811 0 0 0 0 0 0 25 925096 4 1 0 1 1 1 25 925096 0 1 0 0 0 0 25 925096 0 1 0 0 0 1 25 925096 0 1 0 0 0 0 26 439565 28 1 0 1 0 0 26 439565 28 1 1 1 0 0 26 439565 ...... 26 439565 40 1 1 1 0 0 27 420000 0 0 0 0 0 0 27 420000 0 1 0 0 0 0 27 420000 ...... 27 420000 0 1 0 0 0 1 28 920009 0 1 0 0 0 1 28 920009 7 0 1 1 0 0 28 920009 0 0 0 0 0 0 28 920009 0 1 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 30 800941 0 0 0 0 1 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 31 276956 0 1 0 0 0 0 31 276956 10 1 1 1 0 0 31 276956 23 1 1 1 0 0 31 276956 13 0 1 1 0 0 32 955730 4 1 1 1 1 1 32 955730 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 33 766726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0

212 SUB 6-DIGIT PDURAT1 ASUC1 LSUC1 PSUC1 A1 A2 # # MIN 0=no suc 0=no suc 0=no suc 0=NO 80/800=NO 80/80 1=suc 1=suc 1=suc 1=80/80 1=80/80 Articaine Articaine 1 min 4 min 34 686959 17 1 1 1 0 1 34 686959 20 1 1 1 1 1 34 686959 13 1 0 1 0 1 34 686959 13 1 0 1 0 1 35 618584 0 0 0 0 0 0 35 618584 0 1 0 0 0 0 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 36 981968 4 1 1 1 0 1 36 981968 4 1 0 1 0 1 36 981968 4 1 0 1 0 0 36 981968 0 1 0 0 0 0 37 955873 10 1 0 1 0 0 37 955873 4 1 0 1 0 0 37 955873 ...... 37 955873 0 0 0 0 0 0 38 276896 16 1 1 1 0 0 38 276896 0 1 1 0 0 1 38 276896 0 0 0 0 0 0 38 276896 16 1 1 1 0 0 39 125699 0 0 0 0 0 0 39 125699 4 1 1 1 0 0 39 125699 0 0 1 0 0 0 39 125699 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 4 0 0 1 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 ...... 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 43 522107 7 1 1 1 0 1 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 44 197812 0 1 0 0 1 0 44 197812 0 1 0 0 0 0 44 197812 0 1 1 0 1 1 44 197812 0 1 1 0 1 1

213 SUB 6-DIGIT PDURAT1 ASUC1 LSUC1 PSUC1 A1 A2 # # MIN 0=no suc 0=no suc 0=no suc 0=NO 80/800=NO 80/80 1=suc 1=suc 1=suc 1=80/80 1=80/80 Articaine Articaine 1 min 4 min 45 283376 28 0 0 1 0 0 45 283376 4 0 0 1 0 0 45 283376 0 0 0 0 0 0 45 283376 0 0 1 0 0 0 46 830214 10 1 1 1 0 1 46 830214 22 1 1 1 0 1 46 830214 31 1 0 1 0 1 46 830214 0 1 0 0 0 0 47 452838 0 1 1 0 0 1 47 452838 0 1 1 0 0 1 47 452838 0 1 1 0 0 0 47 452838 0 0 1 0 0 0 48 104096 0 1 1 0 1 1 48 104096 4 1 1 1 0 1 48 104096 0 1 1 0 1 1 48 104096 0 1 1 0 1 1 49 118637 4 1 1 1 0 1 49 118637 0 1 1 0 0 1 49 118637 0 1 1 0 1 1 49 118637 0 1 1 0 0 1 50 875755 0 1 0 0 0 0 50 875755 0 1 0 0 0 0 50 875755 27 1 1 1 1 1 50 875755 30 1 1 1 1 1 51 830285 7 0 0 1 0 0 51 830257 0 0 0 0 0 0 51 830257 13 1 0 1 0 1 51 830257 28 1 0 1 0 1 52 146915 0 1 1 0 0 0 52 146915 0 1 1 0 0 0 52 146915 ...... 52 146915 16 1 1 1 0 0 53 400386 10 1 1 1 0 0 53 400386 4 1 1 1 0 0 53 400386 0 1 1 0 0 0 53 400386 4 1 1 1 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 1 0 0 0 0 55 723292 4 1 0 1 0 1 55 723292 0 1 0 0 0 1 55 723292 19 1 1 1 1 1 55 723292 36 1 1 1 1 1

214 SUB 6-DIGIT PDURAT1 ASUC1 LSUC1 PSUC1 A1 A2 # # MIN 0=no suc 0=no suc 0=no suc 0=NO 80/800=NO 80/80 1=suc 1=suc 1=suc 1=80/80 1=80/80 Articaine Articaine 1 min 4 min 56 587571 4 1 1 1 0 0 56 587571 4 0 0 1 0 0 56 587571 4 1 0 1 0 0 56 587571 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 58 276155 0 1 0 0 1 1 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 1 0 0 0 0 59 834661 0 0 0 0 0 0 60 301970 7 1 1 1 1 1 60 301970 7 0 0 1 0 0 60 301970 26 1 0 1 0 0 60 301970 22 1 0 1 0 0

215 SUB 6-DIGIT A3 A4 A5 A6 A7 A8 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Articaine Articaine Articaine Articaine Articaine Articaine 7 min 10 min 13 min 16 min 19 min 22 min 1 382985 1 1 1 0 0 0 1 382985 0 0 1 1 1 1 1 382985 1 1 1 1 1 1 1 382985 1 1 1 1 1 1 2 349175 0 0 1 0 0 0 2 349175 0 0 1 1 1 0 2 349175 1 1 1 1 1 1 2 349175 1 1 1 1 1 1 3 950234 1 1 1 1 1 1 3 950234 1 1 1 1 0 1 3 950234 1 1 1 1 1 1 3 950234 1 1 1 1 1 1 4 952149 0 0 0 0 1 1 4 952149 0 0 1 0 0 0 4 952149 1 1 1 1 1 1 4 952149 1 1 1 1 1 1 5 111173 0 1 1 0 0 0 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 5 111173 0 1 0 0 0 1 6 317625 0 0 1 1 0 1 6 317625 0 0 0 0 0 0 6 317625 0 1 1 1 1 1 6 317625 1 1 1 1 1 1 7 282284 0 0 0 0 0 0 7 282284 0 0 0 0 0 0 7 282284 0 0 0 0 0 0 7 282284 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 1 0 1 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 9 670812 1 1 1 1 1 1 9 670812 1 0 1 0 1 1 9 670812 1 1 1 1 1 1 9 670812 1 1 1 1 1 1 10 283330 0 0 0 0 0 0 10 283330 0 0 0 0 1 0 10 283330 0 0 0 0 0 0 10 283330 1 1 1 0 0 0 11 519077 0 0 0 0 0 0 11 519077 0 0 0 1 0 0 11 519077 0 0 1 0 0 0 11 519077 ......

216 SUB 6-DIGIT A3 A4 A5 A6 A7 A8 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Articaine Articaine Articaine Articaine Articaine Articaine 7 min 10 min 13 min 16 min 19 min 22 min 12 469015 1 0 0 0 1 1 12 469015 0 0 0 0 1 1 12 469015 1 0 1 1 0 1 12 469015 0 0 0 0 0 0 13 103606 0 0 1 1 0 1 13 103606 0 0 0 0 0 1 13 103606 ...... 13 103606 0 0 0 1 1 0 14 535402 0 1 0 0 1 0 14 535402 0 0 1 1 1 1 14 535402 1 0 1 1 1 0 14 535402 0 0 0 0 0 0 15 603918 1 0 0 0 1 0 15 603918 0 0 0 0 0 0 15 603918 1 1 0 0 0 0 15 603918 0 0 0 0 0 0 16 906941 0 0 1 1 1 1 16 906941 1 1 1 1 1 1 16 906941 1 1 1 1 1 0 16 906941 1 0 1 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 1 1 1 1 1 17 834521 1 1 1 1 1 0 17 834521 0 0 0 0 1 0 18 462988 0 0 1 1 1 1 18 462988 0 0 0 0 0 1 18 462988 0 0 1 0 0 0 18 462988 0 0 0 0 0 0 19 950932 1 1 1 0 1 1 19 950932 0 1 0 0 0 0 19 950932 1 1 1 1 1 0 19 950932 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 1 0 0 0 20 990449 1 1 1 1 1 1 20 990449 0 0 0 0 1 0 21 998782 1 1 1 1 1 1 21 998782 0 0 0 0 0 0 21 998782 1 1 1 1 1 1 21 998782 1 1 1 1 1 1 22 296243 0 0 0 0 0 0 22 296243 0 0 0 0 0 0 22 296243 0 0 0 0 0 0 22 296243 0 0 0 0 0 0

217 SUB 6-DIGIT A3 A4 A5 A6 A7 A8 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Articaine Articaine Articaine Articaine Articaine Articaine 7 min 10 min 13 min 16 min 19 min 22 min 23 190786 1 1 1 1 1 1 23 190786 0 1 1 1 1 1 23 190786 0 1 1 1 1 1 23 190786 0 0 0 0 0 0 24 946811 1 1 0 0 0 0 24 946811 1 1 1 1 1 1 24 946811 0 0 1 0 0 1 24 946811 0 1 0 0 0 0 25 925096 1 1 1 1 1 0 25 925096 0 0 1 1 1 0 25 925096 1 1 1 1 1 0 25 925096 1 1 1 1 1 1 26 439565 0 0 0 1 1 1 26 439565 1 1 1 1 1 1 26 439565 ...... 26 439565 1 1 1 1 1 1 27 420000 0 0 0 0 0 0 27 420000 0 0 0 0 0 1 27 420000 ...... 27 420000 1 1 1 1 1 1 28 920009 1 0 1 1 1 0 28 920009 0 0 0 0 0 0 28 920009 0 0 0 0 0 0 28 920009 0 0 0 0 1 1 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 31 276956 0 0 0 1 1 1 31 276956 0 1 0 1 1 1 31 276956 1 0 0 1 1 1 31 276956 0 0 0 0 0 0 32 955730 0 0 0 0 0 1 32 955730 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 32 955730 0 0 0 0 0 1 33 766726 0 0 0 0 0 0 33 776726 0 0 0 1 0 0 33 776726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0

