A PROSPECTIVE, RANDOMIZED SINGLE-BLIND STUDY TO EVALUATE THE REVERSAL OF SOFT TISSUE ANESTHESIA IN ENDODONTIC PATIENTS
A Thesis
Presented in Partial Fulfillment of the Requirements for
The Degree of Master of Science in the
Graduate School of The Ohio State University
By
Sara Megan Fowler, D.M.D.
Graduate Program in Dentistry
The Ohio State University 2010
Master’s Examination Committee:
Dr. John M. Nusstein, Advisor
Dr. Al Reader
Dr. Melissa Drum
Dr. F. Michael Beck
Copyright by
Sara M. Fowler
2010 ABSTRACT
The purpose of this prospective, randomized, single-blind study was to evaluate
the reversal of soft tissue anesthesia in endodontic patients. Eighty-five adult subjects
(51 females and 34 males) who had asymptomatic teeth requiring endodontic treatment received either OraVerse™ or sham injection(s) at the end of the procedure. Soft tissue anesthesia was monitored by the subjects every 15 minutes for 5 hours. Subjects reported postoperative injection site and experimental tooth pain using a Heft-Parker visual analog scale every 30 minutes for the first two postoperative hours, and every hour for three hours.
There was a statistically significant difference in time to return to normal sensation for the maxillary lip/cheek, mandibular lip, maxillary gingiva, and mandibular gingiva. Subjects who received OraVerse™ experienced a 88-minute decrease in time to return to normal maxillary lip/cheek sensation, a 47-minute decrease in time to return to normal mandibular lip and maxillary gingival sensation, and a 41-minute decrease in time to return to normal mandibular gingival sensation. There was a 27-minute decrease in time to return to normal tongue sensation for subjects in the OraVerse™ group, which was not statistically significant.
Subjects who received OraVerse™ did not experience significantly more postoperative discomfort at the injection site or from the endodontically-treated tooth.
Postoperative complications were minimal, and no adverse reactions to the OraVerse™
ii were reported. OraVerse™ may be beneficial for asymptomatic patients who would like to experience a faster return to normal soft tissue function and sensation after the administration of local anesthesia for endodontic treatment.
iii Dedication
To my husband, Ron – Thank you for hanging in and holding on, for having my back, and for making me laugh. I’m blessed to have you for a husband and Evan is blessed to have you for a father. We make a great team.
To my son, Evan – You have given love and life new meaning. You will always be my “why.”
To my family and friends who have been steadfast supporters of everything I do. Your wholehearted belief in me is unmatched. I am forever blessed and eternally grateful.
iv ACKNOWLEDGMENTS
Dr. John Nusstein...It has been wonderful working with you on this thesis. It goes without saying that I couldn’t have done this without you, but please understand how grateful I am to you for your guidance and encouragement. Thank you for all the work you do to make Endodontics the best department at Ohio State.
Dr. Al Reader…Your devotion to the residents is so very genuine and so very appreciated. Thank you for making this a family, not just a program. I’ll always remember you saying “It will be fine” and knowing that it will be.
Dr. Melissa Drum…I hope you know how precious and rare and amazing you are. I can’t thank you enough for all of your personal and professional support. I’m so happy that now, finally, we can be friends.
Dr. William Meyers…Some of my best memories of my time here at Ohio State are of the time and conversations we shared in predoc while I was in the Fellowship. I’ve learned so much about endodontics and life from you. Thank you for being you.
Dr. Mike Beck…It has been a privilege to work with you. Thank you for all of your help and dedication to the residents and our program. Thanks for making statistics as pleasant for us as it can possibly be.
To the staff and student workers of the Endodontics Division…Thank you for your support of the residents and dental students. I hope you know how important you are in making this experience so rewarding for us. You are an integral part of the endo family and always very dearly appreciated.
To my co-residents Matt Martin, Mike Simpson, and Kevin Wells…It has been wonderful sharing the last 27 months with you guys. You made every day fun and I will miss you all so very much.
v VITA
December 16, 1978……………………… Born – Columbus, Ohio
2002………………………………………B.S. Health Science, University of Nevada, Reno
2006………………………………………D.M.D., University of Nevada, Las Vegas, School of Dental Medicine
2007……………………………………...General Practice Residency Post-Doctoral Certificate, The Ohio State University
2008……………………………………...Fellowship in Endodontics The Ohio State University
2010……….……………………………..Specialization in Endodontics Post-Doctoral Certificate, The Ohio State University
FIELDS OF STUDY
Major Field: Dentistry
Specialization: Endodontics
vi TABLE OF CONTENTS
Page Abstract…………………………………………………………………………………...ii Dedication………………………………………………………………………………...iv Acknowledgments………...……………………………………………………………....v Vita……………………………………………………………………………………….iv
List of Tables……………………………………………………………………………...ix List of Figures…………………………………………………………………………….xi
Chapters:
1. Introduction……………………………………………………………………………..1
2. Literature Review………………………………………………………………………4 Lidocaine………………………………….……………………………………....4 Mechanism of Action of Lidocaine……………………………………….5 Pharmacology of Lidocaine…………….…………………………………8 Safety of Lidocaine……………………….……………………………...11 Efficacy of Lidocaine for the Inferior Alveolar Nerve Block……………13 Efficacy of Lidocaine in Maxillary Infiltrations…………………………15 Onset and Duration of Lidocaine for the Inferior Alveolar Nerve Block..15 Onset and Duration of Lidocaine for Maxillary Infiltration……………..16 Onset and Duration of Lidocaine for Soft Tissue Anesthesia……………17 Vasoconstrictors………………………………………………………….17 Phentolamine Mesylate (OraVerseTM)...... 20 Pharmacology of Phentolamine Mesylate……………………………….20 Efficacy and Safety of Phentolamine Mesylate as a Dental Anesthetic Reversal Agent………………………………………………………...…23 Post-Operative Endodontic Pain…………………………………………………29 Visual Analogue Scale……………………………………………………..….…34
3. Materials and Methods………………………………………………………………...36
4. Results…………………………………………………………………………………46
5. Discussion of Materials and Methods...... 57
vii 6. Discussion of Results...... 79
7. Summary and Conclusions…………………………………………………………..116
Appendices A. Tables…………………………………………………………...121 B. Figures…………………………………………………………..138 C. Consent…………………………………………………………145 D. HIPAA Forms……………..……………………………………153 E. Random Code List...……………………………………………157 F. VAS Form...…………………………………………………….161 G. Follow-up Questionnaire: Lip Numbness…..…………………..163 H. Follow-up Questionnaire: Gums Numbness...………………….165 I. Follow-up Questionnaire: Tongue Numbness…..……………...167 J. Five Hour Postoperative Pain Survey…………………...……...169 K. Raw Data including biographical data...... …………………..177
References…………………………………………………….………….……...…...….190
viii LIST OF TABLES
Table Page
1. Biographical data for all subjects…………………………………....………….122
2. Experimental Tooth Characteristics……………………………………………123
3. Mean VAS Values (mm ± SE) of Anesthetic Injection Discomfort Ratings for Males and Females by Jaw and Group………………………………………....124
4. Summary of Anesthetic Injection Discomfort Ratings by Gender, Jaw, and Group……………………………………………...………………….………...125
5. Anesthetic Administered by Jaw and Group……………….…………………..126
6. Procedure Time (minutes) and Case Completion Status by Jaw and Group…………………………………………………………………………...127
7. Mean VAS Values (mm ± SE) of OraVerse™/Sham Injection Discomfort Levels by Jaw and Group...... 128
8. Summary of OraVerse™/Sham Injection Discomfort Ratings by Gender, Jaw, and Group…………………………………………..……………………………...... 129
9. Maxillary Adjusted Mean Time of Soft Tissue Anesthesia (minutes) by Group and Jaw………………………………………………………………………….130
10. Mandibular Adjusted Mean Time of Soft Tissue Anesthesia (minutes) by Group and Gender………………………………………………………………...... 131
11. Adjusted Mean Duration of Maxillary Lip/Cheek Anesthesia (minutes, ± adjusted SE) …………………………………………………………………………..….132
12. Adjusted Mean Duration of Mandibular Lip and Tongue Anesthesia (minutes ± adjusted SE) ……………………………………………...…………………….133
ix 13. Adjusted Mean Duration of Maxillary and Mandibular Gingival Anesthesia (minutes ± adjusted SE) ………….…...………………………………………..134
14. Mean VAS Values (mm) of Postoperative Injection Site Discomfort Ratings ………………………………………………………………………....135
15. Mean VAS Values (mm) of Postoperative Tooth Discomfort Ratings ………………………………………………..………………………..136
16. Frequency of Subject-reported Postoperative Complications by Time Period (minutes) ……………………………………………………….………………137
x LIST OF FIGURES
Figure Page
1. Duration of Maxillary Soft Tissue Anesthesia. ……….………….…...……….139
2. Duration of Mandibular Soft Tissue Anesthesia …...……….….………………140
3. Maxillary Postoperative Injection Site Pain ………………...…………………141
4. Mandibular Postoperative Injection Site Pain ….…………………….………..142
5. Maxillary Postoperative Tooth Pain ……..……………………...……………..143
6. Mandibular Postoperative Tooth Pain ……………………….………………...144
xi CHAPTER 1
INTRODUCTION
The dental profession has continually searched for an effective method to help
reverse the effects of soft tissue numbness following dental injections. The duration of
soft tissue numbness is considerably longer than that of pulpal anesthesia and the
duration of the typical dental appointment. Patients feel that residual soft tissue
numbness interferes with their normal daily activities in three specific areas – perceptual
(perception of altered physical appearance); sensory (lack of sensation); and functional
(diminished ability to speak, smile, drink, and control drooling) (1). Many dental patients
complain that they were unable to eat a meal or to talk normally for many hours after
their last dental visit because their lip and/or tongue were still numb.
Lidocaine is the most commonly used dental anesthetic and remains the standard
for all local anesthetic comparisons (2). Hersh et al. (3) found that an inferior alveolar
nerve block with 2% lidocaine with 1:100,000 epinephrine provides peak soft tissue
numbness between 30 and 45 minutes post-injection with reduction of anesthesia
beginning between 90 and 120 minutes. Some patients reported soft tissue numbness
beyond 180 minutes.
Phentolamine mesylate (OraVerse™, Novalar Pharmaceuticals, San Diego, CA)
has been developed to accelerate the return of soft tissue feeling after routine dental
1 procedures. Phentolamine is a nonselective, alpha-adrenergic blocking agent that has been available in the United States since 1952. The primary action of phentolamine is vasodilation (1, 4-6). It is currently available in 1.7 mL cartridges prepared for local injection in the same manner dental local anesthetic is delivered with a standard aspirating syringe.
Clinically, the dental patient receives a local anesthetic injection, usually containing a vasoconstrictor, at the beginning of the dental appointment. This generally provides anesthesia for the dental filling or endodontic procedure. However, soft tissue numbness is still present hours after the end of the appointment. A number of well- controlled studies have shown that phentolamine statistically reduces the time of soft tissue numbness of the lip by 55% (about 85 minutes) when compared to a placebo injection (1, 4-6). Two clinical trials enrolling 484 adults and 152 pediatric patients reported similar reductions in soft tissue anesthesia following the administration of phentolamine. Side effects were minimal and similar to a placebo injection (5, 6). The
FDA approved the use of OraVerse™ for dental treatment in May 2008. For adults, the dosage is 1 to 2 cartridges of phentolamine mesylate (a dose of 0.4 mg to 0.8 mg), given in the same location as the local anesthetic injection in a 1:1 ratio (7).
The previously mentioned clinical trials evaluated the use of OraVerse™ with patients undergoing routine, nonsurgical, operative or periodontal procedures. There are no studies evaluating the use of phentolamine in endodontics for patients with asymptomatic teeth. The overall trend in the literature is that 80 to 90% of patients undergoing endodontic treatment of an asymptomatic tooth report only mild postoperative pain (9). These types of patients could receive OraVerse™ at the
2 completion of their root canal procedures and would not be expected to experience more postoperative pain as a result of a decreased duration of soft-tissue numbness. Earlier return to normal function and sensation of the soft tissues may have a significant benefit to such asymptomatic endodontic patients.
The purpose of this prospective, randomized, single-blinded study was to evaluate the reversal of soft tissue anesthesia in endodontic patients following endodontic treatment of their asymptomatic teeth.
3 CHAPTER 2
LITERATURE REVIEW
Selected portions of the following have been adapted from previous theses by
Evans (8), Chandler (9), Oleson (10), and Agarwala (11) from the Division of
Endodontics at The Ohio State University College of Dentistry.
LIDOCAINE
“Lidocaine (2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide), the first amide
local anesthetic, was synthesized in 1943 by Nils Lofgren (2). In 1947, Bjorn and Huldt
(40) introduced lidocaine to dentistry. When epinephrine was added to lidocaine, the
overall anesthetic effect was enhanced while systemic toxicity was reduced. Although
procaine is still available in dental cartridges, most injectable local anesthetics used in
dentistry today are amide anesthetics (lidocaine, mepivacaine, prilocaine, bupavicaine,
articaine and etidocaine). Amides replaced the first-generation ester anesthetics because
of enhanced properties including faster onset, increased duration, more profound
anesthesia, increased potency, and decreased allergenicity (76).
After its introduction, lidocaine gained widespread popularity among dentists, and it remains the standard for all local anesthetic comparisons (2). Lidocaine is prepared as
4 a hydrochloride salt to improve its water solubility and stability in aqueous media (77).”
(8)
Mechanism of Action of Lidocaine
“The primary action of a local anesthetic is interference with the excitation-
conduction process of nerve fibers and endings (78). A nerve fiber has the capability to
respond to a stimulus by excitation and to propagate this stimulus along the nerve fiber to
its point of termination (79). This conduction of the stimulus is temporarily interfered
with by the action of the local anesthetic (78).
The electrophysiological properties of the neuronal membrane rely on both the
permeability of the membrane to specific electrolytes and to the concentration of these
electrolytes in the cytoplasmic and extracellular fluid (78). A nerve cell membrane is
fully permeable to potassium and chloride ions in its resting state and relatively
impermeable to proteins, amino acids, and sodium ions (2, 80). As a result of this
selective permeability, cations (+) including sodium ions are concentrated extracellularly and anions (-), potassium ions, are concentrated intracellularly. The permeability of the
nerve cell membrane along with the cytoplasmic and extracellular electrolyte
concentrations combine to determine the electrophysiologic properties of the nerve cell
membrane. The electrochemical gradient set up between the inside of the nerve
membrane and the outside results in an electrical potential of approximately -70 to -90
mV across the cell membrane (41). Stimulating the nerve results in increased sodium
permeability through a transitory widening of the transmembrane channels. This
5 widening allows sodium ions to rapidly diffuse to the interior of the cell resulting in depolarization of the neural cell membrane to a firing threshold of approximately -50 to
60 mV. Upon reaching the firing threshold, sodium permeability increases remarkably and a rapid influx of sodium ions occurs across the cell membrane. At the end of the depolarization phase, the electrical potential is actually reversed across the membrane to approximately +40 mV (2, 80).
Once depolarization is complete, the permeability of the nerve membrane to sodium ions decreases and the high permeability to potassium is restored. The resulting movement of the sodium ions out, and the potassium ions in, by passive diffusion, restores the normal resting potential of the nerve cell membrane. When the resting potential is achieved, there is excess of sodium ions intracellularly and of potassium ions extracellularly (41). The ‘sodium pump’ actively transports the excess sodium ions out of the cell. This process is energy dependent, the source being adenosine triphosphate
(ATP), which is oxidatively metabolized to provide the necessary energy (2, 41). Once the normal ionic gradient is restored, the nerve is again in its resting state. This repolarization process takes approximately 0.7 msec, after which the nerve cell membrane re-achieves its normal resting potential of approximately -90 mV (2).
The exact mechanism of action of local anesthetics is not known. The presently accepted theory on the action of local anesthetics is that they prevent depolarization by blocking the transmembrane sodium channels (2, 42, 43, 63, 64, 80-83). This is believed to be accomplished by either of the following mechanisms: the specific receptor mechanism and/or the membrane expansion mechanism (2, 42, 43, 80-83).
6 The specific receptor theory is based on four proposed binding sites within the sodium channel, to which local anesthetic molecules can attach. Molecules may bind to the inner mouth of the channel pore resulting in a tonic block. Binding to a second site deeper within the pore will result in a use-dependent block (84). The other two proposed sites are located at the gate of the sodium channel and are related to the action of scorpion venom (42). Only the charged, or ionized, forms of the local anesthetic can bind to these sites and this form is unable to cross the nerve membrane (41, 82, 84). The unionized form of the local anesthetic diffuses across the membrane thus establishing a chemical equilibrium. Once the unionized form of the local anesthetic has entered the cell, approximately 75% of it is converted to the ionized form. It is this ionized form of the anesthetic molecule that is capable of binding to the receptor sites resulting in decreased membrane permeability to sodium and leading to a prevention of the firing of the membrane (2, 41, 82).
The second theory, known as the membrane expansion theory, states that the anesthetic agent acts by penetrating the nerve membrane, resulting in an expansion of the membrane and a decrease in the diameter of the sodium channel, thereby preventing sodium permeability (2, 41, 83). This theory offers an explanation for the action of anesthetics that do not exist in the ionized form such as benzocaine (2).” (10)
7 Pharmacology of Lidocaine
“Local anesthetics are agents, which produce a loss of sensation, or feeling, when injected or applied to a particular area of the body (2). These agents inhibit the excitation-conduction process of the nerve endings and fibers in a reversible manner (41).
The chemical composition of local anesthetics consists of an aromatic group with an ester or amide linkage to an intermediate hydrocarbon chain, and a secondary or tertiary amino group (41, 43). The local anesthetic's hydrophilic properties are due to the secondary or tertiary amino groups, while the lipophilic properties are derived from the aromatic residue, which originates from benzoic acid or aniline (43). Either an ester or an amide linkage between the aromatic residue and the intermediate carbon chain determines the anesthetics metabolism, allergenicity, and classification (43, 44).