218 SUB 6-DIGIT A3 A4 A5 A6 A7 A8 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Articaine Articaine Articaine Articaine Articaine Articaine 7 min 10 min 13 min 16 min 19 min 22 min 34 686959 1 1 1 1 0 0 34 686959 1 1 1 1 1 0 34 686959 1 1 1 1 1 1 34 686959 1 1 0 0 1 0 35 618584 0 0 0 1 0 0 35 618584 0 0 0 1 1 1 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 36 981968 1 1 1 1 1 1 36 981968 1 1 1 1 1 1 36 981968 0 1 1 1 1 1 36 981968 0 1 1 1 1 1 37 955873 1 0 1 0 0 1 37 955873 0 0 0 0 0 1 37 955873 ...... 37 955873 0 0 0 0 0 0 38 276896 0 0 1 1 1 1 38 276896 0 0 1 1 1 0 38 276896 0 0 0 0 0 1 38 276896 0 1 1 0 1 1 39 125699 0 0 0 0 0 0 39 125699 0 1 1 0 1 0 39 125699 0 0 0 0 0 0 39 125699 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 ...... 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 43 522107 1 1 1 1 0 0 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 44 197812 0 1 1 1 1 0 44 197812 0 1 1 1 1 1 44 197812 1 1 1 1 1 1 44 197812 1 1 1 1 1 1

219 SUB 6-DIGIT A3 A4 A5 A6 A7 A8 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Articaine Articaine Articaine Articaine Articaine Articaine 7 min 10 min 13 min 16 min 19 min 22 min 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 46 830214 1 1 1 1 1 1 46 830214 1 0 0 0 1 1 46 830214 1 1 1 1 1 1 46 830214 0 1 1 1 1 1 47 452838 1 1 1 1 1 1 47 452838 1 1 1 1 1 1 47 452838 1 0 1 1 0 0 47 452838 0 0 0 0 0 0 48 104096 1 1 1 1 1 1 48 104096 1 1 1 1 1 1 48 104096 1 1 1 1 1 1 48 104096 1 1 1 1 1 1 49 118637 1 1 1 1 1 1 49 118637 1 1 1 1 1 1 49 118637 1 1 1 1 1 1 49 118637 1 1 1 1 1 1 50 875755 1 1 0 0 0 0 50 875755 1 0 0 0 0 0 50 875755 1 1 1 1 1 1 50 875755 1 1 1 1 1 1 51 830285 0 0 0 0 1 0 51 830257 0 0 0 0 0 0 51 830257 1 1 1 1 1 1 51 830257 1 1 1 1 1 1 52 146915 1 0 1 1 1 1 52 146915 0 1 1 1 0 1 52 146915 ...... 52 146915 1 1 1 1 1 1 53 400386 1 1 1 1 1 1 53 400386 1 1 1 1 1 1 53 400386 1 1 1 1 1 1 53 400386 1 1 1 1 1 1 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 1 0 0 0 54 302414 0 0 0 0 0 0 55 723292 1 0 0 0 0 0 55 723292 1 0 1 0 1 0 55 723292 1 1 1 1 1 1 55 723292 1 1 1 1 1 1

220 SUB 6-DIGIT A3 A4 A5 A6 A7 A8 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Articaine Articaine Articaine Articaine Articaine Articaine 7 min 10 min 13 min 16 min 19 min 22 min 56 587571 0 0 1 0 1 1 56 587571 0 0 0 0 0 0 56 587571 1 1 1 1 1 1 56 587571 0 0 0 0 1 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 58 276155 1 1 0 1 1 1 58 276155 1 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 1 0 1 1 0 59 834661 0 0 0 0 0 0 60 301970 0 1 0 1 0 1 60 301970 0 0 0 0 0 0 60 301970 0 0 0 1 1 1 60 301970 0 0 0 0 1 1

221 SUB 6-DIGIT A9 A10 A11 A12 A13 A14 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Articaine Articaine Articaine Articaine Articaine Articaine 25 min 28 min 31 min 34 min 37 min 40 min 1 382985 0 0 0 0 1 1 1 382985 0 0 1 0 0 0 1 382985 1 1 1 1 0 0 1 382985 1 1 1 1 1 1 2 349175 0 0 1 0 0 0 2 349175 0 0 0 0 0 0 2 349175 1 1 1 1 1 1 2 349175 1 1 1 1 1 1 3 950234 1 1 1 0 0 0 3 950234 1 1 0 1 1 1 3 950234 0 0 0 1 1 1 3 950234 1 1 1 1 1 1 4 952149 1 0 0 0 1 0 4 952149 0 0 0 0 0 0 4 952149 1 1 1 1 1 0 4 952149 1 1 1 1 1 0 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 5 111173 1 1 0 0 0 0 6 317625 0 0 0 0 0 0 6 317625 0 0 0 0 0 0 6 317625 1 1 1 0 0 0 6 317625 1 1 1 1 0 0 7 282284 0 0 0 0 0 0 7 282284 0 0 0 0 0 0 7 282284 0 0 0 0 0 0 7 282284 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 1 0 0 0 0 0 8 726248 0 0 0 0 0 1 8 726248 0 0 0 0 0 0 9 670812 1 1 1 1 1 1 9 670812 1 1 1 1 0 1 9 670812 1 1 0 1 1 0 9 670812 1 1 1 1 0 0 10 283330 1 0 0 0 0 0 10 283330 0 0 0 0 0 0 10 283330 0 0 0 0 0 0 10 283330 0 0 0 0 0 0 11 519077 0 0 0 0 0 0 11 519077 0 0 0 0 0 0 11 519077 0 0 0 0 0 0 11 519077 ......

222 SUB 6-DIGIT A9 A10 A11 A12 A13 A14 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Articaine Articaine Articaine Articaine Articaine Articaine 25 min 28 min 31 min 34 min 37 min 40 min 12 469015 1 1 1 1 1 1 12 469015 1 0 0 1 0 0 12 469015 1 1 0 1 1 0 12 469015 0 0 0 0 0 0 13 103606 1 1 1 0 0 0 13 103606 1 0 0 0 0 0 13 103606 ...... 13 103606 0 1 0 0 0 0 14 535402 0 0 0 0 0 1 14 535402 1 1 1 1 1 1 14 535402 1 0 0 0 0 0 14 535402 0 0 0 0 0 0 15 603918 0 1 0 0 0 1 15 603918 0 1 0 0 1 1 15 603918 0 0 0 1 0 0 15 603918 0 1 0 0 0 0 16 906941 0 1 0 0 0 0 16 906941 1 0 0 0 0 0 16 906941 1 1 0 0 1 0 16 906941 1 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 18 462988 1 1 1 1 1 0 18 462988 0 1 1 1 1 1 18 462988 0 0 0 0 0 0 18 462988 0 0 0 0 0 0 19 950932 1 0 0 0 0 0 19 950932 1 0 0 0 0 0 19 950932 1 1 0 0 1 1 19 950932 1 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 1 1 1 1 1 1 20 990449 1 0 0 0 0 0 21 998782 1 1 1 1 1 1 21 998782 0 0 0 0 0 0 21 998782 1 1 1 1 0 0 21 998782 1 1 1 0 0 0 22 296243 0 0 0 0 0 0 22 296243 0 0 0 0 0 0 22 296243 0 0 0 0 0 0 22 296243 0 0 0 0 0 0

223 SUB 6-DIGIT A9 A10 A11 A12 A13 A14 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Articaine Articaine Articaine Articaine Articaine Articaine 25 min 28 min 31 min 34 min 37 min 40 min 23 190786 1 1 1 1 0 0 23 190786 1 1 0 0 0 0 23 190786 1 1 1 1 1 1 23 190786 0 0 0 0 0 0 24 946811 0 0 0 1 0 0 24 946811 0 0 0 0 0 1 24 946811 1 1 0 0 0 0 24 946811 0 0 0 0 0 0 25 925096 1 1 0 1 1 1 25 925096 1 0 1 0 1 1 25 925096 1 0 1 1 1 1 25 925096 1 1 1 1 1 1 26 439565 1 1 0 1 0 0 26 439565 1 1 1 1 1 1 26 439565 ...... 26 439565 1 1 1 1 1 1 27 420000 0 0 0 0 0 0 27 420000 1 0 0 0 0 0 27 420000 ...... 27 420000 1 1 1 1 1 1 28 920009 1 0 1 0 0 0 28 920009 0 0 0 0 0 0 28 920009 0 0 0 0 0 0 28 920009 1 1 1 1 0 0 29 142718 0 0 0 0 0 0 29 142718 1 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 31 276956 1 1 1 1 1 1 31 276956 1 1 1 1 1 1 31 276956 1 1 1 1 1 0 31 276956 0 0 0 0 0 0 32 955730 1 0 0 0 0 0 32 955730 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 33 766726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0

224 SUB 6-DIGIT A9 A10 A11 A12 A13 A14 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Articaine Articaine Articaine Articaine Articaine Articaine 25 min 28 min 31 min 34 min 37 min 40 min 34 686959 1 0 1 1 0 0 34 686959 0 0 1 1 1 0 34 686959 1 0 1 1 1 0 34 686959 0 0 1 1 0 0 35 618584 0 0 0 0 0 0 35 618584 1 1 1 1 1 1 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 36 981968 1 1 1 1 1 1 36 981968 1 1 0 0 0 0 36 981968 1 1 1 1 1 1 36 981968 1 0 1 0 0 0 37 955873 1 1 0 1 1 0 37 955873 1 1 1 0 0 0 37 955873 ...... 37 955873 0 0 0 0 0 1 38 276896 1 1 1 1 1 1 38 276896 1 1 1 1 0 1 38 276896 0 0 0 0 0 0 38 276896 1 1 1 1 1 1 39 125699 0 0 0 0 0 0 39 125699 1 1 1 1 1 1 39 125699 0 0 0 0 0 0 39 125699 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 ...... 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 43 522107 1 0 0 0 0 1 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 44 197812 1 0 1 0 0 0 44 197812 1 1 0 0 0 0 44 197812 1 1 1 1 1 1 44 197812 1 1 1 1 1 1

225 SUB 6-DIGIT A9 A10 A11 A12 A13 A14 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Articaine Articaine Articaine Articaine Articaine Articaine 25 min 28 min 31 min 34 min 37 min 40 min 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 46 830214 1 1 1 1 1 1 46 830214 1 1 1 1 1 1 46 830214 1 1 1 1 0 1 46 830214 1 0 1 1 1 0 47 452838 1 1 0 0 1 1 47 452838 1 1 1 1 0 0 47 452838 1 1 1 0 0 0 47 452838 0 0 0 0 0 0 48 104096 1 1 1 1 1 1 48 104096 1 1 1 1 1 1 48 104096 1 1 1 1 1 1 48 104096 1 1 1 1 1 1 49 118637 1 1 1 1 1 1 49 118637 1 1 1 1 1 1 49 118637 1 1 1 1 1 1 49 118637 1 1 1 1 1 1 50 875755 0 0 0 1 0 1 50 875755 0 0 0 0 1 1 50 875755 1 1 1 1 1 1 50 875755 1 1 1 1 1 1 51 830285 0 0 0 0 0 0 51 830257 0 0 0 0 0 0 51 830257 1 1 1 1 1 1 51 830257 1 1 1 1 1 1 52 146915 0 1 0 0 0 1 52 146915 1 1 0 1 0 1 52 146915 ...... 52 146915 1 1 1 1 0 0 53 400386 1 1 1 1 0 0 53 400386 1 1 1 1 0 0 53 400386 1 1 1 1 1 0 53 400386 1 0 0 0 1 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 1 1 0 0 0 0 55 723292 0 0 0 0 0 0 55 723292 1 1 0 0 0 0 55 723292 1 1 1 1 1 0 55 723292 1 1 1 1 0 0