Esters or procaine-like anesthetics undergo hydrolysis in the plasma by pseudocholinesterase and, to a lesser degree, by esterases in the liver (41, 43). This hydrolysis produces para-amino benzoic acid as its primary metabolite, which is capable of inducing allergic reactions in a small percentage of the general population (2, 41).
The liver is the primary site for enzymatic degradation of the amide or lidocaine- like anesthetics. This metabolism is carried out by the liver microsomes with initial N- dealkylation of the tertiary amino terminus followed by hydrolysis of the resulting secondary amine by hepatic amidase activity (43, 85). “Lidocaine has an elimination half-life of 96 minutes and a hepatic clearance approaching 75% of the total liver blood flow (79, 80). Anything that alters liver blood flow may affect lidocaine metabolism.
Reports of allergic reactions to amide anesthetics are extremely rare, as they are not
8 metabolized to para-amino benzoic acid (78). The kidneys primarily carry out excretion
of amide and ester drugs and their metabolites (2, 44, 86).
The anesthetic properties of each compound are dependent on its lipid solubility,
protein binding capacity, pKa, pH, tissue diffusibility, and intrinsic vasodilating
properties (78). The potency of the anesthetic compound is primarily determined by its
ability to penetrate the nerve cell membrane, which is directly related to its lipid
solubility. Highly lipid soluble anesthetic compounds can easily penetrate the nerve
membrane thereby requiring lower concentrations to produce adequate anesthesia (2, 41,
86). Lidocaine is considered to be of intermediate potency.
Duration of action is primarily determined by the local anesthetics protein-binding
characteristics. The stronger the binding ability of the local anesthetic, the longer the
duration of action. Poor protein binding results in a short duration of anesthesia.
Lidocaine has intermediate duration of action (41, 42).”(10)
“A chemical compound's pKa is defined as the pH at which the ionized and unionized forms exist in equilibrium. The pKa is constant and ranges from low for mepivacaine at 7.6 to high for procaine at 9.1 (2, 41, 43, 44). Lidocaine has a pKa of 7.9.
It is the unionized form of the drug that penetrates the neuronal membrane (78). At a tissue pH of 7.4, 2-40% of the drug will exist in the unionized form. The onset time of the agent is also related to the pKa. The lower the pKa value, the faster the onset time.
Lidocaine has a relatively fast clinical onset time (from one to three minutes for maxillary infiltration and one to four minutes for IAN block) because its pKa is close to the pH of the tissue (26, 41, 42).
9 Anesthetic compounds can only act on nerve membranes after they diffuse through non-nervous tissue and contact the nerve. Tissue diffusibility has been shown to have a direct relationship on the rate of onset. Despite its importance, the factors that determine the rate of diffusibility through non-nervous tissues are poorly understood (78).
The vasodilator activity of anesthetic compounds influences potency and duration. The increased blood vasodilatation, caused by the anesthetic will in turn result in the quicker removal of the anesthetic compound from the injection site; thereby decreasing the amount of anesthetic available to act upon the nerve. With the exception of cocaine, all local anesthetic agents have vasodilator properties (41).
Cartridges of local anesthetic compounds exist in the form of a hydrochloride salt solution, which is stable for long periods of time (41). These preparations have a pH of
4.5-6.0 (85). Because the compounds have pKa values greater than these pH values, most of the solutions are in the ionized form. This form is more water-soluble and diffuses through the non-nervous tissue more rapidly (41, 85). A rapid buffering by the tissues increases the pH and increases the amount of free base, which is able to diffuse through the nerve sheath (2, 41).
Various evaluations of local anesthetic toxicity have been reported. The earliest and most common response to a local anesthetic overdose is CNS excitation. Initially, a feeling of light-headedness or dizziness occurs. Auditory and visual disturbances may also be noted. The patient may become disoriented and develop slurred speech, tremors, muscle twitching and generalized convulsions. Generalized CNS depression follows, with loss of consciousness and respiratory arrest. With doses three to six times higher, the cardiovascular depressant effects of local anesthetics, such as decreased myocardial
10 contractility, decreased peripheral resistance, hypotension, and circulatory collapse, will
also be seen (43).” (10)
“Lidocaine is available in a 2% concentration, either plain or with epinephrine as
a vasoconstrictor in concentrations of 1:50,000, 1:100,000, or 1:200,000. Vasoconstrictor is added to lidocaine to counteract its vasodilating properties. Without the
vasoconstrictor, absorption is increased, local efficacy is decreased, and toxic levels are
reached more rapidly.
A standard cartridge of 2% lidocaine with 1:100,000 epinephrine contains 20
mg/mL lidocaine, 10 μg/mL epinephrine bitartrate as a vasoconstrictor, 6 mg/mL sodium
chloride for isotonicity, 0.2 mg/mL citric acid to produce the desired pH, and
0.5 mg/mL sodium metabisulfite as an antioxidant for the vasoconstrictor. Cartridges are
filled under nitrogen gas to avoid oxidation.” (8)
Safety of Lidocaine
“Lidocaine has a maximum safe dose of 7 mg/kg for uncompromised patients.
Lidocaine has a maximum milligram dose of 500 mg for an average, healthy, 70 kg adult.
At a body weight of 70 kg, an average adult’s maximum lidocaine dose would be 490 mg
of lidocaine, which is equivalent to 13.6 cartridges of 2% lidocaine with epinephrine.
Sodium metabisulfate (88) is a sulfite in lidocaine preparations that may cause allergic-
type reactions including anaphylactic symptoms and life-threatening or less severe
asthmatic episodes in certain susceptible people. The overall prevalence of sulfite
sensitivity (88) in the general population is unknown but is seen more frequently in
asthmatic than non-asthmatic people.
11 Lidocaine has been classified by the Food and Drug Administration as a pregnancy category B drug. Reproduction studies have been performed in rats at doses up to 6.6 times the human dose and have revealed no evidence of harm to the fetus caused by lidocaine. There are, however, no adequate and well-controlled studies in pregnant women (88).
Hawkins and Moore (89) note that lidocaine has an extremely low rate of inducing allergic reaction, with fewer than twenty case reports of allergic reactions in the literature over the past fifty years. The authors report that given how often lidocaine is used in the US and Canada, between 500,000 – 1,000,000 injections a day, the extremely low incidence of hypersensitivity reactions is an important clinical advantage.
Malamed et al. (90) investigated the safety of lidocaine in adult dental patients.
443 patients undergoing general dental procedures were evaluated for adverse effects of the injected anesthetic solution. Subjects received lidocaine for both simple and complex procedures. Safety was evaluated by measuring vital signs before administration and 1 and 5 minutes post-administration of the medication, and at the end of the procedure.
Adverse events were also solicited during follow-up telephone calls both 24 hours and 7 days after the procedure. Results showed that adverse events occurred in 20% (89 of 443 patients) of lidocaine injections. One patient had to discontinue the study due to chest pain and dizziness. No deaths were reported due to the use of lidocaine in this study. Of
443 patients receiving a lidocaine injection, 16 (4%) had adverse events considered by the investigator to be drug-related. The most common drug-related adverse events were headache (0.7%), rash (0.7%), paresthesia (0.45%), and dizziness (0.45%).
12 Simon et al. (91) investigated 0.5% lidocaine in intravenous regional anesthesia
(dorsum of hand) in a double-blind randomized clinical trial. There were no objective
symptoms of toxicity, either local or systemic, during injection of the local anesthetic, nor
were there any subjective complaints. There were no changes in blood pressure, heart
rate, or oxygen saturation noted at any time during the test procedure or after the tourniquet was deflated. Finally, there were no toxic symptoms nor subjective complaints seen following cuff release and no changes recorded on the electrocardiogram in any of the 12 leads.
In a 21-year retrospective study of reports of paresthesia following local anesthetic administration, Haas and Lennon (92) stated that local anesthetics are considered to be very safe, overall, and it is assumed that the incidence of adverse reactions is low. With 3,062,613 cartridges of lidocaine used in Canada in 1993, there were no episodes of paresthesia caused by the injection of lidocaine.” (10)
Efficacy of Lidocaine for the Inferior Alveolar Nerve Block
The traditional method for determining the success of the inferior alveolar nerve
(IAN) block is lip numbness, which occurs within five to seven minutes of injection.
Studies have demonstrated that this clinical sign merely confirms that the anesthetic has blocked the nerves supplying the soft tissues of the lip, but pulpal anesthesia may not have necessarily been obtained (14-24). A total missed IAN block, no soft tissue nor pulpal anesthesia, occurs about 5% of the time. Successful mandibular pulpal anesthesia, as defined as numb (80/80 reading with the electric pulp tester) within fifteen minutes of injection and continuously numb for one hour (22), has been reported to occur in 55% of
13 molars, 60% of premolars, and in only 31% of lateral incisors with normal pulps, using
2% lidocaine with 1:100,000 epinephrine (14-17, 20-27, 29, 30).
Patients in pain, for example those diagnosed with irreversible pulpitis, have additional anesthetic difficulties. Based on research conducted at the Advanced
Endodontics Program of The Ohio State University, overall, IAN block success in patients with irreversible pulpitis ranges from 25%-68% (11, 28, 31-33). Therefore, not all patients will experience pulpal anesthesia after what would appear to be a clinically successful (lip numbness) IAN block. In these cases supplemental injections of anesthetic would be required to work on the tooth. There are many theories that might explain this problem: 1) conventional techniques, as mentioned previously do not always result in profound pulpal anesthesia, especially in the mandible; 2) inflamed tissue exhibits a lower pH, thereby reducing the amount of the base form of anesthetic to penetrate the nerve membrane; 3) nerves arising from inflamed tissue have altered resting potentials and decreased excitability thresholds; these changes are not restricted to the inflamed pulp, but affect the entire neuron membrane, perhaps extending to the central nervous system; 4) the tetrodotoxin-resistant (TTXr) class of sodium channels have been shown to be resistant to the action of local anesthetics; and 5) patients in pain are often apprehensive, which lowers their perceived pain threshold (34).
Researchers have attempted to determine if varying the volume, type, and vasoconstrictor concentration of the local anesthetic will provide more predictable anesthesia for endodontic patients. Hinkley et al. (60) found no significant difference in
IAN block success using 1.8 mL of 4% prilocaine with 1:200,000 epinephrine, 1.8 mL of
2% mepivacaine with 1:20,000 levonordefrin, and 1.8 mL of 2% lidocaine with
14 1:100,000 epinephrine. Dagher et al. (61) compared the degree of anesthesia obtained
when 2% lidocaine was administered with three different concentrations of epinephrine
(1:50,000, 1:80,000, and 1:100,000) for inferior alveolar nerve block. No significant
differences were found in anesthetic success among the solutions.
Efficacy of Lidocaine in Maxillary Infiltrations
Several studies from the Advanced Endodontics Program at The Ohio State
University have evaluated the success of maxillary infiltrations using the electric pulp tester. Pulpal anesthetic success, as defined by obtaining an 80/80 reading with an electric pulp tester within 15 minutes and sustaining numbness for 60 minutes (22), ranged from 64% to 100% (36-38).
Scott et al. (39) found no significant difference in anesthetic success when comparing an initial infiltration injection of 1.8 mL of 2% lidocaine with 1:100,000 epinephrine to an additional injection of 1.8 mL of 2% lidocaine with 1:100,000 given 30 minutes later. However, the repeated injection was effective in prolonging pulpal anesthesia in the central incisor, lateral incisor, and canine.
Onset and Duration of Lidocaine for the Inferior Alveolar Nerve Block
The onset of pulpal anesthesia, which can be defined as two consecutive 80/80 readings with an electric pulp tester is usually expected to occur within 10-15 minutes of injection (22). In some patients this may occur sooner, and in about 18-26% of patients there can be a delay in onset of more than fifteen minutes (10). In about 8% of injections, onset of anesthesia can be delayed for 30 to 50 minutes (14, 16, 17, 21-27).
15 Odor et al. (59) studied the anesthetic effects of the IAN block with 2% lidocaine
with 1:80,000 adrenaline. The onset of anesthesia for both hard and soft tissues occurred
as early as 1 minute post-injection with pulpal anesthesia being achieved by 5 minutes in
all but two of the teeth tested. The mean duration of full pulpal anesthesia was longer in
the canine teeth (114 min) than in the molar teeth (88 min) tested. Cowan (95) evaluated the use of lidocaine, mepivacaine, and prilocaine in operative and surgical procedures and concluded that 2% lidocaine with 1:100,000 epinephrine had the fastest onset time and the longest duration.
Onset and Duration of Lidocaine for Maxillary Infiltration
In a series of studies performed by The Ohio State University Advanced
Endodontics Program, the duration of maxillary pulpal anesthesia after infiltration with a lidocaine solution varied from 31 minutes to 100 minutes, with the majority of studies showing duration times of less than 60 minutes (35-38).
Mikesell et al. (38) found that the onset time for the lateral incisor was not significantly less when 3.6 mL was compared to 1.8 mL. It was also found that the duration of complete pulpal anesthesia for teeth adjacent to the injection sites were longer with 3.6 mL of 2% lidocaine with 1:100,000 epinephrine than with 1.8 mL of solution.
Bjorn and Huldt (40) found the average duration of anesthesia obtained using xylocaine- epinephrine was approximately 60 minutes for maxillary lateral incisors, 80 minutes for central incisors, and 75 minutes for canines. Anesthetic duration obtained using xylocaine-epinephrine was much longer than that obtained using procaine-epinephrine.
16 Onset and Duration of Lidocaine for Soft Tissue Anesthesia
In general, administration of 2% lidocaine with 1:100,000 epinephrine can be
expected to produce soft tissue anesthesia for 180-300 minutes (2). Hersh et al. (3) found
that after an IAN block with 2% lidocaine with 1:100,000 epinephrine lip and tongue
anesthesia occurred within 5 minutes of the injection. Seventy-five percent of the
patients achieved a numbness score of at least 50% of the maximum on the visual analog
scale (100 mm) for the lip, while 68% achieved a similar score for the tongue. Peak anesthesia occurred between 30 and 45 minutes post-injection with a recession of
anesthesia starting between 90 and 120 minutes. At 180 minutes, lip anesthesia averaged
between 30% and 40% on the visual analog scale, while tongue anesthesia averaged
between 20% and 25%.
Fernandez et al. (62) tested duration of anesthesia with the IAN block using 1.8 mL
of 2% lidocaine with 1:100,000 epinephrine. The lidocaine solution produced a mean lip
anesthesia onset of 4.89 minutes and mean lip anesthesia duration of 192 minutes. Mean
duration of lip tingling was 220 minutes.
Odor et al. (59) found that with an IAN block with 2% lidocaine with 1:80,000
epinephrine duration of soft tissue anesthesia had a mean value of 151 minutes. Full
recovery occurred at a mean of 266 minutes.
Vasoconstrictors
“All local anesthetic agents produce some vasodilation, therefore, vasoconstrictors are added to local anesthetics to counteract this effect. Vasoconstrictors
17 are drugs capable of constricting blood vessels. They are classified as sympathomimetics
or adrenergic agents because their mode of action resembles the response elicited when a
sympathetic nerve is stimulated. Vasoconstrictors produce the following effects in local
anesthetics: prolong their action, improve the depth of anesthesia, reduce the peak plasma
concentrations of the anesthetic agent, and reduce the amount of hemorrhage in the injected area (2, 26, 41-46).
The vasoconstrictors limit blood flow to the injection site by constricting the lumens of the blood vessels. This enables a higher concentration of local anesthetic to
remain at the injection site longer, acting to increase the quality and duration of
anesthesia. In addition, the ability of the vasoconstrictor to produce hemostasis at the site
of administration also makes them an adjunct in dental surgical procedures (26, 41, 45,
46, 93).
The most commonly used vasoconstrictors in dental local anesthetics are
epinephrine and levonordefrin (26). Alpha and beta-receptors are directly affected by
epinephrine, although the beta effects predominate. On the other hand, levonordefrin
predominantly affects alpha-receptors with less beta activity. Levonordefrin is only 15%
as effective as epinephrine as a vasopressor (2, 26, 45). The local and systemic effects of
the vasoconstrictors are a result of their alpha and beta stimulating properties.
Stimulation of alpha-receptors results in smooth muscle contraction of peripheral
blood vessels (vasoconstriction). Beta-1 stimulation increases systolic and diastolic
blood pressure, heart rate, strength of contraction, stroke volume, cardiac output, and
myocardium oxygen consumption. Beta-2 stimulation causes bronchodilation and
vasodilation in skeletal muscle (45, 46, 93).
18 When local anesthetics containing epinephrine are injected intraorally,
vasoconstriction occurs as the alpha effects predominate. This vasoconstriction response
causes decreased regional blood flow. The duration and efficacy of the local anesthetic are then enhanced. As the local epinephrine concentration diminishes, the alpha-
adrenergic effects subside and the beta effects begin to predominate. This results in
increased local blood flow and the hemostatic effect caused by epinephrine is lost (26).
Normal dental doses of epinephrine are from 18 to 72 µg. This amount of epinephrine is that found in one to four cartridges (1.8 mL in a cartridge) of 2% lidocaine
with 1:100,000 epinephrine. The maximum recommended dose of epinephrine for the
healthy adult per office visit is 200 µg or 20 mL of a 1:100,000 concentration (the
equivalent of 11 dental cartridges of 1.8 mL each). Forty micrograms, 4 mL of a
1:100,000 concentration, or 2.2 cartridges, is the recommended maximum dose for those
with "clinically significant cardiac impairment" (2). A 1:100,000 solution of epinephrine
contains 10 µg of epinephrine per mL of solution or 0.01mg/mL. A 1:50,000 solution of
epinephrine contains 20 µg/mL of solution and a 1:200,000 solution contains 5 µg/mL.
An overdose of epinephrine results in CNS symptoms of fear and anxiety, tension, restlessness, throbbing headache, tremor, weakness, dizziness, pallor, respiratory
difficulty, and palpitations. Signs of overdose include sharp elevation in blood pressure
(primarily systolic), elevated heart rate, and possible cardiac arrhythmias, including
paraventricular contractions and ventricular fibrillation. As blood levels of the drug rise,
the incidence and severity of the cardiac arrhythmia increase. Systolic blood pressure in
excess of 300 mm Hg and diastolic pressures in excess of 200 mm Hg may lead to
19 cerebral hemorrhage. In patients with coronary insufficiency, an overdose results in
anginal episodes (2).
Contraindications to vasoconstrictors in the concentrations found in dental local
anesthetics are few in number. Vasoconstrictors should be used with caution in patients
with hypertension, cardiovascular disease, and hyperthyroidism. These patients may be
particularly sensitive to the pressor effects of the vasoconstrictors (2, 43, 45).
Contraindications as a result of drug interactions have also been proposed.
Known drug interactions between vasoconstrictors and monoamine oxidase inhibitors
(MAOIs), tricyclic antidepressants, phenothiazines, and beta-blockers have been reported
(42, 26, 94, 182, 183). However, it has been shown that the concomitant use of
epinephrine, levonordefrin, and norepinephrine with MAOIs or phenothiazines is not
contraindicated (94). Vasoconstrictors may also be used in patients taking tricyclic
antidepressants but the dosage should be kept to a minimum (0.05 mg). Medical
conditions such as thyrotoxicosis and pheochromocytoma are absolute contraindications
to the use of epinephrine (26, 27).” (10)
PHENTOLAMINE MESYLATE (ORAVERSE™)
Pharmacology of Phentolamine Mesylate
Phentolamine mesylate is an alpha-adrenergic antagonist that was initially approved for use as an antihypertensive medication in the United States in 1952.
Phentolamine Mesylate for Injection is used to prevent or control hypertension due to stress during preoperative preparation in patients with pheochromocytoma. It can also be used to diagnose pheochromocytoma by the phentolamine blocking test. It is indicated
20 for prevention or treatment of dermal necrosis and sloughing following intravenous
administration or extravasation of norepinephrine (47, 49). Phentolamine mesylate has
also been investigated for its usefulness in treating male erectile dysfunction (13, 50, 51),
to alleviate the pain of pancreatic carcinoma (52), to treat complex regional pain
syndrome (53), and to treat female sexual arousal disorder (54).
OraVerse™ (Novalar Pharaceuticals, Inc.) is a novel formulation of phentolamine
mesylate approved for use as a dental anesthetic reversal agent. It is the only local anesthesia reversal agent that accelerates return of normal function and sensation in oral
soft tissues, i.e. lip, gingiva, tongue, following submucosal injection of a local anesthetic
with vasoconstrictor.
OraVerse™ Injection is a clear, colorless, sterile, non-pyrogenic, isotonic, preservative-free solution packaged in standard dental anesthetic cartridges. Each cartridge contains 1.7 mL of solution (0.4 mg phentolamine mesylate, D-mannitol, edetate disodium, and sodium acetate). The recommended dose of OraVerse™ is based on the number of cartridges of local anesthetic with vasoconstrictor initially administered.
It is recommended that it be given in a 1:1 anesthetic to OraVerse™ ratio following the dental procedure using the same location(s) and technique(s) used to give the local anesthetic. It is not recommended for use in patients under the age of six, and/or who weigh less than 15 kilograms (33 pounds). The maximum dose is 0.2 mg (1/2 cartridge) for children weighing less than 30 kilograms (56 pounds). A dose of more than one cartridge of OraVerse™ has not been studied in children under the age of 12 (7).
Phentolamine mesylate decreases total peripheral resistance and venous return to the heart by competitive blockade of presynaptic and postsynaptic alpha-adrenergic
21 receptors. This results in vasodilation when applied to vascular smooth muscle. The
alpha-adrenergic block is of relatively short duration. It also has direct positive inotropic and chronotropic effects on cardiac muscle (47). Inotropic effects of a medication refer to those which alter the force of muscular contraction, while drugs with chronotropic effects change the heart rate (63, 64).
The hypothesis for its mechanism of action is that OraVerse™ acts as a vasodilator, allowing faster dissipation of the local anesthetic into the vasculature. As the local anesthetic diffuses into the cardiovascular system away from the injection site, less of the drug is available for sodium channel blockade, thus diminishing anesthesia
(numbness). This, in turn, accelerates return of normal sensation (48).
Contraindications to the use of phentolamine mesylate are myocardial infarction, history of myocardial infarction, coronary insufficiency, angina, or other evidence suggestive of coronary artery disease, and hypersensitivity to phentolamine or related compounds. Myocardial infarction, cerebrovascular spasm, and cerebrovascular occlusion have been reported following the parenteral administration of phentolamine, usually in association with marked hypotensive episodes (47). Although uncommon after the administration of OraVerse™, tachycardia and cardiac arrhythmias may occur with the use of phentolamine or other alpha-adrenergic blocking agents. Reported adverse reactions include acute and prolonged hypotensive episodes, tachycardia, and cardiac arrhythmias. Weakness, dizziness, flushing, orthostatic hypotension, nasal stuffiness, nausea, vomiting, and diarrhea may occur. The most common adverse reaction reported with oral injection of OraVerse™ was local injection site pain. There are no known drug interactions with OraVerse™ (7).
22 Phentolamine is a Pregnancy Category C drug and should not be used in pregnant women
unless the benefit to the patient outweighs the potential risk to the fetus. It is not known
if OraVerse™ is excreted in human milk, thus the unknown risks of limited infant exposure to phentolamine through breast milk should be weighed against the benefits of breastfeeding (7).
Efficacy and Safety of Phentolamine Mesylate as a Dental Anesthetic Reversal
Agent
Several studies have evaluated the efficacy and safety of phentolamine mesylate
for use in dentistry. Laviola et al. (12) conducted a double-blind, randomized,
multicenter, Phase 2 study to test the hypothesis that local injection of phentolamine
mesylate would shorten the duration of soft-tissue anesthesia following routine dental
procedures. Study participants received one or two cartridges of one of the following
local anesthetics: 2% lidocaine with 1:100,000 epinephrine, 4% articaine with 1:100,000
epinephrine, 2% mepivacaine with 1:20,000 levonordefrin, and 4% prilocaine with
1:200,000 epinephrine. Immediately after treatment, 1.8 mL of the study drug
(containing 0.4 mg phentolamine mesylate or placebo) was injected per cartridge of local
anesthetic used. The authors found that phentolamine was well-tolerated and decreased
median duration of soft tissue anesthesia in the lip from 155 to 70 minutes (p<0.0001) for
all of the treatment groups combined. Forty-three percent of the subjects who received
phentolamine and three percent of subjects who received placebo injections returned to
normal lip sensation within one hour. Median recovery time was reduced by 105 minutes
for the maxilla and by 49 minutes for the mandible. Overall, there was an 85-minute
23 difference in median recovery time for normal lip sensation between the placebo and phentolamine groups. No significant effects of age, gender, time interval between anesthetic and study drug injections, number of injections of study drug, or type of dental procedure on the primary efficacy endpoint (time to return of normal sensation) were found.
Hersh et al. (6) evaluated the reversal of soft-tissue local anesthesia with phentolamine mesylate in adolescents and adults. After completion of a routine dental restorative or periodontal procedure, subjects received either a phentolamine mesylate or sham injection at the same site as the local anesthetic injection. The local anesthetics used were 2% lidocaine with 1:100,000 epinephrine, 4% articaine with 1:100,000 epinephrine, 4% prilocaine with 1:200,000 epinephrine, and 2% mepivacaine with
1:20,000 levonordefrin. In patients receiving maxillary infiltrations, the median time to recovery of normal sensation of the upper lip was 50 minutes for subjects in the phentolamine group and 133 minutes for patients in the sham injection group. The difference between these times was significant. For patients who received an IAN block, the median time to recovery of normal lower lip sensation was 70 minutes with phentolamine and 155 minutes with the sham injection. The median time to recovery of normal tongue sensation was 60 minutes with phentolamine and 125 minutes with the sham injection. The differences between lip and tongue recovery times were statistically significant. In summary, phentolamine mesylate reduced median time to recovery of normal lip sensation by 85.0 minutes in the lower lip, 82.5 minutes in the upper lip, and
65.0 minutes in the tongue as compared to the subjects in the sham group (p<0.0001).
24 Recovery from actual functional deficits and subject-perceived altered function,
sensation and appearance also showed significant differences. Phentolamine mesylate
was equally efficacious in all age groups and with all local anesthetics with the following
exceptions: it was less efficacious in the maxillary arches of 12 to 17-year- olds, and
there was lack of efficacy after injection of 4% prilocaine with 1:200,000 epinephrine in
the maxillary arch. The authors explained that this may have been due to the potential
error associated with the small sample sizes for these groups.
The authors measured soft tissue recovery with the Soft Tissue Anesthesia
Recovery (STAR) questionnaire. This study assessment tool developed by Novalar
Pharmaceuticals to quantify a patient’s perceived clinical benefit from reversing soft tissue anesthesia measured each subject’s perception of altered function, sensation, and
appearance. Subjects answered the STAR questionnaire every thirty minutes for five
hours. The Functional Assessment Battery (FAB) measured smiling, speaking, presence
or absence of drooling, and drinking 3 ounces of water. Smiling, speaking and drooling
were rated by both a researcher and the subject at 10 minutes and then every five minutes
until all three functions returned to normal. Once this occurred, drinking 3 ounces of
water was added to the assessment and rated every five minutes until all functional
assessments returned to normal according to the subject and researcher for two
consecutive five-minute time intervals. Then, all four functions were assessed every five
minutes for the remainder of the five hour period. A particularly interesting finding was
that actual function recovered before perceived function and sensation recovered. This is
a clinically significant finding because at the time subjects perceived that their soft-tissue
numbness had worn off, completely normal function had already returned.
25 The authors concluded that an injection of phentolamine mesylate at the same
volume and site as a local anesthetic with vasoconstrictor significantly and safely reduced
the duration of soft-tissue anesthesia and associated functional deficits in subjects who had undergone routine, nonsurgical dental procedures. In patients for whom rapid return to normal function is sought and significant postprocedural pain is not anticipated, phentolamine mesylate has a useful application.
Tavares et al. (5) examined the use of phentolamine mesylate for reversal of soft- tissue local anesthesia in pediatric patients. Subjects (n=152) received injections with 2% lidocaine with 1:100,000 epinephrine prior to undergoing routine nonsurgical dental procedures, followed by either a phentolamine mesylate or sham injection in the same site as the local anesthetic was administered in a 1:1 cartridge ratio. Subjects in the phentolamine group had a median lip sensation recovery time of 60 minutes compared to
135 minutes for subjects in the sham injection group. This was a 55.6% difference
(p<0.0001). There was also a statistically significant difference in tongue recovery time.
Phentolamine patients’ tongues returned to normal sensation at a median of 45 minutes, while sham group patients’ tongues recovered at a median of 112.5 minutes, a 60% difference (p<0.0003). Overall, there was a reduction in median time-to-normal sensation of 120 minutes in the mandible and 52.5 minutes in the maxilla for subjects in the phentolamine mesylate group. The phentolamine mesylate was well tolerated and safe for children 4 to 11 years old, and accelerated reversal of soft-tissue anesthesia in 6-
11 year olds. One of the clinical implications is that phentolamine mesylate may help reduce the number of post-treatment soft-tissue injuries due to inadvertent lip, tongue, and cheek biting or chewing. Data on such events was not collected in this study.
26 Moore et al. (1) assessed the pharmacokinetics of lidocaine and phentolamine,
and the impact of phentolamine on the pharmacokinetics of 2% lidocaine with 1:100,000
epinephrine. Blood levels of phentolamine were determined following intraoral and
intravenous administration. The four treatment groups were as follows: intravenous
administration of one cartridge of phentolamine mesylate (1Piv), intraoral administration
of one cartridge of lidocaine and one cartridge of phentolamine mesylate 30 minutes later
(1L1P), intraoral administration of four cartridges of lidocaine followed by two cartridges
of phentolamine mesylate 30 minutes later (4L2P), and intraoral administration of four
cartridges of lidocaine (4L). Eleven (1Piv group) or 14 (groups 1L1P, 4L2P, and 4L) blood samples were drawn and analyzed over a period of 8.0-8.5 hours, starting immediately prior to the first injection of local anesthetic or intravenous injection of phentolamine mesylate. The time to peak plasma concentration (Tmax) of phentolamine
mesylate was 7 minutes for the 1Piv group, 15 minutes for the 1L1P group, and 11
minutes for the 4L2P group. After intraoral administration of lidocaine, there was an
initial peak in lidocaine blood concentration. The authors found a second peak in the
lidocaine concentration immediately following administration of phentolamine in both the 1L1P and 4L2P groups. The Tmax was 28 minutes for the 4L group and was 43
minutes for the 4L2P group. The authors proposed that this likely represents
phentolamine’s ability to reverse the vasoconstrictive effects of epinephrine, which
accelerates the clearance of lidocaine from oral tissues into the systemic circulation, thus
decreasing soft-tissue duration of anesthesia.
Rutherford et al. (55) conducted two Good Laboratory Practices studies in beagle
dogs to investigate systemic toxicity and the local effects of single and repeated dosing of
27 OraVerse™ on the inferior alveolar nerve and branches of the superior alveolar nerve and
adjacent soft tissues after local administration. No evidence of systemic toxicity was noted and no changes were observed in the nerves at injection sites of dogs from any dose group (235 μg/mL, 2350 μg/mL, or zero) that were considered directly related to the phentolamine mesylate. This study showed that single and repeated intraoral administrations of OraVerse™ were well tolerated in beagle dogs.
Froum et al. (179) studied the use of phentolamine mesylate to evaluate mandibular nerve damage following implant placement in a clinical trial with 10 patients undergoing implant placement. The authors propose that phentolamine may be useful in the early detection of mandibular nerve compression or damage that may occur during implant placement surgery. Administration of phentolamine, which reverses the effect of soft tissue local anesthesia, would allow clinicians to make an early determination as to the presence of nerve damage and could then decide whether implant removal or other intervention is necessary.
In this study, four subjects received IAN blocks using one cartridge of 4%
articaine with 1:200,000 epinephrine and a buccal infiltration injection with one cartridge
of the same anesthetic. Five subjects received one cartridge of 2% lidocaine with
1:100,000 epinephrine as an IAN block, and one cartridge of the same anesthetic as a
buccal infiltration. One subject received an IAN block with one cartridge of 2%
lidocaine with 1:100,000 epinephrine and a buccal infiltration with one cartridge of 4%
articaine with 1:200,000 epinephrine. Dental implants were placed in the mandible with
the aide of CT or CBCT scans, an implant simulation program, and surgical guides. At
the end of each surgery, the subjects received two cartridges of phentolamine mesylate
28 (0.4 mg/1.7 mL), one as an IAN block and one as a buccal infiltration. Patients recorded the time that lip and tongue numbness subsided and the time that normal oral function returned. Normal oral function was defined as complete sensation of the lips, gingiva, and tongue, the ability to drink water with full control, and no spilling, drooling, or accidental biting of soft tissue. All patients received postoperative analgesics immediately following surgery.
All 10 subjects agreed that the reversal injections improved their dental experience and reduced the expected duration of numbness. Nine of the 10 patients reported “mild” and one patient reported “moderate” postoperative discomfort. The average time to return to normal sensation for the lip was 50.6 minutes. Mean time to return to normal sensation of the tongue was 60.5 minutes, and oral function returned at an average of 59.9 minutes. In subjects who received 2% lidocaine with 1:100,000 epinephrine, lip and tongue sensation and normal oral function returned faster than in patients who received 4% articaine with 1:200,000 epinephrine. The authors concluded that the reversal of local anesthesia in a shorter period allows the clinician to assess any
IAN damage and take measures to treat the problem as early postsurgically as possible.
POSTOPERATIVE ENDODONTIC PAIN
“Researchers and practitioners have studied postoperative endodontic pain for years. In 1905, Buckley suggested that debris extruded into the periapical region of the root would cause severe postoperative pain (184). He recommended premedicating the pulp chamber and coronal portions of the canals during the first appointment to neutralize or sterilize the remaining debris in order to prevent exacerbations. In 1961, Seltzer et al.
29 (185) examined the effect of intracanal medicaments on post-treatment pain. They found
a 40 percent incidence of pain, with 20 percent of the subjects reporting moderate-to-
severe pain. Clem (104) reported a 25 percent incidence of post-treatment pain overall,
but only 16 percent reported moderate-to-severe pain when the diagnosis was chronic
periapical periodontitis. There was a natural progression during this period toward
debridement of the canal systems at the initial appointment, particularly for cases in
which pain was a factor. Schilder (186) discovered that there was less post-treatment pain with more debridement. He suggested that incomplete debridement was a major cause of postoperative pain. Harrison et al. (187) analyzed medicaments and irrigants
and found that were no significant differences among the materials on pain after
instrumentation.
Genet et al. (188) reported a positive correlation between the incidence of
postoperative pain and several factors: the presence of preoperative pain in conjunction
with a non-vital pulp; the presence of a radiolucency larger than 5 mm in diameter; the
number of root canals treated, and the sex of the patient. Yesilsoy et al. (189) found
similar results. Once again, preoperative pain and a necrotic tooth lead to increased
postoperative pain. He found one important difference. A comparison of original
endodontic diagnoses with respect to one-day postobturation pain showed that pulpally
necrotic cases with periapical radiolucent lesions demonstrated a higher percentage of
overall pain (63.6% vs. 22.9%) and mild pain (45.5% vs. 8.0%) when compared to vital,
inflamed cases. A comparison of original endodontic diagnoses with respect to four-day
postobturation pain showed that compared to vital inflamed cases, pulpally necrotic teeth
30 with periapical radiolucencies had a higher percentage of overall pain (18.3% vs. 8.0%),
and severe pain (18.2% vs. 1.7%).