226 SUB 6-DIGIT A9 A10 A11 A12 A13 A14 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Articaine Articaine Articaine Articaine Articaine Articaine 25 min 28 min 31 min 34 min 37 min 40 min 56 587571 0 0 0 0 1 0 56 587571 0 0 0 0 0 0 56 587571 1 1 1 1 0 1 56 587571 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 58 276155 1 1 1 1 1 1 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 1 0 0 0 0 0 59 834661 0 0 0 0 0 0 60 301970 1 1 1 1 1 1 60 301970 1 0 0 1 0 0 60 301970 1 1 0 1 0 0 60 301970 1 1 1 1 0 0

227 SUB 6-DIGIT A15 A16 A17 A18 A19 A20 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Articaine Articaine Articaine Articaine Articaine Articaine 43 min 46 min 49 min 52 min 55 min 58 min 1 382985 0 0 0 0 0 0 1 382985 0 0 1 0 0 0 1 382985 0 0 0 0 0 0 1 382985 0 1 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 1 1 1 1 1 0 3 950234 1 0 0 0 0 0 3 950234 1 0 0 0 0 0 3 950234 1 1 1 1 1 1 3 950234 0 0 0 0 0 0 4 952149 0 0 1 0 0 1 4 952149 0 0 0 1 0 0 4 952149 1 1 1 1 1 1 4 952149 1 1 1 1 1 1 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 6 317625 0 0 0 0 0 0 6 317625 0 0 0 0 0 0 6 317625 0 0 0 0 0 0 6 317625 0 0 0 0 0 0 7 282284 0 0 0 0 0 0 7 282284 0 0 0 0 0 0 7 282284 0 0 0 0 0 0 7 282284 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 9 670812 1 1 1 1 1 1 9 670812 1 1 0 0 0 0 9 670812 0 1 0 0 0 0 9 670812 0 1 0 0 0 0 10 283330 0 0 1 0 0 0 10 283330 0 0 0 0 0 0 10 283330 0 0 0 0 0 0 10 283330 0 0 0 0 0 0 11 519077 0 0 0 0 0 0 11 519077 0 0 0 0 0 0 11 519077 0 0 0 0 0 0 11 519077 ......

228 SUB 6-DIGIT A15 A16 A17 A18 A19 A20 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Articaine Articaine Articaine Articaine Articaine Articaine 43 min 46 min 49 min 52 min 55 min 58 min 12 469015 0 0 1 1 1 0 12 469015 0 0 0 0 0 1 12 469015 0 0 1 0 0 0 12 469015 0 0 0 0 0 0 13 103606 0 0 0 0 0 0 13 103606 0 0 0 0 0 0 13 103606 ...... 13 103606 0 0 0 0 0 0 14 535402 0 0 0 0 0 0 14 535402 0 0 0 0 0 0 14 535402 0 0 0 0 0 0 14 535402 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 16 906941 0 0 0 0 0 0 16 906941 0 0 0 0 0 0 16 906941 0 0 0 0 0 0 16 906941 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 18 462988 1 1 1 0 0 1 18 462988 0 0 0 0 0 0 18 462988 0 0 0 0 0 0 18 462988 0 0 0 0 0 0 19 950932 0 0 0 0 0 0 19 950932 0 0 0 0 0 0 19 950932 0 0 1 0 1 1 19 950932 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 1 1 0 0 0 0 20 990449 0 0 0 0 0 0 21 998782 1 0 0 0 0 0 21 998782 0 0 0 0 0 0 21 998782 0 0 0 0 0 0 21 998782 0 0 0 0 0 0 22 296243 0 0 0 1 0 0 22 296243 1 1 0 1 0 0 22 296243 0 0 0 0 0 0 22 296243 0 0 0 0 0 0

229 SUB 6-DIGIT A15 A16 A17 A18 A19 A20 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Articaine Articaine Articaine Articaine Articaine Articaine 43 min 46 min 49 min 52 min 55 min 58 min 23 190786 0 0 0 0 0 0 23 190786 0 0 0 0 0 0 23 190786 1 1 1 1 0 0 23 190786 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 25 925096 1 1 0 1 1 1 25 925096 1 0 0 1 1 1 25 925096 1 1 1 1 1 1 25 925096 1 1 1 1 1 1 26 439565 0 1 0 0 0 0 26 439565 1 1 1 0 1 0 26 439565 ...... 26 439565 1 1 1 1 1 1 27 420000 0 0 0 0 0 0 27 420000 0 0 0 0 0 0 27 420000 ...... 27 420000 1 1 1 0 0 0 28 920009 0 0 0 0 0 0 28 920009 0 0 0 0 0 0 28 920009 0 0 0 0 0 0 28 920009 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 31 276956 1 0 0 0 0 0 31 276956 1 1 1 0 0 0 31 276956 1 0 0 0 0 0 31 276956 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 33 766726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0

230 SUB 6-DIGIT A15 A16 A17 A18 A19 A20 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Articaine Articaine Articaine Articaine Articaine Articaine 43 min 46 min 49 min 52 min 55 min 58 min 34 686959 0 1 0 1 0 0 34 686959 0 1 1 0 0 1 34 686959 0 1 0 0 0 1 34 686959 0 0 0 1 1 0 35 618584 0 0 0 0 0 0 35 618584 1 1 1 1 0 1 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 36 981968 0 0 0 1 1 0 36 981968 0 0 0 0 0 0 36 981968 1 1 0 1 1 1 36 981968 0 0 0 0 0 0 37 955873 0 0 0 0 0 0 37 955873 0 0 0 0 0 0 37 955873 ...... 37 955873 0 0 0 0 0 0 38 276896 0 0 0 0 0 0 38 276896 0 0 0 0 0 0 38 276896 0 0 0 0 0 0 38 276896 1 1 1 0 0 0 39 125699 0 0 0 0 0 0 39 125699 1 0 0 0 0 0 39 125699 0 0 0 0 0 0 39 125699 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 ...... 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 44 197812 0 0 0 1 0 0 44 197812 0 0 0 1 0 0 44 197812 1 1 1 1 1 1 44 197812 1 1 1 1 1 1

231 SUB 6-DIGIT A15 A16 A17 A18 A19 A20 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Articaine Articaine Articaine Articaine Articaine Articaine 43 min 46 min 49 min 52 min 55 min 58 min 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 46 830214 1 1 1 1 0 0 46 830214 1 1 1 1 1 0 46 830214 1 1 1 1 1 1 46 830214 0 0 0 0 0 0 47 452838 0 0 0 0 0 0 47 452838 0 0 0 0 0 0 47 452838 0 0 0 0 0 0 47 452838 0 0 0 0 0 0 48 104096 1 1 1 1 1 1 48 104096 1 1 1 1 1 1 48 104096 1 1 1 1 1 1 48 104096 1 1 1 1 1 1 49 118637 1 1 1 1 1 1 49 118637 1 1 0 0 0 0 49 118637 1 1 1 1 1 1 49 118637 1 1 1 1 1 1 50 875755 0 1 1 1 1 1 50 875755 1 0 0 0 0 0 50 875755 1 1 1 1 1 1 50 875755 1 1 1 1 0 0 51 830285 0 0 0 0 0 0 51 830257 0 0 0 0 0 0 51 830257 1 1 1 1 1 1 51 830257 1 1 1 1 1 1 52 146915 0 0 0 0 0 0 52 146915 0 0 0 0 1 0 52 146915 ...... 52 146915 1 0 0 0 0 0 53 400386 0 0 0 0 0 0 53 400386 0 0 0 0 0 0 53 400386 0 0 0 0 0 0 53 400386 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 55 723292 0 0 0 0 0 0 55 723292 0 0 0 0 0 0 55 723292 0 0 0 0 0 0 55 723292 0 0 0 0 0 0

232 SUB 6-DIGIT A15 A16 A17 A18 A19 A20 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Articaine Articaine Articaine Articaine Articaine Articaine 43 min 46 min 49 min 52 min 55 min 58 min 56 587571 0 0 1 0 0 0 56 587571 0 0 0 0 0 0 56 587571 0 0 0 0 0 0 56 587571 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 58 276155 1 1 1 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 60 301970 1 1 1 1 0 1 60 301970 0 0 0 1 0 1 60 301970 0 0 0 1 0 0 60 301970 0 0 0 0 0 0

233 SUB 6-DIGIT L1 L2 L3 L4 L5 L6 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine 1 min 4 min 7 min 10 min 13 min 16 min 1 382985 0 0 0 0 0 0 1 382985 0 0 0 0 0 0 1 382985 0 0 0 1 0 0 1 382985 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 0 0 1 1 0 0 3 950234 0 1 1 1 1 1 3 950234 0 0 1 1 1 1 3 950234 0 1 1 1 1 1 3 950234 0 0 1 1 1 1 4 952149 0 1 1 1 1 1 4 952149 0 0 0 0 0 0 4 952149 0 1 1 1 1 1 4 952149 1 1 1 1 1 1 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 6 317625 0 0 0 0 0 1 6 317625 0 0 0 0 0 0 6 317625 0 0 0 0 0 0 6 317625 1 1 1 1 1 1 7 282284 0 0 1 1 0 1 7 282284 0 0 0 0 0 0 7 282284 0 0 1 0 1 1 7 282284 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 9 670812 0 1 1 1 1 1 9 670812 0 1 1 1 1 1 9 670812 0 1 1 1 0 1 9 670812 0 1 1 1 1 1 10 283330 0 0 0 0 0 0 10 283330 0 0 1 1 1 1 10 283330 0 0 0 0 0 0 10 283330 1 1 1 1 1 1 11 519077 0 0 0 0 1 1 11 519077 0 0 0 0 0 0 11 519077 1 1 1 1 1 1 11 519077 ......