Siqueira et al. (168) reported on the incidence of post-treatment endodontic pain in necrotic teeth. Undergraduate students in their first clinical year performed pulpectomies utilizing a crown-down technique. The canals were then medicated with a calcium hydroxide/camphorated paramonochlorophenol (CPMC) paste. Patients were instructed to take mild analgesics if they experienced pain. At one-week follow-up appointments, subjects were asked to rate the pain that they experienced postoperatively.
Ten percent of the patients reported mild pain, 3.3% moderate pain and only 1.9% reported severe levels in which the pain experienced was ‘difficult to bear and… analgesics, if used, were ineffective in relieving pain.’ There was no statistical
difference in the amount of pain experienced between initial and retreatment cases.
Previously symptomatic teeth without periapical lesions were significantly associated
with postoperative pain (p<0.01). The results of this research, however, may be
questionable secondary to the study design. Six hundred and twenty-seven teeth were
used. Of these teeth, 257 (41%) were without radiographic periapical pathosis. No
definition of what constituted the diagnosis of pulpal necrosis and/or periapical periodontitis or by whom this diagnosis was made was given in the publication. Only 75 teeth (12%) were reported to be symptomatic with a periradicular lesion. Another possible design flaw was the lack of control patients. All subjects received the medicated
CaOH2/CPMC paste. There was no standardization of the postoperative analgesics taken
by the patients, as well. Finally, the accuracy of reporting postoperative pain levels one
31 week after treatment is suspect. A more exact or true recording of such levels might have been accomplished through the use of daily surveys.” (9)
“O’Keefe (103) reported that patients presenting in severe pain had more severe postoperative pain than patients with mild or no pre-operative pain. Clem (104) reported a 25 percent incidence of post-treatment pain in an examination of 318 endodontically treated teeth. Fox et al. (105) found that teeth without periapical radiolucencies had more associated post-treatment pain than teeth with periapical radiolucencies. The study by
Marshall et al. (106) again found that patients with no radiographic periapical lesions had significantly more pain than patients with periapical lesions at 8, 24, 48, and 72 hours post-op. Kleier et al. (107) examined 40 endodontic cases on vital teeth and reported that
40 percent of the patients had some degree of postoperative pain. Harrison et al. (108) attempted to correlate clinical factors to the incidence of interappointment pain. They examined factors including vitality, presence of rarefaction, tooth type, type of irrigant used, and use of an intracanal medicament. They found complete unpredictability with no correlation between the factors and interappointment pain. In contrast, Torabinejad et al.(109) found that age, sex, tooth type, presence of preoperative pain, presence of allergies, absence of periapical lesions, sinus tract stomas, and retreated cases as well as those receiving prescribed analgesics all had significant effects on the incidence of interappointment pain. The commonality to most of the recent literature on the subject of endodontic treatment pain is that the patients who are asymptomatic when they present to the endodontist have a significantly lower incidence and degree of postoperative pain than those who present with pain.” (11)
32 “Post-treatment pain is related to many factors. The postoperative pain in teeth
without periapical radiolucencies is thought to be related, in part, to a periapical
inflammatory response produced by the endodontic instrumentation (110). The causes of the acute inflammation of the apical periodontal ligament space may be one or a combination of severing the pulpal tissue, instrumenting beyond the apex and into the periapical tissues, or forcing medication and/or debris through the apices (111). Root canal therapy does not immediately eliminate the periapical inflammation, thus the pain may persist postoperatively. However, Oguntebi et al. (190) showed that post-treatment pain develops in a relatively low percentage of patients with symptomatic irreversible pulpitis after endodontic emergency procedures.” (11)
Mattscheck et al. (56) studied the factors associated with posttreatment pain in patients undergoing root canal retreatment and initial root canal treatment. There was no significant difference in post-treatment pain with respect to retreatment or initial root canal treatment, type of original obturating material, or pretreatment diagnosis. Patients who reported higher pretreatment pain levels had significantly increased post-treatment pain (p<0.05) up to 24 hours after the procedure. Pretreatment pain level was found to influence post-treatment pain levels more than whether it was retreatment or initial treatment, what type of obturating material was originally used, or what the pretreatment diagnosis was.
Alacam and Tinaz (57) studied the incidence of interappointment pain in symptomatic and asymptomatic necrotic teeth and found no significant differences in the incidence of flare-ups attributable to gender, age, symptomatic or asymptomatic diagnoses, diameter of lesion, taking analgesics, placebos, or no medication.
33 El Mubarak et al. (66) found that the incidence of postoperative pain in patients who presented without preoperative pain was low (7.1%). This was a statistically significant difference when compared to patients who reported preoperative pain
(15.9%). The trend in the literature demonstrates that between 80 to 90% of the patients receiving endodontic treatment of an asymptomatic tooth report only mild pain post endodontic treatment (9).
VISUAL ANALOG SCALE
“The visual analog scale (VAS) is a line, the length of which is taken to represent
the continuum of some experience like pain. It is a simple, sensitive, and reproducible
instrument that enables a patient to express the severity of his/her pain in such a way that
it can be given a numerical value (65). The scale is ideal for crossover experiments,
enabling one patient to express an opinion about the relative value of different treatments.
The extremes of the line are taken to represent the limits of the pain experience; one end
is therefore defined as ‘no pain’ and the other as ‘severe pain’ (65).
The line should have ‘stops’ at each end to limit the distribution of results. The
scale may be vertical or horizontal (65). Although 4- and 5-point scales have wide
acceptance in literature, they appear to lack sufficient sensitivity to measure the pain
experience (67). Since a visual analog scale is difficult to use with no guides, other than
the endpoints, a hybrid between the two scales was developed in 1983 by Heft and Parker
(67). The resulting graphic rating scale is a horizontal line with category word
designations on the line (67). Clusters tend to occur around descriptors. However, when
34 the line is horizontal this grouping is not seen (67). Good correlation has been found
between pain measurements using visual analog and simple descriptive pain scales (65).
Ohnhaus and Adler (191) assessed the correlation between the visual analog scale
and a verbal rating scale. The verbal rating scale is the most widely used instrument to
measure pain. The primary problems with this scale are that it forces the patient to
translate a feeling into words and the intervals between the categories do not represent
identical steps in pain intensity. The visual analog scale seems to assess more closely
what a patient actually experiences. Although the subject number was small, they found
a close correlation between the two scales. The visual analog scale generally had lower values than the verbal rating scale.
Kreimer (68) investigated the efficacy and pain of injection of 2% lidocaine with
1:100,000 epinephrine versus a solution of 2% lidocaine with 1:100,000 epinephrine and
1.82 mL mannitol. He used both a hybrid visual analog scale and a numerical scale. The hybrid visual analog scale had 8 descriptive words on a 170 mm scale. There was a very high correlation between the visual analog scale and the numerical scale. The mean correlation value for all of the pain ratings was 0.92. Thus, there was a very strong correlation between the two scales. Kreimer (68) stated that the visual analog scale allowed the subjects to describe their pain more accurately and the results obtained from the visual analog scale were easy to analyze statistically. Therefore, Kreimer (68) felt that the visual analog scale was superior to the numerical pain scale.” (9)
The visual analog scale has been used to measure injection pain (8-11, 14-18, 20,
22-25, 28-33, 35-39, 60, 62) and post-operative pain (9, 11, 20, 22, 24, 25, 32) in many
studies conducted by the Advanced Endodontics Program at The Ohio State University.
35 CHAPTER 3
MATERIALS AND METHODS
One hundred adult patients presenting for endodontic treatment at The Ohio State
University College of Dentistry were used in this study. All subjects were in good health
as determined by a written health history and oral questioning. Patients taking
medications that may alter pain perception or are allergic to phentolamine or lidocaine
were excluded. All female subjects were questioned regarding pregnancy or suspected
pregnancy and were not allowed to participate if pregnant, suspected a pregnancy, were
nursing, or were trying to become pregnant. Females were required to take a urine
pregnancy test before participation, at the start of the appointment. Also excluded were
subjects who had contraindications to the injection techniques or to the anesthetic
solution (2% lidocaine with 1:100,000 epinephrine), or to the reversal agent (OraverseTM
– phentolamine mesylate). Approval for this study was obtained from The Ohio State
University Human Subjects Review Committee and written consent was obtained from each participant.
To qualify for the study, subjects must have presented with an asymptomatic maxillary or mandibular tooth requiring endodontic treatment. A periapical image of the tooth, using a paralleling device (Rinn Corp., Elgin, IL) and digital radiography (Schick
Technologies, Long Island, NY) was used in the determination of the presence and size
36 of a radiolucency. The subject must have presented with no pain, had no visible swelling, but may have had a draining sinus tract. The diagnosis was made in the Endodontic
Clinic at The Ohio State University College of Dentistry and confirmed by the principal investigator.
Clinical information was collected and recorded in the patient record for each patient prior to patient recruitment into the study. The clinical exam conducted prior to treatment gave information on tooth restorability, periodontal status and endodontic condition. The presence of a sinus tract was recorded. Pain or visible swelling excluded the patient from the study. The periodontal condition was recorded as sulcular pocket depths in millimeters. The clinical condition of the tooth was ascertained by noting the type and condition of any restorations present. The probable etiology of the current endodontic condition was recorded as well.
Radiographic findings were recorded by examination of the pretreatment radiograph. The presence of a radiolucency was recorded. A history of previous endodontic therapy was recorded as well. The endodontic obturation, if present, was described as to its condition. The canal system was evaluated for the number of canals present radiographically and whether sclerosis was present or absent. Age, gender, and medical status were reported in each patient’s medical history information form.
The experimental tooth and an adjacent tooth were tested with Cold SnapTM
(Benco Dental, Wilkes-Barre, PA) and a Kerr Electric Pulp Tester (Analytic Technology,
Redmond, WA). The tooth to be tested was dried with cotton gauze. The TFE was sprayed onto a cotton pellet held by cotton forceps until the pellet was saturated. This
37 pellet was then applied to the middle one third of the buccal enamel surface (the lingual
surface was used as an alternate site if no buccal surface existed). The pellet was
removed as soon as the patient indicated a feeling of cold or pain, and then a positive
response was recorded. If the patient felt nothing and the TFE had evaporated from the pellet, a “no response” was recorded. The experimental tooth and adjacent teeth were
tested with the electric pulp tester. Non-latex gloves were worn by the tester requiring the use of a lip clip to maintain a ground for electric pulp testing. The lip clip was firmly
held in the hand of the subject. The rate of current increase remained constant throughout
the study and was set at 25 seconds to increase from no output (0) to the maximum output
(80). Nickel-cadmium batteries (General Electric, Gainesville, FL) were used and changed as needed. The testing procedure was as follows: the tested teeth were isolated
with cotton rolls and dried with 2"x2" cotton gauze. A small amount of Crest® gel toothpaste (Proctor and Gamble, Cincinnati, OH), enough to cover the tip of the electrode, was used as the electrolyte between the electrode of the pulp tester and the tooth. The electrode was placed on sound enamel in the middle third of the facial or buccal surface of the crown of the tooth. The electrode was not placed on restorations or on exposed dentin. The pulp testing commenced upon contact of the electrode to the tooth surface and ended when the subject indicated an initial sensation in the tooth or if
an 80/80 was obtained.
For the mandibular teeth, the inferior alveolar nerve block was administered using
a standard syringe, 27-gauge 1½-inch needle, and 1.8 mL of 2% lidocaine with 1:100,000
epinephrine (Xylocaine®, DENTSPLY Pharmaceutical, York, PA). The conventional
inferior alveolar injection technique as described by Fischer (58) and modified by
38 Jorgensen and Hayden (59) was used. Before each injection, approximately 0.2 mL of
20% benzocaine topical anesthetic gel (Patterson Dental, Saint Paul, MN) was placed
passively at the injection site for 60 seconds. The injection site was the soft tissue
overlying the medial surface of the ramus, lateral to the pterygomandibular raphe, at a
height determined by the coronoid notch on the anterior border of the ramus. With the
subjects’ mouth wide open, the thumb of the non-injecting hand was placed over the
pterygomandibular triangle and then pulled laterally until the deepest depression in the
anterior border of the ramus was felt. The first or second finger of the non-injecting hand
palpated the posterior portion of the ramus, finding a slight depression. The line between
the thumb and the finger established the vertical height of the injection site. The direction of the needle insertion was from the contralateral mandibular premolars and directed parallel to the occlusal plane.
For the maxillary teeth, a standard maxillary infiltration injection was administered. Before each injection, approximately 0.2 mL of 20% benzocaine topical anesthetic gel was placed passively at the injection site for 60 seconds. The target site was centered over the maxillary tooth apex using a 27-gauge one-inch needle attached to a standard syringe. One cartridge of 2% lidocaine with 1:100,000 epinephrine was administered on the buccal or labial aspect of the tooth. One quarter of a cartridge of
lidocaine solution was also deposited 3 mm apical from the gingival margin of the treatment tooth on the palate. This was done to numb the tissue for the rubber dam retainer.
For all injections, after initial penetration, the needle was advanced over a time
period of approximately 10 seconds to the target site (needle placement). The needle
39 was withdrawn 1 mm, aspiration was performed, and 1.8 mL of the anesthetic solution was deposited over a period of 1 minute. Positive aspirations were recorded. Prior to insertion of the needle and deposition of the anesthetic solution, each subject was informed of the rating scales to be utilized for rating needle insertion, needle placement, and deposition of the anesthetic solution. Each subject was asked to rate each of the above procedures utilizing a Visual Analog Scale (VAS) (Appendix F) for all initial injections. At each stage of the injection the patient was asked to mark the VAS sheet to rate the pain they experienced at the initial insertion of the needle, placement of the needle to the target site, and deposition of the anesthetic solution at the target site. The
VAS was divided into four categories: no pain, mild pain, moderate pain, and severe pain. 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 and less than 114 mm. Severe pain was defined as equal to or greater than 114 mm. Severe pain included the descriptors of strong, intense and maximum possible.
Following deposition of the anesthetic at the target site each patient was asked, every minute for 20 minutes, if they were experiencing lip numbness for mandibular teeth and soft tissue numbness over the tooth for maxillary teeth. If numbness was not achieved within 20 minutes, an additional cartridge of 2% lidocaine with 1:100,000 epinephrine was administered by IAN block or maxillary infiltration near the same location of the initial injection. The need for a second injection was recorded. The principal investigator performed all injections.
40 Following application of the rubber dam, endodontic treatment was initiated by making an opening into the occlusal or incisal surface of the treatment tooth with a number 4 round bur using a high-speed, air-driven handpiece. Instrumentation of the canals was performed using hand and rotary endodontic files.
If the patient felt pain during access or instrumentation of the tooth, supplemental anesthesia was provided. For mandibular teeth, buccal infiltration with 1.7 mL 4% articaine with 1:100,000 epinephrine solution, and/or intraosseous injection with 1.8 mL
2% lidocaine with 1:100,000 epinephrine, and/or intrapulpal injection of 2% lidocaine
with 1:100,000 epinephrine solution was administered. For maxillary teeth, supplemental
anesthesia was administered via intraosseous injection with 1.8 mL 2% lidocaine with
1:100,000 epinephrine and/or intrapulpal injection of 2% lidocaine with 1:100,000
epinephrine. The mandibular buccal infiltration injection was administered using a
standard cartridge of articaine (Septocaine®, Septodont, New Castle, DE) using a
standard aspirating syringe equipped with a 27-gauge 1-inch needle (Monoject,
Sherwood Medical, St. Louis, MO). After rubber dam removal, with the subject in a
reclining position, a mandibular buccal infiltration injection was administered. No
topical anesthetic was placed prior to the infiltration. The target site was centered
buccally to the treatment tooth. The needle was inserted and then directed to a depth
approximately equal to the apices of the treatment tooth. The needle was then withdrawn
1 mm and aspiration was conducted. Following aspiration, 1.7 mL of anesthetic solution
was injected over one minute. Following the injection, the operator waited five minutes
before continuing with root canal treatment to give the anesthetic solution sufficient time
for onset.
41 The intraosseous injection was given using the Stabident System (Fairfax Dental
Inc., Miami, FL). The injection was given distal to the treatment tooth except for second and third molars in which the injections were given mesial. The area of cortical plate perforation was determined by the horizontal line of the buccal gingival margins of the
experimental and adjacent teeth and a vertical line that passed through the interdental
papilla. A point approximately 2 mm below the intersection of these lines, in the attached
gingiva, was used as the perforation site. The cortical bone was perforated using the
Stabident perforator in a contra-angle, slow-speed handpiece. The intraosseous injection
followed as the Stabident needle was placed in the perforation to the hub and the
anesthetic solution was deposited at a rate of 1.8 mL/min.
If additional pulpal anesthesia was required, an intrapulpal injection was given
using 2% lidocaine with 1:100,000 epinephrine and a 27-gauge needle placed directly
into the pulp chamber or the root canal that remained painful to instrumentation. The
injection was given under back-pressure to ensure successful anesthesia.
The amount and delivery method of supplemental anesthetic was recorded. Upon
completion of endodontic treatment, a sterile cotton pellet was placed in the access
opening and the access was sealed with Cavit (ESPE™, 3M™, Maplewood, MN). The rubber dam was then removed. One of the following treatment categories was recorded for each experimental tooth: finished with obturation materials within or to the radiographic apex, finished with obturation materials beyond the radiographic apex, or treatment not finished.
At the end of the treatment appointment, the phentolamine solution or a sham
injection was administered. Before the experiment, the two treatments (phentolamine
42 or sham treatment) were randomly assigned six-digit numbers from a random number table. The random numbers were used to assign a patient to a treatment group.
The patients assigned to the phentolamine group received one cartridge (1.7 mL)
of phentolamine mesylate (0.4 mg, OraVerseTM, Novalar Pharamaceuticals, San Diego,
CA) at the same injection site as was used previously (nerve block or infiltration). If the
patient received a two cartridge volume (3.6 mL) of the lidocaine solution, they received
2 cartridges of the phentolamine (0.8 mg dose). The phentolamine was packaged in a
standard anesthetic cartridge (1.7 mL). The cartridge of phentolamine was placed in a
standard aspirating syringe, equipped with a 27-gauge 1½ inch needle, and injected over
a period of one minute. The patient recorded the pain of needle insertion, needle
placement and solution deposition using a VAS scoring sheet, similar to that used to
record pain during the initial anesthetic injection (Appendix F).
The patients assigned to the sham injection had a capped 27-gauge 1½ inch
needle, attached to a standard aspirating syringe, pressed against the alveolar mucosa. No
soft tissue penetration occurred due to the needle remaining capped. The time of
administration of the sham injection was the same as for the administration of the phentolamine injection (1 min) and mimicked needle insertion, placement and solution
deposition. The patient recorded the pain of the sham needle insertion, needle placement
and solution deposition using the VAS scoring sheet. All patients for the phentolamine
and sham treatments were blindfolded during this phase of the study. The length of
treatment was calculated in minutes, beginning with the time of the first injection of
anesthetic and ending with the time that the phentolamine or sham injection was given.
43 Following the study/sham injection, the patient assessed the pain at the injection
site and for the tooth using a VAS every 30 minutes for two hours and every 60 minutes
for three hours. They were also requested to record any side effects and/or adverse reactions at each time interval (Appendix J).
Patients were asked to palpate the lip and tongue (mandibular teeth) on the side of injection, or the lip and gums (maxillary teeth) over the injected tooth, and record when a
tingling sensation (pins and needles feeling) or return to normal sensation occurred
(absence of pins-and-needles sensations). Patients were trained how to accurately palpate
the lip and tongue (mandibular teeth) or lip and gums (maxillary teeth) and were
instructed to use hygienic methods to perform the palpations. They performed the
palpations every 15 minutes for 5 hours following treatment and recorded their level of
sensation (numb, tingly, or normal) by marking an “X” in the corresponding column on
three data sheets (one each for the lip, gums, and tongue) (Appendices G-I). These
recordings were used to calculate the efficacy of reversal of soft tissue anesthesia using
phentolamine. The time to recovery of normal soft tissue was the number of minutes
elapsed from the injection of the phentolamine, or sham treatment, to the first of two
consecutive times at which the patient reported a normal sensation of the soft tissues.
Patients were asked to return the post-treatment surveys either in-person or by mail.
The data from this study were collected and statistically analyzed. With a sample size of
approximately 90 subjects, we determined, at a 95% confidence interval of +/- 15% for a
statistical reduction in the time of soft tissue numbness. However, because of dropouts,
we enrolled 100 subjects. Between group comparisons of needle insertion, needle
placement and solution deposition pain and postoperative pain were made using ANOVA
44 with Tukey-Kramer multiple-comparison test. Time to return of normal sensation analysis used time-to-event analysis (Kaplan-Meier methodology) to compare median times to recovery and their corresponding 95% confidence intervals between treatment groups. Comparisons were considered significant at p<0.05.
45 CHAPTER 4
RESULTS
The data from this study can be found in Appendices A through K. The results are summarized in Tables 1 through 16 and in Figures 1 through 6.
Ninety-five subjects were enrolled in this study. Eighty-five subjects completed the post-treatment questionnaires. Thirty-four females and 51 males, ranging in age from
18 to 81 years, completed the study. The overall average age of all participants was 36.1 years (Table 1). The OraVerse™ and Sham groups were well-balanced with regard to age and gender.
Table 2 presents the experimental teeth characteristics including tooth type and pulpal diagnosis. Thirty-seven (43.5%) of the experimental teeth were maxillary and 48
(56.5%) were mandibular. In the maxilla, there were 7 (15.2%) anteriors, 6 (13%) premolars, and 11 (23.9%) molars in the OraVerse™ group and 4 (10.2%) anteriors, 3
(7.7%) premolars, and 6 (15.4%) molars in the Sham group. In the mandible, there were no anteriors, 5 (10.9%) premolars, and 17 (36.9%) molars in the OraVerse™ group, and 1
(2.6%) anterior, 3 (7.7%) premolars, and 22 (56.4%) in the Sham group (Table 2). There were no statistically significant differences between the groups for experimental tooth type.
46 Thirteen (28%) of the maxillary experimental teeth in the OraVerse™ group had
necrotic pulps, and 11 (23.9%) were vital. Eight (20.5%) of the maxillary experimental teeth in the Sham group had necrotic pulps, and 5 (12.8%) were vital (Table 2). In the mandible, 16 (34.8%) of the experimental teeth in the OraVerse™ group were necrotic, while 6 (13%) were vital. In the Sham group, 17 (43.6%) mandibular teeth were necrotic, while 9 (23.1%) were vital. The OraVerse™ and Sham groups were balanced with regard to experimental tooth diagnosis (Table 2).
During the initial anesthetic injection procedure, subjects rated pain for needle insertion, needle placement, and solution deposition. A hybrid 170-mm Visual Analog
Scale (VAS) with descriptors was used for this study (Appendix F). Mean pain ratings for needle insertion, needle placement, and solution deposition during the IAN block and maxillary infiltration injections are presented in Table 3. Frequency of pain ratings by category (none, mild, moderate, and severe) are summarized in Tables 4.
Overall mean needle insertion, needle placement, and solution deposition pain ratings in the maxilla for the OraVerse™ and Sham groups were in the “mild” pain category (Table 3). Solution deposition was rated the most painful stage for both groups.
Male subjects reported mean solution deposition pain in the “mild” category (35.2 mm and 40.6 mm for the OraVerse™ and Sham groups, respectively). Female subjects with maxillary experimental teeth reported mean solution deposition pain in the “moderate” category (62.2 mm and 56.4 mm for the OraVerse™ and Sham groups, respectively).
In the mandible, overall mean needle insertion and needle placement pain for the
OraVerse™ and Sham groups were in the “mild” pain category. Overall mean solution deposition ratings for both groups fell in the “moderate” category (59.0 ± 9.7 mm
47 OraVerse™ and 59.2 ± 6.6 mm Sham). Male subjects’ mean solution deposition pain in the mandible was “mild” (40.1 ± 9.9 mm OraVerse™ and 43.5 ± 8.3 mm Sham). Female subjects’ mean solution deposition pain in the mandible was “moderate” (69.9 ± 13.6 mm
OraVerse™ and 70.7 ± 8.7 mm Sham). Solution deposition was the most painful phase for both groups. The IAN block injection was more painful than the maxillary infiltration injections for all three phases of the injection (Table 3).
The frequency of needle insertion, needle placement, and solution deposition pain ratings for the initial anesthetic injection for each group and jaw can be found in Table 4.
The descriptive scale (“none,” “mild,” “moderate,” “severe”) as measured on the VAS was utilized. In the maxillary injections for both genders and groups, approximately 71% of the subjects reported none-to-mild pain, and 29% reported moderate-to-severe pain.
Twenty-three percent of the females and 7% of the males in both groups who received maxillary injections reported severe pain at any of the three stages of the injection.
For the mandibular injections for both genders and groups, approximately 63% of the subjects reported none-to-mild pain, and 37% reported moderate-to-severe pain.
Thirty-eight percent of the females and 11% of the males in both groups who received mandibular injections reported severe pain at any of the three stages of the injection
(Table 4).
Table 5 presents anesthetic administered by jaw and group. The groups were balanced with regard to mean anesthetic dose administered for both maxillary and mandibular injections. In subjects with maxillary experimental teeth, the mean lidocaine dose was 2.5 mL in the OraVerse™ group, and 2.0 mL in the Sham group. There was not a statistically significant difference between the groups. Ten (41.7%) subjects with
48 maxillary experimental teeth in the OraVerse™ group required more than one primary
anesthetic injection. Two (15.4%) patients in the Sham group with maxillary
experimental teeth required more than one primary injection. The mean articaine dose
for subjects with maxillary experimental teeth was 0.07 mL in the OraVerse™ group and
0 mL in the Sham group. There was not a statistically significant difference between the groups for maxillary mean articaine dose. None of the subjects with maxillary teeth in either the OraVerse™ or Sham groups required an intraosseous injection.
In subjects with mandibular experimental teeth, the mean lidocaine dose was 4.0 mL for the OraVerse™ group, and 3.6 mL for the Sham group. There was not a statistically significant difference between the groups. Seventeen (77.2%) patients in the
OraVerse™ group with mandibular experimental teeth required more than one primary injection. Twenty-one (80.7%) subjects with mandibular experimental teeth in the Sham group required more than one primary injection. The mean articaine dose in the mandible was 0.46 mL in the OraVerse™ group and 0.13 mL in the Sham group. There was not a statistically significant difference between the groups. No subjects with
mandibular experimental teeth in the OraVerse™ group required an intraosseous
injection. Two subjects with mandibular experimental teeth in the sham group required an intraosseous injection. There was not a statistically significant difference between the groups (Table 5).
Procedure time and case completion status is presented in Table 6. The procedure time was recorded after completion of the first anesthetic injection and ended when the
first cartridge of OraVerse™ or the sham injection was delivered. The groups were
balanced with regard to procedure time. Mean procedure time for subjects with maxillary
49 experimental teeth was 71.4 ± 4.2 minutes in the OraVerse™ group and 66.6 ± 3.3 minutes in the Sham group (P=0.4485). Mean procedure time for subjects with mandibular experimental teeth was 83.5 ± 4.7 minutes in the OraVerse™ group and 85.4
± 3.9 minutes in the Sham group (P=0.7472).
Twenty (83.3%) of the maxillary experimental teeth in the OraVerse™ group were not obturated beyond the radiographic apex. None of the maxillary teeth in the
OraVerse™ group had obturation material extended beyond the radiographic apex, and 4
(16.7%) teeth were not obturated. Ten (76.9%) of the maxillary experimental teeth in the sham group were not obturated beyond the radiographic apex. Three (23.1%) of the maxillary teeth in the Sham group had obturation material extended beyond the radiographic apex, and none of the teeth in this subgroup were not obturated. There was a significant difference between the OraVerse™ and Sham groups in the maxilla with regard to case completion status (P=0.0215).
In the mandible, 16 (72.7%) of the teeth in the OraVerse™ group were not obturated beyond the radiographic apex. Four (18.2%) teeth had obturation material extended beyond the radiographic apex, and 2 (9.1%) teeth were not obturated. Twenty
(76.9%) mandibular experimental teeth in the Sham group were not obturated beyond the radiographic apex, 5 (19.2%) teeth had obturation material extended beyond the radiographic apex, and one (3.8%) tooth was not obturated. There was not a statistically significant difference between the two groups in the mandible with regard to case completion status (Table 6).
Table 7 presents the mean VAS pain values of the OraVerse™/Sham injections.
Mean needle insertion, needle placement, and solution deposition pain values for
50 administration of OraVerseTM and the Sham injection were in the “mild” category for both groups, genders, and jaws. The overall mean VAS values for needle insertion in the maxilla were 3.8 ± 1.9 mm in the OraVerse™ group and 4.0 ±2.6 mm in the Sham group
(P=1.0000). The overall mean VAS values for needle placement in the maxilla were 5.8
± 1.8 mm in the OraVerse™ group and 2.4 ± 2.5 mm in the Sham group (P=0.9002). The overall mean VAS values for solution deposition in the maxilla were 9.3 ± 3.5 mm in the
OraVerse™ group and 8.4 ± 4.8 mm in the Sham group. No significant differences were found between the groups in subjects with maxillary experimental teeth (Table 7).
The overall mean VAS values for needle insertion in the mandible were 3.7 ± 3.8 mm in the OraVerse™ group and 0.9 ± 1.2 mm in the Sham group (P=0.5878). The overall mean VAS values for needle placement in the mandible were 4.0 ± 1.5 mm in the
OraVerse™ group and 0.7 ± 1.4 mm in the Sham group. The overall mean VAS values for solution deposition in the mandible were 3.9 ± 2.1 mm in the OraVerse™ group and
2.7 ± 1.9 mm in the Sham group (P=0.9981). There were no statistically significant differences between the groups in subjects with mandibular experimental teeth (Table 7).
The frequency of needle insertion, needle placement, and solution deposition pain ratings for the OraVerse™/Sham injection for each group and jaw can be found in
Table 8. The descriptive scale (“none,” “mild,” “moderate,” “severe”) as measured on the VAS was utilized. There were no pain ratings in the “severe” category for either group, jaw, or gender. For solution deposition, 93% of the OraVerse™ injections were rated in the none-to-mild pain range.
A summary of the adjusted mean soft tissue anesthesia time in the maxilla can be found in Table 9. Duration of maxillary soft tissue anesthesia for the lip/cheek and gums
51 is presented in Figure 1. There was a statistically significant shorter duration of anesthesia in the OraVerse™ group for maxillary lip/cheek “numb,” maxillary lip/cheek
“tingly,” maxillary lip/cheek “normal,” maxillary gums “numb,” and maxillary gums
“tingly.” There was not a statistically significant difference in time to maxillary gums
“normal.”
Table 10 presents the adjusted mean time of mandibular soft tissue anesthesia.
The duration of mandibular soft tissue numbness for the lip, gums, and tongue is presented in Figure 2. There was a statistically significant shorter duration of anesthesia in the OraVerse™ group for mandibular lip “numb” and mandibular lip “tingly.” There was not a statistically significant difference between the groups for mandibular lip
“normal.”
Duration of mandibular gums “numb” was significantly shorter in the OraVerse™ group for male subjects, but not for female subjects. There was a statistically significant shorter duration of mandibular gums “tingly” and mandibular gums “normal” in the
OraVerse™ group (Table 10).
There was a statistically significant shorter time to tongue “normal” in the
OraVerse™ group, however there were no statistically significant differences between the groups for tongue “numb,” and tongue “tingly” (Table 10).
Table 11 presents the adjusted mean duration of maxillary lip/cheek anesthesia.
The adjusted mean maxillary lip/cheek numbness was 99.1 ± 7.8 minutes in the
OraVerse™ group and 134.2 ± 10.9 minutes in the Sham group. There was a statistically significant difference between the groups (P=0.0145). Return to normal soft tissue sensation, defined as the length of time (in minutes) of “numb” plus length of time (in
52 minutes) of “tingly,” was 135.5 ± 12.1 minutes in the OraVerse™ group and 223.8 ± 19.1 minutes in the Sham group. There was a statistically significant difference between the groups (P=0.0007). The number of subjects reporting “numbness” and “return to normal sensation (numbness plus tingling)” in Table 11 is not equal to the overall number of subjects in the OraVerse™ and Sham groups with maxillary experimental teeth. This is due to subjects failing to record all portion(s) of the postoperative soft tissue anesthesia survey.
The adjusted mean duration of mandibular lip and tongue anesthesia for the two groups are presented in Table 12. Mean duration of mandibular lip numbness was 120.5
± 8.3 minutes in the OraVerse™ group and 144.7 ± 7.4 minutes in the Sham group.
There was a statistically significant difference between the groups (P=0.0348). The mean time to return to normal sensation (numbness plus tingling) for the mandibular lip was
170 ± 11.9 minutes in the OraVerse™ group and 217.3 ± 10.8 minutes in the Sham group. There was a statistically significant difference between the groups (P=0.0054).
The mean duration of tongue numbness was 106.1 ± 7.5 minutes in the OraVerse™ group and 120.9 ± 6.3 minutes in the Sham group. There was not a statistically significant difference between the groups (P=0.1382). The mean time to return to normal sensation (numbness plus tingling) for the tongue was 141.9 ± 10.5 minutes in the
OraVerse™ group and 169.4 ± 8.9 minutes in the Sham group. There was not a statistically significant difference between the groups (P=0.0649). The number of subjects reporting “numbness” and “return to normal sensation (numbness plus tingling)” in Table 12 is not equal to the overall number of subjects in the OraVerse™ and Sham
53 groups with mandibular experimental teeth. This is due to subjects failing to record all portion(s) of the postoperative soft tissue anesthesia survey.
The adjusted mean duration of maxillary and mandibular gingival anesthesia is reported in Table 13. In the maxilla, the adjusted mean duration of gingival numbness was 107.3 ± 7.6 minutes in the OraVerse™ group and 147.9 ± 10.3 minutes in the Sham group. There was a statistically significant difference between the groups (P=0.0036).
The adjusted mean time for maxillary gingival return to normal sensation (numbness plus tingling) was 148.6 ± 9.1 minutes in the OraVerse™ group and 195.4 ± 14.8 minutes in the Sham group. There was a statistically significant difference between the groups
(P=0.0128). The number of subjects reporting “numbness” and “return to normal sensation (numbness plus tingling)” in Table 13 is not equal to the overall number of subjects in the OraVerse™ and Sham groups. This is due to subjects failing to record all portion(s) of the postoperative soft tissue anesthesia survey.
In the mandible, the adjusted mean duration of gum numbness in female subjects was 133.3 ± 9.8 minutes in the OraVerse™ group and 139 ± 9.8 minutes in the Sham group. There was not a statistically significant difference between the groups in female subjects with mandibular experimental teeth (P=0.6829). For male subjects with mandibular experimental teeth, adjusted mean duration of gum numbness was 112.6 ±
11.4 minutes in the OraVerse™ group and 159.2 ± 9.7 minutes in the Sham group. There was a statistically significant difference between the groups (P=0.0073). The adjusted mean time to return to normal sensation (numbness plus tingling) for all subjects with mandibular experimental teeth was 174.8 ± 12.8 minutes in the OraVerse™ group and
54 216.2 ± 10.6 minutes in the Sham group. There was a statistically significant difference between the OraVerse™ and Sham groups (P=0.0164) (Table 13).