234 SUB 6-DIGIT L1 L2 L3 L4 L5 L6 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine 1 min 4 min 7 min 10 min 13 min 16 min 12 469015 0 0 0 1 0 0 12 469015 0 0 0 0 0 0 12 469015 0 0 1 1 1 0 12 469015 0 0 0 0 0 0 13 103606 0 0 1 1 0 1 13 103606 0 0 0 1 0 1 13 103606 ...... 13 103606 0 0 0 0 1 1 14 535402 1 1 1 1 1 1 14 535402 0 0 1 1 1 1 14 535402 1 1 1 1 0 1 14 535402 0 0 1 1 1 1 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 16 906941 1 0 0 0 1 0 16 906941 1 0 1 0 0 0 16 906941 0 1 1 1 1 0 16 906941 0 0 0 1 1 1 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 18 462988 0 1 1 1 1 1 18 462988 0 0 0 1 1 0 18 462988 0 0 1 1 1 1 18 462988 0 0 1 1 1 0 19 950932 0 0 1 0 1 1 19 950932 0 0 0 0 0 0 19 950932 0 0 0 1 0 1 19 950932 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 21 998782 1 1 1 1 1 1 21 998782 0 0 0 1 0 0 21 998782 0 0 0 0 0 0 21 998782 0 0 0 0 0 0 22 296243 0 0 0 1 1 0 22 296243 0 0 1 1 1 1 22 296243 0 0 0 0 1 1 22 296243 0 0 0 0 0 0

235 SUB 6-DIGIT L1 L2 L3 L4 L5 L6 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine 1 min 4 min 7 min 10 min 13 min 16 min 23 190786 0 0 1 1 1 1 23 190786 0 0 1 1 1 1 23 190786 0 0 0 0 0 1 23 190786 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 25 925096 0 0 0 0 0 0 25 925096 0 1 0 0 0 0 25 925096 0 0 0 0 0 0 25 925096 0 0 0 0 0 0 26 439565 0 0 0 0 0 0 26 439565 0 0 0 0 1 1 26 439565 ...... 26 439565 0 1 1 1 1 1 27 420000 0 0 0 0 0 0 27 420000 0 0 0 0 0 0 27 420000 ...... 27 420000 0 0 0 0 0 0 28 920009 0 0 0 0 0 0 28 920009 0 0 0 1 1 1 28 920009 0 0 0 0 0 0 28 920009 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 31 276956 0 0 0 0 0 0 31 276956 0 0 0 0 0 0 31 276956 0 0 0 0 1 1 31 276956 0 0 0 0 1 1 32 955730 0 1 1 0 0 0 32 955730 0 0 0 0 0 0 32 955730 0 0 0 1 0 0 32 955730 0 0 0 0 1 0 33 766726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0

236 SUB 6-DIGIT L1 L2 L3 L4 L5 L6 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine 1 min 4 min 7 min 10 min 13 min 16 min 34 686959 0 0 0 0 1 0 34 686959 0 1 1 1 1 1 34 686959 0 0 0 1 0 0 34 686959 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 36 981968 0 0 1 0 0 0 36 981968 0 0 0 0 0 0 36 981968 0 0 0 0 1 0 36 981968 0 0 0 0 0 0 37 955873 0 1 0 0 0 0 37 955873 0 0 0 0 0 0 37 955873 ...... 37 955873 0 0 0 0 0 0 38 276896 0 0 0 0 0 1 38 276896 0 0 0 0 0 0 38 276896 0 0 0 0 0 0 38 276896 0 0 0 1 0 1 39 125699 0 0 0 0 0 0 39 125699 0 0 1 1 1 1 39 125699 0 0 0 0 0 0 39 125699 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 ...... 42 211252 0 0 0 1 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 1 0 0 42 211252 0 0 0 0 0 0 43 522107 1 1 0 0 1 1 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 44 197812 0 0 0 0 0 0 44 197812 0 0 0 0 0 0 44 197812 0 0 0 1 1 1 44 197812 0 1 1 1 1 1

237 SUB 6-DIGIT L1 L2 L3 L4 L5 L6 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine 1 min 4 min 7 min 10 min 13 min 16 min 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 46 830214 0 0 0 0 1 1 46 830214 0 0 0 0 0 0 46 830214 0 0 0 0 0 0 46 830214 0 0 0 0 0 0 47 452838 0 0 1 1 1 1 47 452838 0 0 1 1 1 1 47 452838 0 0 1 1 1 1 47 452838 0 0 1 1 1 0 48 104096 1 1 0 0 0 1 48 104096 0 0 1 1 1 0 48 104096 0 1 1 1 1 1 48 104096 0 1 1 1 1 1 49 118637 1 1 0 0 0 1 49 118637 0 0 0 0 0 1 49 118637 0 1 1 1 1 1 49 118637 0 1 1 1 1 1 50 875755 0 0 0 1 0 0 50 875755 0 0 0 0 0 0 50 875755 0 1 1 1 1 1 50 875755 0 1 1 1 0 1 51 830285 0 1 0 0 0 0 51 830257 0 0 0 0 0 0 51 830257 0 0 0 0 0 0 51 830257 0 0 0 0 0 0 52 146915 0 1 1 1 1 1 52 146915 0 0 0 0 0 1 52 146915 ...... 52 146915 0 0 1 1 1 1 53 400386 0 1 0 0 0 1 53 400386 0 0 0 0 1 1 53 400386 0 0 1 1 1 1 53 400386 0 0 0 1 1 1 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 55 723292 0 0 0 0 0 0 55 723292 0 0 0 0 0 0 55 723292 0 1 1 1 1 1 55 723292 1 1 1 1 1 1

238 SUB 6-DIGIT L1 L2 L3 L4 L5 L6 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine 1 min 4 min 7 min 10 min 13 min 16 min 56 587571 0 0 1 0 0 0 56 587571 0 0 0 0 0 0 56 587571 0 0 0 0 0 0 56 587571 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 58 276155 0 0 0 1 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 1 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 60 301970 0 0 0 0 0 0 60 301970 0 0 0 1 0 0 60 301970 0 0 0 0 0 0 60 301970 0 0 0 0 0 0

239 SUB 6-DIGIT L7 L8 L9 L10 L11 L12 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine 19 min 22 min 25 min 28 min 31 min 34 min 1 382985 0 0 0 0 0 0 1 382985 0 0 0 0 0 0 1 382985 0 0 0 0 0 0 1 382985 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 3 950234 1 1 0 1 0 1 3 950234 1 1 1 1 1 1 3 950234 1 1 1 1 1 1 3 950234 1 0 1 1 1 1 4 952149 1 1 0 0 0 0 4 952149 0 0 0 0 0 0 4 952149 1 1 1 1 1 1 4 952149 1 1 1 1 1 1 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 6 317625 1 0 0 0 0 0 6 317625 0 0 0 0 0 0 6 317625 0 0 0 0 0 0 6 317625 1 1 1 0 1 0 7 282284 0 1 1 1 0 0 7 282284 0 0 0 0 0 0 7 282284 1 1 1 1 1 1 7 282284 1 0 0 1 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 9 670812 1 1 1 1 0 0 9 670812 1 0 0 0 0 0 9 670812 1 0 0 0 0 0 9 670812 1 0 0 0 0 0 10 283330 0 0 0 0 0 0 10 283330 1 1 0 0 0 0 10 283330 0 0 0 0 0 0 10 283330 1 0 0 0 0 0 11 519077 0 1 1 1 1 1 11 519077 0 0 0 0 0 0 11 519077 1 1 1 1 1 1 11 519077 ......

240 SUB 6-DIGIT L7 L8 L9 L10 L11 L12 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine 19 min 22 min 25 min 28 min 31 min 34 min 12 469015 0 0 0 0 0 0 12 469015 0 0 0 0 0 0 12 469015 0 0 0 0 0 0 12 469015 0 0 0 0 0 0 13 103606 0 0 1 0 0 0 13 103606 1 1 1 1 1 0 13 103606 ...... 13 103606 0 0 0 0 0 0 14 535402 1 1 1 1 1 1 14 535402 1 1 1 1 1 1 14 535402 0 1 1 1 1 1 14 535402 1 0 0 1 1 1 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 16 906941 1 0 0 0 1 0 16 906941 1 0 0 0 0 0 16 906941 0 0 1 1 0 0 16 906941 1 1 0 1 0 1 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 18 462988 1 1 0 0 0 0 18 462988 0 0 0 0 0 0 18 462988 1 1 0 0 0 0 18 462988 0 0 0 1 0 0 19 950932 0 1 0 0 0 0 19 950932 0 0 0 0 0 0 19 950932 1 1 1 0 1 0 19 950932 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 21 998782 1 1 1 1 1 1 21 998782 0 0 0 0 0 0 21 998782 0 0 0 0 0 0 21 998782 0 0 0 0 0 0 22 296243 0 0 0 0 0 0 22 296243 0 1 0 0 0 1 22 296243 0 0 0 0 0 0 22 296243 0 0 0 0 0 0

241 SUB 6-DIGIT L7 L8 L9 L10 L11 L12 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine 19 min 22 min 25 min 28 min 31 min 34 min 23 190786 1 1 1 1 1 1 23 190786 1 1 1 1 1 0 23 190786 1 1 0 0 0 1 23 190786 0 1 1 0 0 1 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 25 925096 0 0 0 0 0 0 25 925096 0 0 0 0 0 0 25 925096 0 0 0 0 0 0 25 925096 0 0 0 0 0 0 26 439565 0 1 0 0 0 0 26 439565 1 1 1 1 1 1 26 439565 ...... 26 439565 1 1 1 1 1 1 27 420000 0 0 0 0 0 0 27 420000 0 0 0 0 0 0 27 420000 ...... 27 420000 0 0 0 0 0 0 28 920009 0 0 0 0 0 0 28 920009 0 0 0 1 0 1 28 920009 0 0 0 0 0 0 28 920009 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 31 276956 0 0 0 0 0 0 31 276956 1 1 0 0 0 0 31 276956 1 1 1 1 1 0 31 276956 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 33 766726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0

242 SUB 6-DIGIT L7 L8 L9 L10 L11 L12 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine 19 min 22 min 25 min 28 min 31 min 34 min 34 686959 0 0 0 1 1 1 34 686959 1 1 1 1 1 1 34 686959 0 0 0 0 0 0 34 686959 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 36 981968 1 0 0 1 1 1 36 981968 0 0 0 0 0 0 36 981968 0 0 0 0 0 0 36 981968 0 0 0 0 0 0 37 955873 1 0 0 1 0 1 37 955873 0 0 0 0 0 0 37 955873 ...... 37 955873 0 0 0 0 0 0 38 276896 1 0 1 0 0 0 38 276896 1 1 0 0 0 0 38 276896 1 0 0 0 0 0 38 276896 0 1 1 0 0 0 39 125699 0 0 0 0 0 0 39 125699 1 1 1 1 1 1 39 125699 0 0 0 1 1 0 39 125699 0 0 1 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 ...... 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 43 522107 1 0 1 0 0 0 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 44 197812 0 0 0 0 0 0 44 197812 0 0 0 0 0 0 44 197812 1 1 1 1 1 1 44 197812 1 1 1 1 1 1

243 SUB 6-DIGIT L7 L8 L9 L10 L11 L12 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine 19 min 22 min 25 min 28 min 31 min 34 min 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 1 1 46 830214 1 0 1 1 1 0 46 830214 0 0 1 0 1 1 46 830214 0 0 0 0 0 0 46 830214 0 0 0 0 0 0 47 452838 1 1 1 1 1 0 47 452838 1 1 1 1 1 1 47 452838 1 0 1 1 1 1 47 452838 1 1 1 1 1 0 48 104096 0 0 0 0 0 0 48 104096 1 1 1 1 1 1 48 104096 1 1 1 0 1 1 48 104096 1 1 1 1 1 1 49 118637 1 1 0 1 1 1 49 118637 0 1 1 0 0 0 49 118637 1 1 1 1 1 1 49 118637 1 1 1 1 1 1 50 875755 0 0 0 1 0 0 50 875755 0 0 0 0 0 0 50 875755 1 1 1 0 1 1 50 875755 1 1 1 1 1 1 51 830285 0 0 0 0 0 0 51 830257 0 0 0 0 0 0 51 830257 0 0 0 0 0 0 51 830257 0 0 0 0 0 0 52 146915 1 0 0 1 1 0 52 146915 1 1 1 0 1 0 52 146915 ...... 52 146915 1 1 1 1 1 1 53 400386 0 1 1 1 1 0 53 400386 1 0 0 0 0 0 53 400386 1 1 1 1 1 1 53 400386 1 1 1 1 1 1 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 55 723292 0 0 0 0 0 0 55 723292 0 0 0 0 0 0 55 723292 0 1 0 0 0 0 55 723292 1 1 1 1 0 0

244 SUB 6-DIGIT L7 L8 L9 L10 L11 L12 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine 19 min 22 min 25 min 28 min 31 min 34 min 56 587571 0 0 0 0 1 0 56 587571 0 0 0 0 0 1 56 587571 0 0 0 0 0 0 56 587571 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 58 276155 1 0 0 1 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 60 301970 0 1 1 1 1 1 60 301970 0 0 0 0 1 0 60 301970 0 0 0 0 0 0 60 301970 0 0 0 0 0 0

245 SUB 6-DIGIT L13 L14 L15 L16 L17 L18 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine 37 min 40 min 43 min 46 min 49 min 52 min 1 382985 0 0 0 0 0 0 1 382985 0 0 0 0 0 0 1 382985 0 0 0 0 0 0 1 382985 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 3 950234 0 0 1 1 0 0 3 950234 1 0 0 0 0 0 3 950234 1 1 1 1 1 1 3 950234 1 1 0 0 0 0 4 952149 0 0 0 0 0 0 4 952149 0 1 0 1 0 0 4 952149 1 1 0 0 0 0 4 952149 1 1 1 1 0 0 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 6 317625 0 0 0 1 0 0 6 317625 0 0 0 0 0 0 6 317625 0 0 0 0 0 0 6 317625 0 0 0 1 0 0 7 282284 0 0 1 0 1 0 7 282284 0 0 0 0 0 0 7 282284 1 1 1 1 1 1 7 282284 1 1 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 9 670812 0 0 0 0 0 0 9 670812 0 0 0 0 0 0 9 670812 0 0 0 0 0 0 9 670812 0 0 0 0 0 0 10 283330 0 0 0 0 0 0 10 283330 0 0 0 0 0 0 10 283330 0 0 0 0 0 0 10 283330 0 0 0 0 0 0 11 519077 1 0 0 1 0 1 11 519077 0 0 0 0 0 0 11 519077 1 1 1 1 1 1 11 519077 ......

246 SUB 6-DIGIT L13 L14 L15 L16 L17 L18 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine 37 min 40 min 43 min 46 min 49 min 52 min 12 469015 0 1 0 1 0 1 12 469015 0 0 0 0 0 0 12 469015 0 0 0 0 0 0 12 469015 0 0 0 0 0 0 13 103606 0 0 0 0 0 0 13 103606 0 0 0 0 0 0 13 103606 ...... 13 103606 0 0 0 0 0 0 14 535402 1 0 0 0 0 0 14 535402 1 1 0 0 0 0 14 535402 1 1 0 0 0 0 14 535402 1 0 0 0 0 0 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 16 906941 1 1 1 1 0 1 16 906941 0 0 0 0 0 0 16 906941 1 0 0 0 1 0 16 906941 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 18 462988 1 0 0 0 0 0 18 462988 0 0 0 0 0 0 18 462988 0 0 0 0 0 0 18 462988 0 0 0 0 0 0 19 950932 0 0 0 0 1 0 19 950932 0 0 0 0 0 0 19 950932 1 0 0 0 0 0 19 950932 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 21 998782 1 1 1 0 0 0 21 998782 0 0 0 0 0 0 21 998782 0 0 0 0 0 0 21 998782 0 0 0 0 0 0 22 296243 0 0 0 0 0 1 22 296243 1 1 1 1 1 0 22 296243 0 0 0 0 0 0 22 296243 0 0 0 0 0 0

247 SUB 6-DIGIT L13 L14 L15 L16 L17 L18 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine 37 min 40 min 43 min 46 min 49 min 52 min 23 190786 0 0 0 0 0 0 23 190786 0 0 0 0 0 0 23 190786 1 0 0 0 0 0 23 190786 1 0 0 0 0 0 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 25 925096 0 0 0 0 0 0 25 925096 0 0 0 0 0 0 25 925096 0 0 0 0 0 0 25 925096 0 0 0 0 0 0 26 439565 0 0 0 0 0 0 26 439565 0 0 0 0 0 0 26 439565 ...... 26 439565 1 0 1 1 0 0 27 420000 0 0 0 0 0 0 27 420000 0 0 0 0 0 0 27 420000 ...... 27 420000 0 0 0 0 0 0 28 920009 1 0 0 0 0 0 28 920009 1 0 0 0 0 0 28 920009 0 0 0 0 0 0 28 920009 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 31 276956 0 0 0 0 0 0 31 276956 0 0 0 0 0 0 31 276956 0 0 0 0 0 0 31 276956 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 33 766726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0

248 SUB 6-DIGIT L13 L14 L15 L16 L17 L18 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine 37 min 40 min 43 min 46 min 49 min 52 min 34 686959 0 0 1 0 1 1 34 686959 0 0 0 0 1 0 34 686959 0 0 0 0 0 0 34 686959 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 36 981968 0 1 1 0 0 0 36 981968 0 0 0 0 0 0 36 981968 0 0 0 0 0 0 36 981968 0 0 0 0 0 0 37 955873 0 0 0 0 0 0 37 955873 0 0 0 0 0 0 37 955873 ...... 37 955873 0 0 0 0 0 0 38 276896 0 0 0 0 0 0 38 276896 0 0 0 0 0 0 38 276896 0 0 0 0 0 0 38 276896 0 0 0 0 0 0 39 125699 0 0 0 0 0 0 39 125699 1 0 0 0 0 0 39 125699 0 0 0 0 0 0 39 125699 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 ...... 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 44 197812 0 0 0 0 0 0 44 197812 0 0 0 0 0 0 44 197812 1 1 0 0 0 0 44 197812 1 1 1 1 1 0

249 SUB 6-DIGIT L13 L14 L15 L16 L17 L18 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine 37 min 40 min 43 min 46 min 49 min 52 min 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 46 830214 0 1 1 0 0 0 46 830214 0 0 0 0 0 0 46 830214 0 0 0 0 0 0 46 830214 0 0 0 0 0 0 47 452838 1 0 1 0 0 0 47 452838 1 1 0 0 0 0 47 452838 0 1 1 1 0 0 47 452838 1 1 0 1 0 0 48 104096 0 0 0 0 0 0 48 104096 1 1 1 1 1 1 48 104096 1 1 1 1 1 1 48 104096 1 1 1 1 1 1 49 118637 1 0 1 0 1 1 49 118637 0 1 0 0 0 0 49 118637 1 1 1 1 1 1 49 118637 1 1 1 1 1 1 50 875755 0 0 0 0 0 0 50 875755 0 0 0 0 0 0 50 875755 0 1 0 0 0 0 50 875755 1 1 0 0 0 0 51 830285 0 0 0 0 0 0 51 830257 0 0 0 0 0 0 51 830257 0 0 0 0 0 0 51 830257 0 0 0 0 0 0 52 146915 0 0 1 0 0 0 52 146915 1 1 0 0 0 0 52 146915 ...... 52 146915 1 1 0 0 0 0 53 400386 0 1 0 1 1 1 53 400386 1 0 0 0 1 0 53 400386 1 1 1 1 1 1 53 400386 1 1 1 1 1 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 55 723292 0 0 0 0 0 0 55 723292 0 0 0 0 0 0 55 723292 0 0 0 0 0 0 55 723292 0 0 0 0 0 0

250 SUB 6-DIGIT L13 L14 L15 L16 L17 L18 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine Lidocaine 37 min 40 min 43 min 46 min 49 min 52 min 56 587571 0 0 0 1 1 1 56 587571 0 0 0 0 0 0 56 587571 0 0 0 0 0 0 56 587571 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 60 301970 1 1 0 0 0 0 60 301970 0 0 1 0 0 0 60 301970 0 0 0 0 0 0 60 301970 0 0 0 0 0 0

251 SUB 6-DIGIT L19 L20 P1 P2 P3 P4 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Prilocaine Prilocaine Prilocaine Prilocaine 55 min 58 min 1 min 4 min 7 min 10 min 1 382985 0 0 0 0 0 0 1 382985 0 0 0 0 0 0 1 382985 0 0 0 0 1 0 1 382985 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 0 0 0 0 1 1 3 950234 0 0 0 0 0 0 3 950234 0 0 0 0 1 1 3 950234 1 1 0 1 1 1 3 950234 0 0 0 1 0 1 4 952149 0 0 0 0 1 1 4 952149 0 0 0 0 0 0 4 952149 0 0 0 0 1 1 4 952149 0 0 1 1 1 1 5 111173 0 0 0 0 0 1 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 6 317625 0 0 1 0 0 0 6 317625 0 0 0 0 0 0 6 317625 0 0 0 1 1 1 6 317625 0 0 0 1 1 1 7 282284 1 1 0 0 0 0 7 282284 0 0 0 0 0 0 7 282284 1 0 0 0 0 0 7 282284 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 9 670812 0 0 0 0 0 0 9 670812 0 0 0 0 0 1 9 670812 0 0 0 0 1 0 9 670812 0 0 0 0 0 1 10 283330 0 0 0 1 0 0 10 283330 0 0 0 1 1 0 10 283330 0 0 0 1 0 1 10 283330 0 0 1 1 0 1 11 519077 0 0 0 0 0 0 11 519077 0 0 0 0 0 0 11 519077 1 1 0 1 1 1 11 519077 ......