Mean postoperative pain ratings for the injection site and experimental teeth are presented in Tables 14 and 15 and in Figures 3 through 6. Postoperative pain ratings were within the “mild” category for both groups, genders, and jaws (Tables 14 and 15).
Post-hoc statistical tests revealed no significant differences between groups, genders, or jaws over the 5 hour postoperative pain survey period. For both the OraVerse™ and
Sham groups there was an overall decreasing trend in injection site and experimental tooth postoperative pain over the 5 hour survey period, with slight increases at 60 minutes postoperatively (Figures 3-6).
Table 16 presents the frequency of subject-reported postoperative complications for each time period in the five hour surveys for experimental tooth and injection site pain. At 30 minutes postoperatively, 2 (4.3%) subjects in the OraVerse™ group reported intraoral swelling, and 1 (2.2%) subject in the OraVerse™ group reported feeling light- headed or dizzy. At 60 minutes postoperatively, 2 (4.3%) subjects in the OraVerse™ group reported intraoral swelling, 1 (2.2%) subject in the OraVerse™ group and 1 (2.6%) subject in the Sham group reported nausea, 1 (2.2%) subject in the OraVerse™ group reported feeling light-headed or dizzy, and 1 (2.6%) subject in the Sham group reported feeling a sensation of an “itching” tooth. At 90 minutes postoperatively, 1 (2.2%) subject in the OraVerse™ reported intraoral swelling, and 1 (2.2%) subject in the OraVerse™ group reported nausea. At 120 minutes postoperatively, one (2.2%) subject in the
OraVerse™ group reported intraoral swelling, and 2 (5.1%) subjects in the Sham group reported soreness at the injection site. At 180 minutes postoperatively, 1 (2.2%) subject
55 in the OraVerse™ group reported soreness when biting, and 1 (2.2%) subject reported soreness at the injection site. At 240 minutes postoperatively, 1 (2.2%) subject in the
OraVerse™ group reported intraoral swelling, 1 (2.2%) subject in the OraVerse™ group reported soreness when biting, 1 (2.2%) subject in the OraVerse™ group and 1 (2.6%) subject in the Sham group reported soreness at the injection site, and 1 (2.6%) subject in the Sham group reported bruising at the injection site. At 360 minutes postoperatively, 1
(2.6%) subject in the Sham group reported ringing in their ears, 1 (2.2%) subject in the
OraVerse™ group and 1 (2.6%) subject in the Sham group reported soreness when biting,
1 (2.6%) subject in the Sham group reported soreness at the injection site, and 1 (2.6%) subject in the Sham group reported bruising at the injection site. Statistical analysis of postoperative complications was not performed due to the low number of incidences for each category.
56 CHAPTER 5
DISCUSSION OF MATERIALS AND METHODS
Ninety-five adult subjects ranging in age from 18 to 81 participated in this study.
34 (40%) were male and 51 (60%) were female. The study population was drawn from
patient volunteers presenting for routine nonsurgical endodontic treatment at the
Advanced Endodontics Clinic at The Ohio State University. No attempts were made to balance the number of males and females or the ages of the patients. Gender of the
patients has been shown to have no effect on electric pulp tester thresholds (43) but may
affect pain responses (81). Since this study did not enroll patients under age 18, the results may not be applicable to children.
“All female patients were requested to take a urine pregnancy test prior to
participating in this study. An over-the-counter pregnancy test, Osom® hCG-Urine Test, was utilized to rule out pregnancy before females participated in the study. The Osom®
pregnancy test detects human Chorionic Gonadotropin (hCG), which is present in urine
only during pregnancy. The Genzyme Diagnostics Corporation claims that urine
specimens containing as low as 25 mIU/mL hCG will yield positive results when tested
with the Osom® hCG-Urine Test (117). In normal pregnancy, hCG levels in urine can
reach 25 mIU/mL as early as 7 to 10 days post conception, and continue rising to reach a
maximum concentration in excess of 200,000 mIU/mL at the end of the first trimester
57 (118). McCready et al. (119) claimed that 25 mIU/mL can be detected as early as two to three days before expected menses. In one clinical study, 40 urine specimens were tested with the Osom® hCG-Urine Test and the results were compared to results obtained from other commercially available visual tests for hCG. The Osom® hCG-Urine Test, when compared to other tests, resulted in a sensitivity of 100% and a specificity of 100% (117).
However, several investigators have disputed the accuracy and reliability of home pregnancy test manufacturer claims (120-124). These studies have reported accuracy values from 46% to 89% (120-124), values which are very different from the >99% detection quoted by most manufacturers. Butler et al. (125), in researching manufacturer claims of early detection pregnancy tests, questioned manufacturer claims and concluded that the true accuracy of home pregnancy tests for detecting pregnancy on the day of and/or in the week following the missed menstrual period is uncertain.” (10)
“To determine the risks associated with the use of drugs in pregnancy, the FDA classifies prescription drugs based on fetal injury risk. The Categories range from A to
X. Drugs in Categories A and B are considered safe for use, as no adverse effects have been demonstrated in humans. Drugs in Category C may be used based on animal studies, but no controlled human studies are available. Category D and X drugs have been associated with adverse effects in humans and should be avoided.
Lidocaine is classified in Category B and is considered safe for use in pregnant individuals. Fujinaga et al. (126) studied the teratogenic, reproductive effects, and toxicological effects of local anesthetics (in high and low doses) in the Sprague-Dawley rat. The authors concluded that the administration of local anesthetic agents during pregnancy was devoid of adverse effects on the fetus. Furthermore, the standard of care
58 in dentistry is stated by Malamed (2) and Haas (127) that local anesthetics and
vasoconstrictors used in dentistry are safe to administer in the pregnant patient.” (10)
OraVerseTM is a Pregnancy Category C drug as there are no adequate and well-
controlled studies in pregnant women. Oral administration of phentolamine to pregnant
rats and mice at doses 24 times the recommended dose (based on a 60 kg human) resulted
in slightly decreased growth and slight skeletal immaturity of the fetuses. Oral
phentolamine doses of at least 60 times (based on a 60 kg human) the recommended dose caused a slightly lower rate of implantation in the rat. Oral administration of phentolamine to rabbits at 20 times the recommended dose (based on a 60 kg human) resulted in no embryonic effects or changes in fetal development. No teratogenic or embryonic effects were found in the rat, mouse, or rabbit studies (7).
The main reason for eliminating pregnant patients in this study was for medico- legal considerations. If a patient were knowingly pregnant and participated in this study
and had a miscarriage or a baby with a fetal defect, they could attempt to correlate
participation in this study with those events. Naturally occurring congenital anomalies
occur in 3% of the general population, yet causes can be determined in less than 50% of
these cases (128). Therefore, it seemed prudent to eliminate this population group.
All subjects were in good health as determined by a written health history and oral
questioning. Exclusion criteria were: allergy to local anesthetics; allergy to phentolamine; history of significant medical problem (ASA classification III or greater); history of myocardial infarction; pregnancy; lactating; or inability to give informed consent. A total of $75.00 was paid to each subject who completed the study and
59 returned both post-treatment questionnaires. Participation in this study was voluntary in accordance with The Ohio State University Human Subjects Committee.
No attempt was made to balance the number or type of teeth used in this study.
The general indications and instructions for use of OraVerseTM are the same, regardless of tooth number or type (7). Laviola et al. (4), Tavares et al. (5), and Hersch et al. (6) determined that the effects of phentolamine mesylate are similar in all oral soft tissues.
All experimental teeth were determined to be asymptomatic, regardless of pulpal diagnosis. Asymptomatic teeth were chosen to minimize the possibility that subjects would misinterpret normal post-operative pain associated with endodontic treatment with potential painful after-effects of receiving the phentolamine mesylate injection.
According to Mattscheck et al. (56), pre-treatment pain levels are more predictive of post-treatment pain levels than type of treatment provided (initial or retreatment), type of obturation material used, or pre-treatment diagnosis. Thus, patients with teeth that are asymptomatic prior to endodontic treatment would be expected to report less pain postoperatively. Also, patients experiencing pre-treatment pain were excluded since they could be randomly assigned to the phentolamine group and therefore, potentially, return to their pretreatment level of pain more quickly due to the test drug. This would have been an undesirable outcome for these types of patients. Unfortunately, it was not possible to eliminate all potential post-treatment pain (unrelated to the study drug) by excluding the patients with symptomatic teeth. Patients who presented with asymptomatic necrotic teeth were informed of the possibility of post-operative flare-up.
In a meta-analysis of literature on endodontic flare-ups Tsesis et al. (162) reported an average incidence of 8.4% within 48 hours of completion of treatment. This was beyond
60 the time period for which patients were to evaluate their numbness, therefore the potential
incidence of a post-treatment flare-up would not affect our data collection. Each patient
was questioned by the principal investigator about their symptoms prior to their
recruitment into the study.
The experimental tooth and adjacent teeth were tested initially with Cold Snap
Freeze SprayTM (Benco Dental, Wilkes-Barre, PA). This product contains 1,1,1,2 tetrafluoroethane similar to Green Endo-IceTM. This was done to determine the pulpal
diagnosis (69). If the patient presented with a tooth that had previously had a
pulpectomy, the pulpal diagnosis determined at the initial appointment was recorded. No
further vitality testing was conducted on these teeth. Cold Snap Freeze SprayTM was selected due to its reported low liquid temperature (-26.2° C) and the fact that skin refrigerants have been found to be more reliable than ice or ethyl chloride in determining vitality of the pulp (70).
“The test tooth and adjacent teeth were dried prior to thermal testing. A cotton
pellet was saturated with the Cold Snap Freeze SprayTM and placed in the middle third of
the buccal surface of the teeth. Care was taken not to get any of the material on the gingiva. The patient was asked to raise his/her hand when a cold or painful sensation was felt. The pellet was then immediately removed and a positive response was recorded. If no response occurred, the pellet was left on the tooth until the refrigerant evaporated and a no response was recorded. This took approximately 30 seconds. Seltzer et al. (70)
have shown that teeth that have a painful and prolonged reaction to thermal stimulation
require either root canal therapy or extraction.” (10)
61 A positive response to Cold Snap Freeze SprayTM that dissipated within a few
seconds and did not produce lingering or prolonged pain was considered “normal,” and
the pulp was considered to be asymptomatic. If there was no response to Cold Snap
Freeze SprayTM from the experimental tooth, the tooth was tested with the electric pulp
tester to confirm the pulpal diagnosis. McDaniel et al. (142) reported that the electric
pulp tester was safe to pulpal tissue. The use of the electric pulp tester did not produce
histological changes, such as necrosis or inflammation.
“The Analytic Technology electric pulp tester has been shown by Cooley et al.
(143) and Kitamura et al. (144) to be extremely accurate (97-99%). This instrument has
an internal resistance of 150 k/ohms in order to negate the effects of high resistance in
teeth as recommended by Bjorn (67) and Mumford and Bjorn (145). The maximum
voltage of this instrument is 300 volts. One hundred and forty volts was found, by
Matthews (146,147) to be sufficient to stimulate all vital pulps in normal, asymptomatic
teeth. Fifty microamperes is the maximum amperage of the Kerr electric pulp tester. The
current output must be sufficient to stimulate the pulpal tissue but not to stimulate tissues
beyond the confines of the tooth. A current of 50 microamperes was found to be
sufficient by Pepper and Smith (148) and Matthews (147), to stimulate healthy pulps and
a current of 200 microamperes was necessary to stimulate the surrounding periodontal
tissues. Researchers have recommended the use of an electric pulp tester, which stimulates with cathode polarity, since tissues have a lower threshold for stimulation using cathode polarity, rather than anode polarity (145,146,148). Matthews (146,147) also suggested that a constant current stimulation system be used. This results in a more valid vitality reading in comparison to an impulse current stimulation system. A constant
62 current system allows the current output to remain stable even if variable resistances are
encountered in tooth structures (149).
The unit delivers a cathodal polarity current output from 0 to 50 microamperes
and generates an output voltage that ranges from 15 to 300 volts. It possesses an internal
resistance of 150 k/ohms and is a constant current stimulation system (149). During the
study, the rate of voltage increase was calibrated so that the elapsed time to obtain an 80
reading starting from a 0 reading was approximately 25 seconds. This rate of voltage
increase was chosen because Kleier et al. (150) found that a slow rise in voltage output
(25 seconds to go from 0/80 to 80/80) resulted in a significantly less painful response to the patient when compared to a more rapid rise (5 seconds to go from 0/80 to 80/80).
Alkaline batteries were used and changed as needed to ensure adequate power supply.”
(73)
All experimental teeth were tested for percussion sensitivity. The teeth were gently tapped using the rounded end of the dental mirror. Pain upon percussion was recorded as either positive or negative. Percussion sensitivity may indicate the presence of inflammation originating in the dental pulp and extending into the periodontum (71).
Owatz et al. (72) concluded that periradicular mechanical allodynia contributed to the early stages of odontogenic pain due to the inflammation of vital pulp tissue.
“Initial periapical images using digital radiography were taken with a paralleling device to provide an accurate representation of the tooth, the periapical rarefaction, and the surrounding periodontium. In an in vitro study, Forsberg (151) compared paralleling
and bisecting angle radiographic techniques. The paralleling technique was significantly
63 more reliable and reproducible than the bisecting technique. Therefore, the paralleling
technique alone was used in this study for initial periapical films.” (9)
The biographical information gathered included the following: tooth number, age,
gender, preoperative pulpal diagnosis, presence of a periapical radiolucnecy, whether or
not the tooth was endodontically obturated, and if any obturation material was extended
beyond the apex. The data was tabulated in the attempt to identify factors that may
contribute to postoperative pain.
Twenty percent benzocaine gel was applied for topical anesthesia in this study.
The use of topical anesthetic has been advocated as an aid in reducing the pain of needle
insertion. “While Rosivack et al. (152) demonstrated the effectiveness of topical
anesthetic, Gill and Orr (153) and Kincheloe et al. (154) showed no significant pain
reduction with the use of topical anesthetic. Nusstein et al. (74) conducted a study to
compare the effectiveness of 20% benzocaine in reducing the pain of needle insertion
during maxillary posterior and anterior infiltration and inferior alveolar nerve block
injections. Logistic regression analysis showed no differences in pain ratings between
topical and no topical groups for the inferior alveolar nerve block and posterior maxillary infiltration injections. The use of topical anesthetic did reduce the pain of needle insertion with the maxillary anterior injections. For the inferior alveolar nerve block injection,
Yonchak et al. (17) and Nist et al. (18) concluded that there was not a significant difference in patient discomfort following application of topical anesthetic, Vaseline, or nothing to the site of injection. Martin et al. (155) found that if the patient thought they were receiving topical, whether they did or not, pain ratings were lower. Therefore, the
64 most important aspect of using topical anesthetic may not be its clinical effectiveness, but
rather the psychological effect on the patient who feels the practitioner is doing
everything possible to prevent pain (155).” (73) The principal investigator chose to use topical anesthetic due to this positive psychological effect and evidence from Nusstein et
al. (74) showing efficacy for use with infiltration injections.
“The inferior alveolar nerve (IAN) block utilized in this study was given in the
manner described by Fischer (156) and modified by Jorgensen and Hayden (157).
Subjects with mandibular experimental teeth were placed in the supine position with the
neck extended and the mouth opened as wide as possible when the inferior alveolar nerve
block was given. The injection site was the soft tissue overlying the medial surface of the
ramus, lateral to the pterygomandibular raphe, at a height determined by the coronoid
notch on the anterior border of the ramus (2). For the mandibular block, a 27-gauge 1¼-
inch needle with a standard dental syringe, was inserted 2-3 mm below the mucosal
surface coming from the contralateral mandibular premolar area and being directed
parallel to the occlusal plane. A 27-gauge 1¼-inch needle was used for all IAN block
injections based on the Robison et al. (58) study of needle deflection and breakage as
related to gauge size. They found no consistent pattern in the amount of deflection
among gauges of needles. All needles passed the ADA specifications for resistance to
breakage. A 1¼-inch needle gave adequate needle length for insertion into the
pterygomandibular space. Needle penetration was approximately 16-20 mm (158).” (10)
A separate long buccal nerve block was administered using a standard aspirating
syringe and a 27-gauge 1 ¼-inch needle. As described by Malamed (2), the syringe was aligned parallel with the occlusal plane on the side of injection and buccal to the teeth.
65 With the subject’s buccal soft tissue retracted, the needle was inserted 2-4 mm into the mucosa distal and buccal to the last mandibular molar. After aspiration, 0.9 mL 2% lidocaine with 1:100,000 epinephrine was delivered. The injection pain of the long buccal nerve block was not rated.” (10)
The principal investigator administered infiltration anesthesia injections for maxillary experimental teeth. With the subject’s mouth open, the operator’s free hand retracted the lip and buccal mucosa adjacent to the experimental tooth. The direction of the needle insertion was from an inferior, anterior and lateral direction into the buccal vestibule. The infiltration injection was administered using a standard aspirating syringe and a 27-gauge, 1-inch needle.
After initial penetration, the needle was advanced to the target site within two to three seconds. The needle was advanced until the tip of the needle was estimated to be at or just above the root apex. No effort was made to align the bevel of the needle in any particular direction. Malamed (2) stated that “The orientation of the needle bevel is not a significant factor in the success or failure of an injection technique.” Steinkruger et al.
(130) also found that for IAN blocks administered with a 27-gauge needle, positioning the needle bevel away or toward the mandibular ramus did not affect anesthetic success.
No anesthetic solution was deposited during needle advancement. Steinkruger et al. (131) studied the effects of a 2-stage injection technique on IAN block pain and found that there was no significant difference in pain between needle insertion and solution deposition in men or women. However, there was significantly less pain with the 2-stage injection technique for needle placement in women.