252 SUB 6-DIGIT L19 L20 P1 P2 P3 P4 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Prilocaine Prilocaine Prilocaine Prilocaine 55 min 58 min 1 min 4 min 7 min 10 min 12 469015 1 1 0 0 0 0 12 469015 0 0 0 0 0 0 12 469015 0 0 0 0 0 0 12 469015 0 0 0 0 0 0 13 103606 0 0 0 0 0 0 13 103606 0 0 0 0 0 0 13 103606 ...... 13 103606 0 0 0 0 0 0 14 535402 0 0 0 0 0 1 14 535402 0 0 0 0 1 0 14 535402 0 0 0 0 1 1 14 535402 0 0 0 0 1 0 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 16 906941 0 1 0 0 0 0 16 906941 0 0 0 0 0 0 16 906941 0 0 0 0 0 0 16 906941 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 18 462988 0 0 0 0 0 0 18 462988 0 0 0 0 0 0 18 462988 0 0 0 0 1 1 18 462988 0 0 0 0 0 0 19 950932 0 0 0 0 0 0 19 950932 0 0 0 0 0 0 19 950932 0 0 0 0 0 0 19 950932 0 0 0 0 0 1 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 21 998782 1 1 1 1 0 0 21 998782 0 0 0 0 1 0 21 998782 0 0 0 0 0 0 21 998782 0 0 0 0 0 0 22 296243 0 0 0 0 1 1 22 296243 0 1 1 1 1 1 22 296243 0 0 0 0 1 1 22 296243 0 0 0 0 0 1

253 SUB 6-DIGIT L19 L20 P1 P2 P3 P4 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Prilocaine Prilocaine Prilocaine Prilocaine 55 min 58 min 1 min 4 min 7 min 10 min 23 190786 0 0 0 0 0 0 23 190786 0 0 0 0 0 0 23 190786 0 0 0 0 0 0 23 190786 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 25 925096 0 0 0 0 0 0 25 925096 0 0 0 0 0 0 25 925096 0 0 0 0 0 0 25 925096 0 0 0 0 0 0 26 439565 0 0 0 1 1 1 26 439565 0 0 0 1 1 1 26 439565 ...... 26 439565 0 0 0 1 1 1 27 420000 0 0 0 0 0 0 27 420000 0 0 0 0 0 0 27 420000 ...... 27 420000 0 0 0 0 0 0 28 920009 0 0 0 0 1 0 28 920009 0 0 0 1 0 0 28 920009 0 0 0 0 0 0 28 920009 0 0 0 0 0 0 29 142718 0 0 1 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 31 276956 0 0 0 0 0 0 31 276956 0 0 0 0 0 1 31 276956 0 0 0 0 1 1 31 276956 0 0 0 0 0 1 32 955730 0 0 1 1 0 0 32 955730 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 32 955730 0 0 1 0 0 0 33 766726 0 0 1 0 0 0 33 776726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0

254 SUB 6-DIGIT L19 L20 P1 P2 P3 P4 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Prilocaine Prilocaine Prilocaine Prilocaine 55 min 58 min 1 min 4 min 7 min 10 min 34 686959 0 1 1 1 1 1 34 686959 1 0 1 1 1 1 34 686959 0 0 0 1 1 1 34 686959 0 0 0 1 1 1 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 36 981968 0 0 0 0 1 1 36 981968 1 0 0 0 0 1 36 981968 0 0 0 0 0 0 36 981968 0 0 0 0 0 0 37 955873 0 0 1 0 0 0 37 955873 0 0 0 0 0 0 37 955873 ...... 37 955873 0 0 0 0 0 0 38 276896 0 0 0 0 0 1 38 276896 0 0 0 0 0 1 38 276896 0 0 0 0 0 0 38 276896 0 0 0 0 1 1 39 125699 0 0 0 0 0 0 39 125699 0 0 0 0 1 0 39 125699 0 0 0 0 0 0 39 125699 0 0 0 0 0 0 40 456093 0 0 1 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 ...... 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 44 197812 0 0 0 0 1 0 44 197812 0 0 0 0 0 0 44 197812 0 0 0 0 0 0 44 197812 0 0 0 0 0 0

255 SUB 6-DIGIT L19 L20 P1 P2 P3 P4 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Prilocaine Prilocaine Prilocaine Prilocaine 55 min 58 min 1 min 4 min 7 min 10 min 45 283376 0 0 0 0 1 1 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 46 830214 0 0 0 1 1 1 46 830214 0 0 0 0 1 1 46 830214 0 0 0 0 1 1 46 830214 0 0 0 0 0 1 47 452838 0 0 0 0 0 0 47 452838 0 0 0 0 0 0 47 452838 0 0 0 0 0 0 47 452838 0 0 0 0 0 0 48 104096 0 0 0 0 0 0 48 104096 1 1 0 0 1 1 48 104096 1 1 0 0 0 0 48 104096 1 1 0 0 0 0 49 118637 1 1 1 1 0 1 49 118637 0 0 0 0 0 0 49 118637 1 1 0 0 0 0 49 118637 1 1 0 0 0 0 50 875755 0 0 0 0 0 0 50 875755 0 0 0 0 0 0 50 875755 0 0 0 1 1 1 50 875755 0 0 0 0 1 1 51 830285 0 0 0 0 1 1 51 830257 0 0 0 0 0 0 51 830257 0 0 0 0 0 0 51 830257 0 0 0 0 0 1 52 146915 1 0 0 0 0 0 52 146915 0 0 0 0 0 1 52 146915 ...... 52 146915 0 0 0 1 1 1 53 400386 1 0 0 0 1 1 53 400386 1 0 0 0 1 1 53 400386 1 1 0 1 0 0 53 400386 0 0 0 0 0 1 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 55 723292 0 0 0 0 0 1 55 723292 0 0 0 0 0 0 55 723292 0 0 0 0 1 1 55 723292 0 0 0 1 1 1

256 SUB 6-DIGIT L19 L20 P1 P2 P3 P4 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Lidocaine Lidocaine Prilocaine Prilocaine Prilocaine Prilocaine 55 min 58 min 1 min 4 min 7 min 10 min 56 587571 0 0 1 1 0 1 56 587571 0 0 1 1 0 1 56 587571 0 0 0 1 0 1 56 587571 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 60 301970 1 0 1 0 1 1 60 301970 0 0 1 1 1 0 60 301970 0 0 1 1 1 1 60 301970 0 0 1 1 1 1

257 SUB 6-DIGIT P5 P6 P7 P8 P9 P10 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine 13 min 16 min 19 min 22 min 25 min 28 min 1 382985 0 0 0 0 0 0 1 382985 0 0 0 0 0 0 1 382985 0 0 0 0 0 0 1 382985 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 0 0 1 0 0 0 2 349175 0 0 0 0 0 0 2 349175 1 0 0 0 0 0 3 950234 0 1 0 1 0 1 3 950234 1 1 1 1 1 1 3 950234 1 1 1 1 1 1 3 950234 1 1 1 1 1 1 4 952149 1 1 1 1 1 1 4 952149 0 1 0 0 0 0 4 952149 1 1 1 1 1 1 4 952149 1 1 1 1 1 1 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 5 111173 0 1 0 0 0 0 6 317625 0 1 0 0 0 0 6 317625 0 1 0 0 0 0 6 317625 1 1 1 0 0 0 6 317625 1 1 1 0 1 1 7 282284 0 0 0 0 0 1 7 282284 0 0 0 0 0 1 7 282284 0 0 0 0 1 1 7 282284 0 1 1 0 1 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 9 670812 0 0 0 0 0 1 9 670812 1 0 0 0 0 1 9 670812 0 0 0 0 0 0 9 670812 1 1 1 1 0 0 10 283330 0 0 0 0 0 0 10 283330 0 0 0 0 1 0 10 283330 0 0 1 0 0 1 10 283330 1 1 1 1 1 1 11 519077 0 0 0 0 0 0 11 519077 0 0 0 0 0 0 11 519077 1 1 1 1 1 1 11 519077 ......

258 SUB 6-DIGIT P5 P6 P7 P8 P9 P10 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine 13 min 16 min 19 min 22 min 25 min 28 min 12 469015 0 0 0 0 0 0 12 469015 0 0 0 0 0 0 12 469015 0 0 0 0 0 0 12 469015 0 0 0 0 0 0 13 103606 0 0 0 0 0 0 13 103606 0 0 0 0 0 0 13 103606 ...... 13 103606 0 0 0 0 0 0 14 535402 0 0 0 0 0 0 14 535402 1 1 1 0 1 0 14 535402 1 0 0 0 1 1 14 535402 1 0 0 0 0 0 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 16 906941 0 0 0 0 0 0 16 906941 0 0 0 0 0 0 16 906941 0 0 0 0 0 0 16 906941 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 18 462988 0 1 1 1 0 1 18 462988 1 0 0 0 0 1 18 462988 1 0 0 0 0 0 18 462988 1 0 0 1 0 0 19 950932 0 0 0 0 0 0 19 950932 0 0 0 0 0 0 19 950932 0 0 0 0 0 0 19 950932 1 1 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 21 998782 0 1 1 1 1 0 21 998782 0 0 0 0 0 0 21 998782 0 0 0 1 0 0 21 998782 0 0 1 0 0 0 22 296243 1 1 1 1 1 0 22 296243 1 1 1 1 1 1 22 296243 1 1 0 0 0 0 22 296243 0 0 0 0 1 0