66 After reaching the target site, aspiration was performed, and one full cartridge of
the anesthetic solution (lidocaine) was deposited over a period of one minute. “A one-
minute period for solution deposition is recommended by Walton (159) as a means of
reducing patient discomfort during injection. ‘Slow deposition of solution permits its
gradual distribution into the tissues…As a general rule, solution deposition should take
approximately 1 minute per cartridge’ (159). The needle was removed after completing
solution deposition.” (73)
Malamed states that it is extremely important to inject slowly with careful
aspiration when giving local anesthesia in order to minimize both the pain of injection
and the possibility of a rapid intravascular injection. “Aspiration allows the clinician to
determine whether the needle tip lies within a blood vessel lumen. Rapid intravascular
injection of 1.8 mL of 2% lidocaine with 1:100,000 epinephrine will produce a blood
level in excess of that required for overdose. Malamed states that a realistic goal for
deposition of a 1.8 mL cartridge of anesthetic is 60 seconds. If this amount of anesthetic
happened to be deposited intravascularly at this rate of injection it would produce levels below the minimum for overdose and if signs and symptoms did occur they would be less severe. Rapid injection is not only dangerous but also painful. If injected too quickly the anesthetic will tear the tissue rather than diffusing along the normal tissue planes leading to immediate discomfort followed by post-op discomfort and possibly trismus (2).” (10)
“Kanaa et al. (160) investigated the speed of injection and the influence it had on the efficacy of the IAN block. The double-blind crossover trial studied the efficacy and discomfort associated with slow (60 seconds) and rapid (15 seconds) IAN block using
2% lidocaine with 1:80,000 epinephrine. Mandibular first molars, premolars and lateral
67 incisors were evaluated in 38 healthy volunteers and the efficacy was determined by an
electric pulp tester. Injection discomfort was self-recorded by the volunteers on a visual
analog scale. Slow IAN block when compared to rapid IAN block produced more
episodes of pulpal anesthesia as evaluated by the electric pulp tester. Slow IAN block was more comfortable than rapid IAN block.” (10)
Subjects were asked, prior to the injection, to rate the discomfort they experienced at three distinct stages of the first injection. The VAS was shown to the patient and it was explained that he/she would receive the entire injection and be asked to rate the three stages after the injection was completed. The three stages of the injection included the time when the needle was placed submucosally (insertion), the placement of the needle to its final location (placement), and the deposition of the anesthetic solution
(deposition). The patient was informed of the needle insertion phase just prior to the initial penetration of the needle. The needle was advanced to the target site and the patient was informed of the needle placement phase. The anesthetic was then administered and the patient was informed of the deposition phase of the injection. Each subject was then asked to rate each of the above phases using a VAS (Appendices # and
#). The subject was given a clipboard with the VAS’s and a marking instrument following the injection. They were asked to mark three separate VAS’s to rate the pain they experienced at the initial insertion of the needle, placement of the needle to the target site, and deposition of the anesthetic solution at the target site. The injection phases were only rated for the first cartridge of 1.8 mL of 2% lidocaine with 1:100,000 epinephrine. Pain ratings of the injection phases for any additional anesthetic needed
68 were not recorded because they would be inaccurate due to the already established soft
tissue anesthesia in the injected area.” (10)
“Kreimer (68) investigated the efficacy and pain of injection of 2% lidocaine
with 1:100,000 epinephrine versus a solution of 2% lidocaine with 1:100,000 epinephrine
and 1.82 mL mannitol. He used both a hybrid visual analog scale and a numerical scale.
The numerical scale consisted of 4 pain ratings: 0 = none; 1 = mild; 2 = moderate; 3 =
severe. The hybrid visual analog scale had 8 descriptive words on a 170 mm scale. The
mean correlation value for all of the pain ratings was reported as 0.92. These results
showed a very high correlation between the visual analog scale and the numerical scale.
Kreimer (68) stated that the results obtained from the visual analog scale were easier to
analyze statistically. Therefore, Kreimer (68) felt that the visual analog scale was
superior to the numerical pain scale.” (73)
Following administration of anesthesia, the patient was asked every minute for 20
minutes whether they were experiencing lip numbness (mandibular anesthesia) and/or soft tissue/cheek numbness (maxillary anesthesia). If her/his lip or soft tissue/cheek was
not numb, the patient was given an additional cartridge of lidocaine at the original
injection site. Once lip numbness was achieved, treatment commenced with placement of
the rubber dam and access of the pulp chamber. If pain was felt during access, the rubber
dam was removed and a supplemental anesthetic injection was given.
For mandibular experimental teeth the patient first received a supplemental
infiltration injection using a cartridge of 4% articaine with 1:100,000 epinephrine
(Septocaine®, Septodont, New Castle, DE). The buccal infiltration injection was
69 administered using a standard aspirating syringe and a 27-gauge 1-inch needle. This
gauge needle was chosen since it is the most commonly used in dentistry (134). The 27-
gauge needles used in this study were consistent with those of previous studies by
Robertson et al. (151), Pabst et al. (132), Nuzum (133), and McEntire (73) allowing
comparisons to be made and additional data to be collected to corroborate the results of
past studies.
After initial penetration, the needle was advanced to the target site within two to three seconds. The target site was defined as the buccal cortical bone near the estimated location of the root apex. The needle was advanced until the tip of the needle was estimated to be at or just above the root apex. No effort was made to align the bevel of the needle in any particular direction. Needle bevel orientation does not significantly affect anesthesia success or failure, as previously mentioned by Malamed (2) and
Steinkruger et al. (130). As the needle was advanced over a period of 2 to 3 seconds, no anesthetic solution was deposited.
“After reaching the target site, aspiration was performed, and the full cartridge of the anesthetic solution (articaine) was deposited over a period of one minute. A one- minute period for solution deposition is recommended by Walton (159) as a means of reducing patient discomfort during injection. The needle was removed after completing solution deposition.” (10)
“Following buccal mandibular infiltration the operator waited five minutes before continuing with root canal treatment to give the anesthetic solution sufficient onset time. Onset time for a mandibular buccal infiltration of articaine was investigated by Robertson et al. (161). The authors used an electric pulp tester to assess first and
70 second molars and first and second premolars for pulpal anesthesia. The onset time for pulpal anesthesia for all teeth was approximately 4.4 + 3.0 minutes.” (10) Pabst et al.
(132) studied the effects of a repeated mandibular buccal infiltration injection with 4% articaine with 1:100,000 epinephrine. The authors found onset time for pulpal anesthesia after the first injection was 5.4-6.2 minutes. These results supported the idea to wait five minutes following the buccal infiltration before proceeding with endodontic treatment.
After rubber dam replacement, endodontic treatment was continued. The success of the supplemental infiltration injection was defined as the ability to access the pulp chamber, place files, and instrument the tooth without pain. If the patient experienced pain during access or instrumentation, the infiltration injection was judged as a failure and an intraosseous injection was administered. Supplemental intraosseous anesthesia has been shown to be effective in achieving pulpal anesthesia when conventional methods have failed. Gallatin et al. (136) compared the Stabident and X- tip (X-tip Technologies, Lakewood, N.J.) intraosseous injection systems’ anesthetic outcomes in primary intraosseous injections in mandibular posterior teeth. Subjects were given 1.8 mL 2% lidocaine with 1:100,000 epinephrine after either a Stabident perforation in attached gingiva distal to the first mandibular molar or an X-tip perforation through alveolar mucosa distal to the first mandibular molar. For both intraosseous techniques onset of pulpal anesthesia was within the first two minutes of testing. The authors found pulpal anesthesia success rates of 81% for Stabident and
83% for X-tip in mandibular second premolars, 95% for both Stabident and X-tip in mandibular second molars, and 93% for both Stabident and X-tip for mandibular first
71 molars. Pulpal anesthesia steadily declined over the 60 minute testing period. Nusstein
et al. (135) compared the degree of pulpal anesthesia achieved with the intraosseous
injection and infiltration injection using 2% lidocaine with 1:100,000 epinephrine. The
authors found the mean onset time of pulpal anesthesia was significantly faster, and the
duration of pulpal anesthesia was significantly shorter with the intraosseous injection.
The success rate for the intraosseous injection was 98%. For this study the supplemental
intraosseous injection was determined to be an effective method of obtaining pulpal
anesthesia without prolonging duration of anesthesia.
The patient received a supplemental intraosseous injection utilizing the Stabident system. The site of injection was designated as distal to the treatment tooth, except if the
treatment tooth was a second molar when it was given mesial to the tooth. The distal site
is recommended in the Stabident manual (137) for mandibular teeth, but this has not been
based on scientific study. The distal site, and the mesial site for second and third molars,
was chosen to maintain consistency with other studies (20, 25, 31, 135, 136) which have evaluated the efficacy of the intraosseous injection in experimental, mandibular first molars and adjacent teeth.
“The perforator was placed at a 90° angle to the cortical bone to allow for
perforation along the shortest route through the bone. Any deviation of this angle may
cause inadequate perforation due to the limited length of the perforator and an increase in the distance required to perforate the bone.
The handpiece and perforator were activated as they lightly contacted bone. Light pressure was applied until a feeling of “break through” was achieved. If this was not
72 achieved within 2-5 seconds, the perforator was withdrawn still activated as
recommended by the Stabident Manual (137). The “break through” feeling represents
perforation into the cancellous bone. This was not always observed within the first 2
seconds of the first attempt. Reinsertion of the perforator in the same hole and
reactivation of the handpiece was accomplished to complete perforation. Generally,
failure was due to not attaining full depth of penetration with the perforator and can be
attributed to the varying thickness of cortical bone. Denio et al. (138) reported a mean
thickness of cortical bone without trabeculation to be between 2.7 mm and 3.0 mm
between mandibular first and second molars. This is the area where all of the perforation
difficulties were observed in this study. Cortical bone in the mandible is generally
thinner in the anterior regions (139). The mean thickness of attached gingiva has been
reported by Goaslind et al. (140) as 1.25 mm. Combining the above data reveals a mean
thickness of between 3.95 mm and 4.25 mm that needs to be perforated. A pilot study
conducted by Dunbar (20) determined that the mean length of the Stabident perforator
was 8.4 mm with a range of 8.0 mm to 9.0 mm. This appears to be an adequate length to
achieve perforation through the cortical bone and this was found to be true in this study.”
(10)
“The perforator was removed from the bone while still activated to prevent
breakage in the bone. The site of perforation was then identified by placing a cotton roll
against the site and upon removal, a small dot of hemorrhage indicated the perforation site. Sometimes additional pressure was required due to heavy bleeding, but finding the perforation was not hindered.” (37)
73 “A 27-gauge ultra-short Stabident needle on an aspirating syringe was then inserted into the perforation site. Due to the location and accessibility of the site, the needle had to be bent to approximately a 45° angle. The 27-gauge needle was found to be adequate in transversing the perforation and it was long enough to enter the cancellous bone. It was also found to be large enough to deliver the anesthetic solution and fit snugly in the perforation to prevent back-flow of the solution into the oral cavity.” (10)
Anesthetic solution, 1.8 mL of 2% lidocaine with 1:100,000 epinephrine, was then delivered into the cancellous space over a 1 minute time period. Pulpal anesthetic success rates for mandibular second premolars and first and second molars range from 83 to 100% using 1.8 mL of 2% lidocaine with 1:100,000 epinephrine in an intraosseous injection (20, 25, 31, 135, 136). The solution was usually delivered without backpressure. In a few patients, backpressure was experienced initially and the anesthetic solution did not advance into the cancellous bone resulting in backflow of the anesthetic solution into the oral cavity. Nusstein et al. (32) studied the effectiveness of supplemental intraosseous injections in patients with irreversible pulpitis. The authors found that in cases in which anesthetic backflow was experienced, pulpal anesthesia was not successful. When there was no backflow pulpal anesthesia success was 82%. When backpressure was experienced in this study, rotation of the needle either clockwise or counterclockwise approximately a quarter turn was done and injection reattempted as suggested by the Stabident Manual (137). This was done to move the lumen of the needle away from the trabeculae of the cancellous bone, the periodontal ligament, the root, or the lamina dura which may have been blocking the deposition of the anesthetic.
If this did not help, the needle was removed and checked for blockage by expressing
74 some solution from the needle tip. The syringe was held in a “pen-gripping” fashion to
allow for improved control of the needle in locating and entering the perforation site.
Following the intraosseous injection, the rubber dam was replaced and
endodontic treatment was continued. Though no subject required additional anesthesia
beyond the supplemental intraosseous injection, an intrapulpal injection would have been
given if the subject continued to feel pain after the intraosseous injection.
K-type hand files and rotary ProFile® GT® files were used for the canal
preparations. If pulpectomy was performed and root canal treatment was not finished,
each canal was prepared to a minimum apical size ISO 25 with 0.04 taper, assuring canal
cleanliness. If root canal treatment was completed and the tooth was obturated, each
canal was prepared to an apical size of at least ISO 30 with 0.04 taper. Canals were
irrigated with 3.0% sodium hypochlorite and dried. Grossman’s sealer was applied to each canal with a hand file. All canals were obturated using the appropriate size gutta percha master cones, accessory cones, and warm gutta percha utilizing the continuous
wave of condensation technique (141). A cotton pellet was placed into the access and
Cavit was used for the temporary restoration.
Post-operative instructions were provided and appropriate post-operative
medications were prescribed. All patients were advised to take 600 mg ibuprofen every six hours as needed for pain. Randomized placebo controlled studies in endodontics have demonstrated significant analgesic benefits for patients treated with ibuprofen (163, 164).
Torabinejad et al. (163) found that ibuprofen was more effective than placebo within the
first 48 hours after complete instrumentation of an endodontically treated tooth. Patients
were offered a prescription of Vicodin (5 mg hydrocodone with 500 mg acetaminophen)
75 for relief from moderate-to-severe post-operative pain. In Hargreaves’ and Abbot’s
analysis of drugs for pain management in dentistry (166), they noted that while opioids
are powerful analgesics, their use should be reserved for patients experiencing severe
pain due to potential increased side effects of the drugs. Since the subjects included in
this study were asymptomatic prior to treatment, they were not expected to experience
moderate-to-severe pain post-operatively. No attempt was made to record or analyze the
amounts or frequency at which post-operative pain medication was consumed.
Depending on when and if pain medication was taken, post-operative pain reports may
have been affected. For example, if a patient took a dose of ibuprofen and/or Vicodin
within the five-hour time period of the post-operative pain questionnaire, their recorded
pain levels may have been less severe than if they had taken no pain medication. Since patients were not observed during the five-hour post-operative period, it was uncertain if
patients took the pain medications recommended or if they consumed alternate pain
medications that may have affected their post-operative pain levels. There are no known
studies that investigate the affect of pain medications on soft tissue anesthesia. The use
of pain medication has not been known to affect soft tissue anesthesia and therefore
should not affect the subjects’ report of duration of anesthesia of the lip, tongue, or
gingiva.
Following treatment, either the OraVerseTM or sham injection was given. If one
cartridge of lidocaine solution was given as a maxillary infiltration or IAN block, one
cartridge of OraVerseTM was given at the original injection site. If two cartridges of
lidocaine solution were utilized for these injections prior to treatment, two cartridges of
OraVerseTM were given at the original injection sites. A maximum of two 1.7 mL
76 cartridges of OraVerseTM were given according to recommendations on the package insert (7). If more than two cartridges of anesthetic were given, only two cartridges of
OraVerseTM were given at the sites of the first two anesthetic injections since the
maximum allowed dosage of OraVerseTM is two 1.7 mL cartridges (7). In cases in which
two IAN blocks and one mandibular buccal infiltration were given, one cartridge of
OraVerseTM was given at the site of the first IAN block and one cartridge was given at
the site of the mandibular buccal infiltration.
There is no published recommendation for rate of injection of OraVerseTM.
Injections were administered at a rate of approximately one cartridge per minute in order to remain consistent with the manner in which the initial anesthetic was given.
Administraiton at the same rate allowed for comparison of solution deposition pain between the initial local anesthetic injection and OraVerseTM /sham injection.
For patients in the sham group, the capped needle on a standard aspirating syringe was placed at the original injection site and a mock injection was given. The patients were blindfolded for this part of the study so as not to bias their post-treatment survey
reporting. A sham injection was chosen rather than administration of a placebo solution
to ensure that the local soft tissue environment was not altered. With a mock injection
we could assume that any reduction in length of soft tissue anesthesia was not due to the
potential effects of a placebo solution. Clinical trials conducted during the development
of OraVerseTM used a sham injection as the control group (5, 6).
Each subject was given verbal instructions as to how to complete the post-
treatment questionnaires. The numbness post-treatment questionnaire tracked how long
77 it took for normal soft tissue sensation to return so that comparisons could be made between the OraVerseTM and sham groups. Patients were instructed to record soft tissue numbness every fifteen minutes for five hours, beginning when treatment was complete and the OraVerseTM or sham injection(s) were given. The fifteen minute interval was chosen because we felt this was a reasonable amount of time for subjects to be expected to comply while minimizing inconvenience. Also, knowing when normal soft tissue sensation returned to within fifteen minutes is a clinically applicable concept. Ideally, subjects would have remained on-site and would have been asked to report soft tissue numbness and pain every minute. This technique would have garnered the most accurate results. However, this method would not have been feasible for patients, and subject enrollment would have been low within the time period this study was conducted. The tooth and injection site pain questionnaire was used to determine patient pain levels related to when their numbness wore off and whether subjects who received the
OraVerseTM injection experienced more pain than those who received the sham injection.
Pain levels were recorded every thirty minutes for the first two hours and then every hour for an additional three hours. We felt that five hours was sufficient time to compare the two subject groups. We monitored changes in pain levels more frequently during the first two hours after treatment ended since it is during this period that differences in pain between OraVerseTM and sham subjects were expected to be most evident.