259 SUB 6-DIGIT P5 P6 P7 P8 P9 P10 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine 13 min 16 min 19 min 22 min 25 min 28 min 23 190786 0 0 0 0 0 0 23 190786 0 0 0 0 0 0 23 190786 0 0 0 0 0 0 23 190786 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 25 925096 0 0 0 1 1 0 25 925096 0 0 0 0 0 0 25 925096 0 0 0 0 0 0 25 925096 0 0 0 0 0 0 26 439565 1 1 1 1 1 1 26 439565 1 1 1 1 1 1 26 439565 ...... 26 439565 1 1 1 1 1 1 27 420000 0 0 0 0 0 0 27 420000 0 0 0 0 0 0 27 420000 ...... 27 420000 0 0 0 0 0 0 28 920009 0 0 0 0 0 0 28 920009 0 1 1 1 0 0 28 920009 0 0 0 0 0 0 28 920009 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 31 276956 0 0 0 0 0 0 31 276956 1 1 1 0 0 0 31 276956 1 1 1 1 1 1 31 276956 1 1 1 1 0 0 32 955730 1 0 0 0 1 1 32 955730 0 0 0 0 0 1 32 955730 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 33 766726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0

260 SUB 6-DIGIT P5 P6 P7 P8 P9 P10 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine 13 min 16 min 19 min 22 min 25 min 28 min 34 686959 1 1 0 0 0 0 34 686959 1 1 1 0 0 0 34 686959 1 1 0 0 0 0 34 686959 1 1 0 0 0 0 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 36 981968 0 0 0 0 0 0 36 981968 1 0 0 0 0 0 36 981968 1 1 0 0 0 0 36 981968 0 0 0 0 0 0 37 955873 1 1 1 1 0 1 37 955873 0 0 0 0 0 1 37 955873 ...... 37 955873 0 0 0 0 0 0 38 276896 1 1 1 1 1 0 38 276896 0 0 0 0 0 0 38 276896 0 0 0 0 0 0 38 276896 1 1 1 1 0 0 39 125699 0 0 0 0 0 0 39 125699 1 0 0 0 1 1 39 125699 0 0 0 0 0 0 39 125699 0 0 0 0 0 0 40 456093 1 0 1 0 0 0 40 456093 0 0 0 0 1 1 40 456093 0 0 1 0 0 0 40 456093 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 0 0 0 1 0 0 41 430391 0 0 0 0 0 0 41 430391 ...... 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 43 522107 0 0 1 0 0 1 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 44 197812 0 0 0 0 0 0 44 197812 0 0 0 0 0 0 44 197812 0 0 0 0 0 0 44 197812 0 0 0 0 0 0

261 SUB 6-DIGIT P5 P6 P7 P8 P9 P10 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine 13 min 16 min 19 min 22 min 25 min 28 min 45 283376 1 1 1 1 1 1 45 283376 1 0 0 1 1 0 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 46 830214 1 1 0 0 0 0 46 830214 1 1 1 1 1 1 46 830214 1 1 1 1 1 1 46 830214 0 0 0 0 0 0 47 452838 0 0 0 0 0 0 47 452838 0 0 0 0 0 0 47 452838 0 0 0 0 0 0 47 452838 0 0 0 0 0 0 48 104096 0 0 0 0 0 0 48 104096 0 0 0 0 0 0 48 104096 0 0 0 0 0 0 48 104096 0 0 0 0 0 0 49 118637 1 1 1 0 0 0 49 118637 0 0 0 0 0 0 49 118637 0 0 0 0 0 0 49 118637 0 0 0 0 0 0 50 875755 0 0 1 0 0 0 50 875755 0 0 0 0 0 0 50 875755 1 1 1 1 1 1 50 875755 1 1 1 1 1 1 51 830285 1 0 0 0 0 1 51 830257 0 0 0 0 0 0 51 830257 1 1 1 1 1 0 51 830257 1 1 1 1 1 1 52 146915 0 0 0 0 1 0 52 146915 0 0 0 0 0 0 52 146915 ...... 52 146915 1 1 1 0 0 0 53 400386 1 1 0 1 0 0 53 400386 0 1 0 0 0 1 53 400386 0 1 0 0 0 0 53 400386 1 0 0 0 1 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 55 723292 1 0 0 0 0 1 55 723292 1 0 1 0 0 0 55 723292 1 1 1 1 1 0 55 723292 1 1 1 1 1 1

262 SUB 6-DIGIT P5 P6 P7 P8 P9 P10 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine 13 min 16 min 19 min 22 min 25 min 28 min 56 587571 1 0 0 0 1 0 56 587571 0 0 0 0 1 1 56 587571 1 0 1 1 1 0 56 587571 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 60 301970 1 0 1 0 0 1 60 301970 1 0 0 0 1 0 60 301970 1 1 1 1 1 0 60 301970 1 1 1 1 0 1

263 SUB 6-DIGIT P11 P12 P13 P14 P15 P16 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine 31 min 34 min 37 min 40 min 43 min 46 min 1 382985 0 0 0 0 0 0 1 382985 0 0 0 0 0 0 1 382985 0 0 0 0 0 0 1 382985 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 2 349175 0 0 0 0 0 0 3 950234 1 0 0 0 0 0 3 950234 0 1 0 0 0 0 3 950234 1 0 0 0 0 0 3 950234 0 0 0 0 0 0 4 952149 1 1 1 1 0 1 4 952149 0 0 0 1 0 1 4 952149 1 1 1 1 1 1 4 952149 1 1 1 1 1 1 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 5 111173 0 0 0 0 0 0 6 317625 1 1 0 0 0 0 6 317625 0 0 0 0 0 1 6 317625 0 0 0 0 0 0 6 317625 0 1 1 1 1 1 7 282284 0 0 0 0 0 0 7 282284 0 0 0 0 0 0 7 282284 0 0 0 0 0 0 7 282284 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 8 726248 0 0 0 0 0 0 9 670812 0 1 0 0 0 0 9 670812 0 1 0 1 0 1 9 670812 0 0 0 0 1 0 9 670812 0 0 0 0 0 0 10 283330 0 0 0 0 0 0 10 283330 0 0 0 0 0 0 10 283330 0 0 0 0 0 0 10 283330 0 0 0 0 0 0 11 519077 0 0 0 0 0 0 11 519077 0 0 0 0 0 0 11 519077 1 1 1 0 0 1 11 519077 ......

264 SUB 6-DIGIT P11 P12 P13 P14 P15 P16 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine 31 min 34 min 37 min 40 min 43 min 46 min 12 469015 0 0 0 0 0 0 12 469015 0 0 0 0 0 0 12 469015 0 0 0 0 0 0 12 469015 1 0 0 0 0 0 13 103606 0 0 0 0 0 0 13 103606 0 0 0 0 0 0 13 103606 ...... 13 103606 0 0 0 0 0 0 14 535402 0 0 0 0 0 0 14 535402 0 0 0 0 0 0 14 535402 0 0 0 0 0 0 14 535402 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 15 603918 0 0 0 0 0 0 16 906941 0 0 0 0 0 0 16 906941 0 0 0 0 0 0 16 906941 0 0 0 0 0 0 16 906941 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 17 834521 0 0 0 0 0 0 18 462988 0 0 0 0 0 0 18 462988 0 0 0 0 0 0 18 462988 0 0 0 0 0 0 18 462988 0 0 0 0 0 0 19 950932 0 0 0 0 0 0 19 950932 0 0 0 0 0 0 19 950932 0 0 0 0 0 0 19 950932 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 20 990449 0 0 0 0 0 0 21 998782 0 0 0 0 0 0 21 998782 0 0 0 0 0 0 21 998782 0 0 0 0 0 0 21 998782 0 0 0 0 0 0 22 296243 1 0 0 0 0 0 22 296243 1 0 1 0 1 0 22 296243 0 0 0 0 0 0 22 296243 0 0 0 0 0 0

265 SUB 6-DIGIT P11 P12 P13 P14 P15 P16 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine 31 min 34 min 37 min 40 min 43 min 46 min 23 190786 0 0 0 0 0 0 23 190786 0 0 0 0 0 0 23 190786 0 0 0 0 0 0 23 190786 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 24 946811 0 0 0 0 0 0 25 925096 0 0 0 0 0 0 25 925096 0 0 0 0 0 0 25 925096 0 0 0 0 0 0 25 925096 0 0 0 0 0 0 26 439565 1 0 1 0 0 0 26 439565 1 0 1 0 0 0 26 439565 ...... 26 439565 1 1 1 1 1 0 27 420000 0 0 0 0 0 0 27 420000 0 0 0 0 0 0 27 420000 ...... 27 420000 0 0 0 0 0 0 28 920009 0 0 0 0 0 0 28 920009 0 0 0 0 0 0 28 920009 0 0 0 0 0 0 28 920009 0 0 0 0 0 0 29 142718 0 1 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 29 142718 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 30 800941 0 0 0 0 0 0 31 276956 0 0 0 0 0 0 31 276956 0 0 0 0 0 0 31 276956 0 0 0 0 0 0 31 276956 0 0 0 0 0 0 32 955730 1 0 1 1 1 1 32 955730 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 32 955730 0 0 0 0 0 0 33 766726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0 33 776726 0 0 0 0 0 0

266 SUB 6-DIGIT P11 P12 P13 P14 P15 P16 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine 31 min 34 min 37 min 40 min 43 min 46 min 34 686959 0 0 0 0 0 0 34 686959 0 0 0 0 0 0 34 686959 0 0 0 0 0 0 34 686959 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 35 618584 0 0 0 0 0 0 36 981968 0 0 0 0 0 0 36 981968 0 0 0 0 0 0 36 981968 0 0 0 0 0 0 36 981968 0 0 0 0 0 0 37 955873 0 1 1 0 0 0 37 955873 1 0 0 0 0 0 37 955873 ...... 37 955873 0 0 0 0 0 0 38 276896 0 0 0 0 0 0 38 276896 0 1 0 0 0 0 38 276896 0 0 0 0 0 0 38 276896 0 0 0 0 0 0 39 125699 0 0 0 0 0 0 39 125699 0 0 0 0 0 0 39 125699 0 0 0 0 0 0 39 125699 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 40 456093 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 0 0 0 0 0 0 41 430391 ...... 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 42 211252 0 0 0 0 0 0 43 522107 1 1 0 0 0 0 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 43 522107 0 0 0 0 0 0 44 197812 0 0 0 0 0 0 44 197812 0 0 0 0 0 0 44 197812 0 0 0 0 0 0 44 197812 0 0 0 0 0 0

267 SUB 6-DIGIT P11 P12 P13 P14 P15 P16 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine 31 min 34 min 37 min 40 min 43 min 46 min 45 283376 1 1 0 0 0 0 45 283376 0 0 0 0 0 0 45 283376 0 0 0 0 0 0 45 283376 0 0 1 0 0 0 46 830214 0 0 0 0 0 0 46 830214 0 0 0 0 0 0 46 830214 1 1 1 0 0 0 46 830214 0 0 0 0 0 0 47 452838 0 0 0 0 0 0 47 452838 0 0 0 0 0 0 47 452838 0 0 0 0 0 0 47 452838 0 0 0 0 0 0 48 104096 0 0 0 0 0 0 48 104096 0 0 0 0 0 0 48 104096 0 0 0 0 0 0 48 104096 0 0 0 0 0 0 49 118637 0 0 0 0 0 0 49 118637 0 0 0 0 0 0 49 118637 0 0 0 0 0 0 49 118637 0 0 0 0 0 0 50 875755 0 0 0 0 0 0 50 875755 0 0 0 0 0 0 50 875755 1 0 0 0 0 0 50 875755 1 1 1 0 0 0 51 830285 0 0 0 0 0 0 51 830257 0 0 0 0 0 0 51 830257 1 1 1 1 1 1 51 830257 1 1 1 0 1 1 52 146915 0 0 0 0 0 0 52 146915 0 0 0 0 0 0 52 146915 ...... 52 146915 0 0 0 0 0 0 53 400386 1 1 1 1 1 1 53 400386 0 0 0 0 0 0 53 400386 0 0 0 0 0 0 53 400386 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 54 302414 0 0 0 0 0 0 55 723292 0 0 0 0 0 0 55 723292 0 0 0 0 0 0 55 723292 0 0 1 1 0 0 55 723292 1 1 1 1 0 0

268 SUB 6-DIGIT P11 P12 P13 P14 P15 P16 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 1=80/80 Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine Prilocaine 31 min 34 min 37 min 40 min 43 min 46 min 56 587571 0 0 1 0 0 1 56 587571 0 0 0 0 0 0 56 587571 0 0 0 0 0 0 56 587571 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 57 505678 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 58 276155 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 59 834661 0 0 0 0 0 0 60 301970 0 0 0 0 0 0 60 301970 1 0 0 0 0 0 60 301970 1 0 0 0 0 0 60 301970 0 0 0 0 0 0

269 SUB 6-DIGIT P17 P18 P19 P20 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 Prilocaine Prilocaine Prilocaine Prilocaine 49 min 52 min 55 min 58 min 1 382985 0 0 0 0 1 382985 0 0 0 0 1 382985 0 0 0 0 1 382985 0 0 0 0 2 349175 0 0 0 0 2 349175 0 0 0 0 2 349175 0 0 0 0 2 349175 0 0 0 0 3 950234 0 0 0 0 3 950234 0 0 0 0 3 950234 0 0 0 0 3 950234 0 0 0 0 4 952149 1 1 1 1 4 952149 0 0 0 0 4 952149 1 1 1 1 4 952149 1 0 0 0 5 111173 0 0 0 0 5 111173 0 0 0 0 5 111173 0 0 0 0 5 111173 0 0 0 0 6 317625 0 1 1 0 6 317625 0 0 0 0 6 317625 1 1 1 1 6 317625 0 0 1 1 7 282284 0 0 0 0 7 282284 0 0 0 0 7 282284 0 0 0 0 7 282284 0 0 0 0 8 726248 0 0 0 0 8 726248 0 0 0 0 8 726248 0 0 0 0 8 726248 0 0 0 0 9 670812 0 0 0 0 9 670812 1 1 0 0 9 670812 0 0 0 0 9 670812 0 1 0 0 10 283330 0 0 0 0 10 283330 0 0 0 0 10 283330 0 0 0 0 10 283330 0 0 0 0 11 519077 0 1 0 0 11 519077 0 0 0 0 11 519077 0 0 0 0 11 519077 . . . .

270 SUB 6-DIGIT P17 P18 P19 P20 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 Prilocaine Prilocaine Prilocaine Prilocaine 49 min 52 min 55 min 58 min 12 469015 0 0 0 0 12 469015 0 0 0 0 12 469015 0 0 0 0 12 469015 0 0 0 0 13 103606 0 0 0 0 13 103606 0 0 0 0 13 103606 . . . . 13 103606 0 0 0 0 14 535402 0 0 0 0 14 535402 0 0 0 0 14 535402 0 0 0 0 14 535402 0 0 0 0 15 603918 0 0 0 0 15 603918 0 0 0 0 15 603918 0 0 0 0 15 603918 0 0 0 0 16 906941 0 0 0 0 16 906941 0 0 0 0 16 906941 0 0 0 0 16 906941 0 0 0 0 17 834521 0 0 0 0 17 834521 0 0 0 0 17 834521 0 0 0 0 17 834521 0 0 0 0 18 462988 0 0 0 0 18 462988 0 0 0 0 18 462988 0 0 0 0 18 462988 0 0 0 0 19 950932 0 0 0 0 19 950932 0 0 0 0 19 950932 0 0 0 0 19 950932 0 0 0 0 20 990449 0 0 0 0 20 990449 0 0 0 0 20 990449 0 0 0 0 20 990449 0 0 0 0 21 998782 0 0 0 0 21 998782 0 0 0 0 21 998782 0 0 0 0 21 998782 0 0 0 0 22 296243 0 0 0 0 22 296243 0 0 0 0 22 296243 0 0 0 0 22 296243 0 0 0 0

271 SUB 6-DIGIT P17 P18 P19 P20 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 Prilocaine Prilocaine Prilocaine Prilocaine 49 min 52 min 55 min 58 min 23 190786 0 0 0 0 23 190786 0 0 0 0 23 190786 0 0 0 0 23 190786 0 0 0 0 24 946811 0 0 0 0 24 946811 0 0 0 0 24 946811 0 0 0 0 24 946811 0 0 0 0 25 925096 0 0 0 0 25 925096 0 0 0 0 25 925096 0 0 0 0 25 925096 0 0 0 0 26 439565 0 1 0 0 26 439565 0 0 0 1 26 439565 . . . . 26 439565 0 0 0 1 27 420000 0 0 0 0 27 420000 0 0 0 0 27 420000 . . . . 27 420000 0 0 0 0 28 920009 0 0 0 0 28 920009 0 0 0 0 28 920009 0 0 0 0 28 920009 0 0 0 0 29 142718 0 0 0 0 29 142718 0 0 0 0 29 142718 0 0 0 0 29 142718 0 0 0 0 30 800941 0 0 0 0 30 800941 0 0 0 0 30 800941 0 0 0 0 30 800941 0 0 0 0 31 276956 0 0 0 0 31 276956 0 0 0 0 31 276956 0 0 0 0 31 276956 0 0 0 0 32 955730 1 1 1 1 32 955730 0 0 0 1 32 955730 0 0 0 0 32 955730 0 0 0 0 33 766726 0 0 0 0 33 776726 0 0 0 0 33 776726 0 0 0 0 33 776726 0 0 0 0

272 SUB 6-DIGIT P17 P18 P19 P20 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 Prilocaine Prilocaine Prilocaine Prilocaine 49 min 52 min 55 min 58 min 34 686959 0 0 0 0 34 686959 0 0 0 0 34 686959 0 0 0 0 34 686959 0 0 0 0 35 618584 0 0 0 0 35 618584 0 0 0 0 35 618584 0 0 0 0 35 618584 0 0 0 0 36 981968 0 0 0 0 36 981968 0 0 0 0 36 981968 0 0 0 0 36 981968 0 0 0 0 37 955873 0 0 0 0 37 955873 0 0 0 0 37 955873 . . . . 37 955873 0 0 0 0 38 276896 0 0 0 0 38 276896 0 0 0 0 38 276896 0 0 0 0 38 276896 0 0 0 0 39 125699 0 0 0 0 39 125699 0 0 0 0 39 125699 0 0 0 0 39 125699 0 0 0 0 40 456093 0 0 0 0 40 456093 0 0 0 0 40 456093 0 0 0 0 40 456093 0 0 0 0 41 430391 0 0 0 0 41 430391 0 0 0 0 41 430391 0 0 0 0 41 430391 . . . . 42 211252 0 0 0 0 42 211252 0 0 0 0 42 211252 0 0 0 0 42 211252 0 0 0 0 43 522107 0 0 0 0 43 522107 0 0 0 0 43 522107 0 0 0 0 43 522107 0 0 0 0 44 197812 0 0 0 0 44 197812 0 0 0 0 44 197812 0 0 0 0 44 197812 0 0 0 0

273 SUB 6-DIGIT P17 P18 P19 P20 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 Prilocaine Prilocaine Prilocaine Prilocaine 49 min 52 min 55 min 58 min 45 283376 0 0 0 0 45 283376 0 0 0 0 45 283376 0 0 0 0 45 283376 0 0 0 0 46 830214 0 0 0 0 46 830214 0 0 0 0 46 830214 0 0 0 0 46 830214 0 0 0 0 47 452838 0 0 0 0 47 452838 0 0 0 0 47 452838 0 0 0 0 47 452838 0 0 0 0 48 104096 0 0 0 0 48 104096 0 0 0 0 48 104096 0 0 0 0 48 104096 0 0 0 0 49 118637 0 0 0 0 49 118637 0 0 0 0 49 118637 0 0 0 0 49 118637 0 0 0 0 50 875755 0 0 0 0 50 875755 0 0 0 0 50 875755 0 0 0 0 50 875755 0 0 0 0 51 830285 1 1 0 0 51 830257 0 0 0 0 51 830257 1 1 0 0 51 830257 1 1 1 1 52 146915 0 0 0 0 52 146915 0 0 0 0 52 146915 . . . . 52 146915 0 0 0 0 53 400386 0 0 1 0 53 400386 0 0 0 0 53 400386 0 0 0 0 53 400386 0 0 0 0 54 302414 0 0 0 0 54 302414 0 0 0 0 54 302414 0 0 0 0 54 302414 0 0 0 0 55 723292 0 0 0 0 55 723292 0 0 0 0 55 723292 0 0 0 0 55 723292 0 0 0 0

274 SUB 6-DIGIT P17 P18 P19 P20 # # 0=NO 80/800=NO 80/800=NO 80/800=NO 80/80 1=80/80 1=80/80 1=80/80 1=80/80 Prilocaine Prilocaine Prilocaine Prilocaine 49 min 52 min 55 min 58 min 56 587571 0 0 0 0 56 587571 0 0 0 0 56 587571 0 0 0 0 56 587571 0 0 0 0 57 505678 0 0 0 0 57 505678 0 0 0 0 57 505678 0 0 0 0 57 505678 0 0 0 0 58 276155 0 0 0 0 58 276155 0 0 0 0 58 276155 0 0 0 0 58 276155 0 0 0 0 59 834661 0 0 0 0 59 834661 0 0 0 0 59 834661 0 0 0 0 59 834661 0 0 0 0 60 301970 0 1 1 0 60 301970 0 0 0 0 60 301970 0 0 0 0 60 301970 0 0 0 0

275

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