78 CHAPTER 6
DISCUSSION OF RESULTS
The mean age in the OraVerse™ groups was 38.2 ± 2.3 years and ranged from 18 to 81 years. The mean age in the Sham group was 34.1 ± 2.3 years and ranged from 19 to
74 years (Table 1). There was not a significant difference between the groups for mean age of subjects. Nordenram and Danielsson (167) studied the affect of age on anesthetic efficacy. They investigated different anesthetic parameters including duration of tooth anesthesia, and soft tissue numbness of commonly used dental local anesthetics in healthy older subjects. The authors found that the anesthetic solutions tested were more effective in the older group than the younger group. The authors speculated that this might be due to a higher pain threshold in the older group possibly due to reduced vascularity, fatty degeneration of bone tissue, or secondary dentin formation. If there would be a difference in duration of soft tissue anesthesia due to age, the similar age distribution between the two groups would minimize the effect such a difference might have on our results. Additionally, patients under the age of 18 were not included in this study and therefore the results of our study may not be applicable to children.
Although the number of males and females in each group was not equal, the proportions of male and female subjects in the groups were similar. It was important to have an approximately equal number of male and female subjects because it is possible
79 that the anesthetic or the OraVerse™ may work differently depending on the subject’s gender. If this were the case, the results would not necessarily be applicable to the gender with low representation in the study. Since there was not a statistically significant
difference in the percentages of male and female subjects between the OraVerse™ and
Sham groups, we can expect that the results of this study are applicable to both male and
female endodontic patients between the ages of 18 and 81 years.
There was not a statistically significant difference between the groups for
experimental tooth type. The type of tooth (anterior, premolar, or molar) undergoing root
canal therapy is important to consider because anesthesia success is not the same for each
tooth type. There are also differences in anesthetic success between the maxilla and
mandible. According to Malamed (2), maxillary anesthesia is more successful than
mandibular anesthesia, and maxillary infiltrations are 95% successful. Evans et al. (36)
found that 1.8 mL of 2% lidocaine with 1:100,000 epinephrine was 62% successful for
maxillary lateral incisor infiltrations, and 73% successful in maxillary first molar
infiltrations in asymptomatic patients. Mikesell at al. (38) reported 97% success for
maxillary lateral incisor infiltrations, 100% success for maxillary first premolars, and
100% success for maxillary first molars with 1.8 mL 2% lidocaine with 1:100,000
epinephrine in asymptomatic patients. Katz et al. (171) reported 83% anesthesia success
for both maxillary lateral incisor and maxillary first molar infiltrations in asymptomatic patients. These studies (8, 38, 171) defined successful anesthesia as numb (80/80 reading with the electric pulp tester) for 60 minutes.
Successful mandibular pulpal anesthesia, as defined as numb (80/80 reading with
the electric pulp tester) within fifteen minutes of injection and continuously numb for one
80 hour (22), has been reported to occur in 55% of molars, 60% of premolars, and in only
31% of lateral incisors with normal pulps, using 2% lidocaine with 1:100,000 epinephrine
(14-17, 20-27, 29, 30).
Another reason why tooth type is important to consider is because it may influence postoperative pain. Clem et al. (104) reported less postoperative discomfort in anterior teeth than in posterior teeth. Roane et al. (172) found that mandibular anterior teeth were the most frequently painful following root canal therapy, although the authors stated that there was not a statistically significant relationship to the anatomic location of the tooth and the frequency of reported postoperative pain. Balaban et al. (173) reported that asymptomatic, necrotic maxillary lateral incisors had the highest frequency of painful postoperative exacerbations. Again, in our study, there was not a significant difference between the OraVerse™ and Sham groups with regard to experimental tooth type. Thus, differences in postoperative tooth pain levels between the two groups cannot be attributed to anatomic location of the experimental tooth. Postoperative tooth pain is discussed later in this section.
The two groups were balanced for both jaws with regard to preoperative pulpal diagnosis (Table 2). All of the subjects were asymptomatic at the time of enrollment in our study, regardless of pulpal diagnosis. This is important because pretreatment pain levels are associated with posttreatment pain levels. We specifically chose these patients so that the potential for postoperative pain was nearly eliminated and would not potentially affect the pain associated with the OraVerse™/sham injection in this endodontic model.
81 In general, there is a tendency toward increased postoperative pain when the patient reports preoperative pain (103, 106, 108-109). Seltzer and Bender (110) found that 49% of patients with teeth that were initially painful and 34% of those with teeth that were not initially painful reported pain following endodontic instrumentation and medication (P<0.005). Siqueira et al. (168) reported on the incidence of post-treatment endodontic pain in necrotic teeth. At one week following treatment, ten percent of the patients reported mild pain, 3.3% moderate pain and only 1.9% reported severe pain.
Pickenpaugh et al. (75) studied the effect of prophylactic amoxicillin on endodontic flare- up (defined as moderate-to-severe postoperative pain or swelling that began around 30 hours after endodontic treatment and persisted for an average of 74 hours) in asymptomatic, necrotic teeth and found no difference in incidence of flare-up between the amoxicillin and placebo groups. The authors reported that 90% of the subjects reported either no pain and no swelling or mild-to-moderate pain and mild swelling within 5 days of treatment. Henry et al. (174) studied the effect of penicillin on postoperative endodontic pain and swelling in symptomatic necrotic teeth and found postoperative penicillin did not have a significant effect on postoperative pain. The authors stated that the majority of patients with symptomatic necrotic teeth had significant postoperative pain and required analgesic medication to manage the pain within 7 days of completion of treatment. Ince et al. (169) studied the incidence of postoperative pain in patients with vital and non-vital pulps and found that there was no difference between the two groups. At three days post-treatment, most patients in both groups reported no or mild pain. The previously mentioned studies (75, 168, 169, 174) collected postoperative pain data over longer periods of time than the 5-hour
82 postoperative reports used in our study. Seltzer and Bender (110) stated that pain after
endodontic treatment generally decreases over time. Our observations may add to the
information about immediate postoperative pain in asymptomatic patients following endodontic treatment.
The overall mean VAS pain values for the initial maxillary anesthetic injections were within the none-to-mild range for all three phases of the injections in both male and female subjects in both treatment groups. Mean needle insertion pain was rated as 29.4 ±
6.3 mm in the OraVerse™ group and 8.5 ± 2.9 mm in the Sham group in the maxilla.
Mean needle placement pain was 32.7 ± 7.5 mm in the OraVerse™ group and 32.8 ±
10.4 mm in the Sham group in the maxilla. Mean solution deposition pain was 50.9 ± 7.5 mm in the OraVerse™ group and 50.3 ± 21.1 mm in the Sham group in the maxilla.
There was a gender difference in solution deposition pain for subjects with maxillary experimental teeth. Male subjects in this category reported “mild” pain for solution deposition in both treatment groups (35.2 ± 9.5 mm OraVerse™, 40.6 ± 23.2 mm Sham).
Female subjects with maxillary experimental teeth reported mean pain values in the
“moderate” category in both the OraVerse™ and Sham groups (62.2 ± 10.1 mm and 56.4
± 14.2 mm, respectively).
Evans et al. (8) studied the efficacy of lidocaine and articaine for maxillary infiltrations in asymptomatic patients and found that female subjects reported higher mean solution deposition pain than males during administration of the maxillary infiltration with 1.8 mL of 2% lidocaine with 1:100,000 epinephrine. In our study, females reported higher mean solution deposition pain values for maxillary infiltrations when compared to other studies involving asymptomatic patients receiving maxillary
83 infiltrations (8, 37, 38). In the OraVerse™ group, 64.3% of the female subjects with
maxillary experimental teeth reported pain in the moderate-to-severe category. In the
Sham group, 62.5% of the female subjects with maxillary experimental teeth reported
pain in the moderate-to-severe category (Table 4). Gross et al. (37) compared the
efficacy of bupivacaine and lidocaine for maxillary infiltration anesthesia in
asymptomatic patients. The authors found that overall, 44% of the subjects reported
“moderate” pain for lidocaine solution deposition over the maxillary lateral incisor, and
36% reported “moderate” pain for solution deposition over the first maxillary molar. In our study, it is important to recognize that while female subjects with maxillary experimental teeth reported moderate-to-severe mean solution deposition pain, the mean values for the OraVerse™ and Sham groups were only 9.2 mm and 3.4 mm beyond the limit for mild pain (54 mm), respectively. Additionally, the small number of subjects in
our study’s subgroups (maxillary/female/OraVerse™ N=14; maxillary/female/Sham
N=8) may have resulted in higher means. Fillingim et al. (170) reviewed recent clinical
and experimental findings regarding sex, gender, and pain. The authors state that “The
available research indicates a potentially important contribution of gender roles to sex
differences in responses to experimentally induced pain, with masculinity and femininity
predicting higher and lower pain sensitivity, respectively.” The authors also cite several
studies in which experimenter gender had an affect on subjects’ self-reported pain. They
found that males showed a higher pressure pain threshold when tested by a female versus
a male experimenter, whereas females’ pain threshold was not influenced by the sex of
the experimenter. Although these studies did not examine differences in anesthetic
solution deposition pain between males and females, it is possible that gender of the
84 subjects and presence of a female experimenter influenced the pain reports of the subjects
in our study.
In the mandible, overall mean pain VAS values for needle insertion for male and
female subjects were in the none-to-mild category in both treatment groups. Mean needle
insertion pain in the OraVerse™ group was 41.1 ± 5.5 mm and was 44.7 ± 7.1 mm in the
Sham group. Twenty-five percent (6/24) of the subjects in the OraVerse™ group and 0%
(0/13) in the Sham group reported needle insertion pain in the moderate-to-severe
category. Mean needle placement pain was also in the none-to-mild category for males
and females in both groups (51.5 ± 6.9 mm OraVerse™ and 46.8 ± 6.3 mm Sham).
Twenty-one percent (5 out of 24) of the subjects in the OraVerse™ group and 31% (4 out of 13) of the subjects in the Sham group reported moderate-to-severe needle placement pain. Overall mean pain VAS values for solution deposition in the mandible were in the
“moderate” category in both groups. There was a difference between the genders for mandibular solution deposition pain. Male subjects reported “mild” mean solution deposition pain, while females reported “moderate” mean solution deposition pain. In the
OraVerse™ group, 57.1% (8 out of 14) of the female subjects with mandibular experimental teeth reported solution deposition pain in the moderate or severe categories.
In the Sham group, 66.7% (10 out of 15) of the female subjects with mandibular experimental teeth reported solution deposition pain in the moderate or severe categories.
As in the maxilla, small numbers of subjects in each subgroup likely affected the overall mean pain values.
Mikesell et al. (35) found that 23% of asymptomatic subjects who received an
IAN block with 2% lidocaine with 1:100,000 epinephrine experienced moderate-to-
85 severe pain on needle insertion. Hinkley et al. (60) compared the efficacy of 2%
lidocaine with 1:100,000 epinephrine to other local anesthetics for the conventional IAN block in asymptomatic patients and reported that 12% of the subjects had moderate-to-
severe pain on needle insertion. Nist et al. (176) and Goldberg at al. (22) reported 26% of
their subjects had moderate-to-severe pain on needle insertion when giving asymptomatic
patients an IAN block with 2% lidocaine with 1:100,000 epinephrine. Vreeland et al.
(16) reported that 37% of their asymptomatic subjects had moderate-to-severe pain on
needle insertion for the IAN block with 1.8 mL 2% lidocaine with 1:100,000 epinephrine.
In the current study, overall, 31% of our subjects reported moderate-to-severe pain on
needle insertion for the IAN block, which is similar to the studies mentioned above.
Utilizing symptomatic patients requiring endodontic therapy, Agarwala (11)
administered IAN blocks with 2% lidocaine with 1:100,000 epinephrine and found that
57% of subjects rated their pain on needle insertion as moderate or severe. Bigby et al.
(31) found that 52% of their subjects with symptomatic irreversible pulpitis rated their
pain on needle insertion as moderate or severe for the injection of lidocaine as an IAN
block. Claffey et al. (177) reported that for IAN blocks in patients with symptomatic,
irreversible pulptis, 63% of patients who received 2% lidocaine with 1:100,000
epinephrine rated their pain of needle insertion as moderate, strong, intense or maximum
possible pain. Nusstein et al. (25, 32) and Reisman et al. (33) also administered IAN
blocks in patients with symptomatic irreversible pulpitis. Nusstein et al. (25, 32) reported
23% and 2.5%, and Reisman et al. (33) reported 27% had moderate-to-severe pain for
needle insertion. Our results for needle insertion pain in the mandible are similar to
Nusstein et al. (25), Reisman et al. (33) group, higher when compared to Nusstein et al.
86 (32), and lower when compared to Claffey et al. (177), Bigby et al. (31), and Agarwala et
al. (11).
“McCartney et al. (192) performed a retrospective analysis investigating the pain
associated with needle insertion, placement, and solution deposition for the conventional
inferior alveolar nerve (IAN) block in patients with symptomatic irreversible pulpitis.
One hundred two emergency patients with irreversible pulpitis received IAN block injections using 2% lidocaine with 1:100,000 epinephrine. The patients recorded pain of the three injection stages on a Heft-Parker visual analog scale. Moderate-to-severe pain
was found to occur 57% to 89% of the time with the IAN block. Needle placement was
significantly more painful than needle insertion for males and significantly more painful
than either insertion or deposition for females (P<0.03). There was no statistical
difference between the pain for males or females with respect to needle insertion,
placement, or deposition pain (P>0.05). Deposition of 0.2 to 0.4 mL of anesthetic during
placement did not significantly reduce placement pain for either gender (P=0.753). In
conclusion, 57% to 89% of patients presenting with irreversible pulpitis have the
potential for moderate-to-severe pain with the IAN block.” (10)
No anesthetic was given during the needle insertion stage in any of the studies
previously discussed, nor in the current study, and therefore differences in pain ratings cannot be attributed to the deposition of anesthetic solution during needle insertion. In all studies, a 27-gauge 1¼-inch needle was used. The depth of insertion as well as time of insertion was similar for all groups. There may be variations between studies due to operator or patient population differences.
87 For IAN blocks with 2% lidocoaine with 1:00,000 epinephrine in asymptomatic patients, Dunbar et al. (20) reported that 24% of the subjects recorded moderate-to-severe pain on needle placement at the target site. Childers et al. (175) reported 35%, Hinkley et al. (60) reported 12%, Nist et al. (176) reported 26%, Goldberg et al. (22) reported 26%,
Vreeland et al. (16) reported 37%, and Clark et al. (23) reported 63% of asymptomatic
patients recorded a moderate-to-severe response for needle placement during an IAN
block with 2% lidocaine with 1:100,000 epinephrine. Mikesell et al. (35) administered
IAN blocks with 2% lidocaine with 1:100,000 epinephrine and found that 61% of
subjects reported moderate-to-severe pain on needle placement.
Overall needle placement pain reported in the current study was in the moderate-
to-severe category for 42% of subjects, which is higher than what was reported by
Dunbar’s (20), Hinkley’s (60), Nist’s (176), Goldberg’s (22), Vreeland’s (16) and
Childers’ (175) groups, and lower than Clark’s (23) and Mikesell’s (35) groups.
Differences in patient populations and operators may have contributed to differences in
reported levels of pain during the needle placement phase of the IAN block injection.
For IAN blocks in symptomatic subjects, Nusstein et al. (25) reported 35%,
Nusstein et al. (32) reported 50%, and Reisman et al. (33) reported 37% of the subjects
recorded a moderate-to-severe response on the VAS for needle placement. There were
more moderate-to-severe pain ratings for needle placement than needle insertion in
Kreimer’s study (68), which was similar to the current study. Agarwala (11) found that
66% of subjects reported moderate-to-severe pain for needle placement for an IAN block
with 2% lidocaine with 1:100,000 epinephrine in subjects with irreversible pulpitis.
Bigby (31) found that in subjects with irreversible pulpitis, 78% of the lidocaine control
88 group rated needle placement as moderate-to-severe. Claffey et al. (177) found that 86% of the lidocaine group rated the needle placement as moderate-to-severe. The subjects in the current study reported lower pain ratings for needle placement than the subjects in
Claffey’s (177), Agarwala’s (11), and Bigby’s (31) studies. Since the current study enrolled asymptomatic patients, injection pain would be expected to be lower when compared to the previously discussed studies (11, 31, 177) that enrolled subjects in pain with irreversible pulpitis.
In terms of lidocaine deposition, Mikesell et al. (35) reported on 2% lidocaine with 1:100,000 for IAN blocks in asymptomatic subjects. Thirty-three percent of the subjects in their study reported moderate-to-severe lidocaine solution deposition pain.
The results of additional studies utilizing the IAN block in asymptomatic subjects reported incidences of moderate-to-severe pain for lidocaine solution deposition as follows: Dunbar et al. (20) – 21%; Childers et al. (175) – 18%; Nist et al. (176) – 25%;
Goldberg (22) – 13%; Hinkley et al. (60) – 11%; Wali (14) – 14%; Vreeland et al. (16) –
37%. In our study, mandibular solution deposition pain was higher than what the previously mentioned authors reported, with 48% of our subjects reporting overall mandibular solution deposition pain in the moderate-to-severe category.
The results of studies utilizing the IAN block in subjects with symptomatic, irreversible pulpitis reported incidences of moderate-to-severe pain for lidocaine solution deposition as follows: Nusstein et al. (25) – 31%; Reisman et al. (33) – 29%, Claffey et al. (177) - 54%-66%, and Nusstein et al. (32) - 34-41%. Agarwala (11) found that 67% of patients rated solution deposition pain as moderate-to-severe in subjects with symptomatic irreversible pulpitis receiving IAN blocks with 2% lidocaine with 1:100,000
89 epinephrine. Bigby at al. (31) reported 83% of subjects with symptomatic irreversible
pulpitis rated lidocaine solution deposition pain during an IAN block as moderate-to-
severe.
In the current study, overall mandibular lidocaine solution deposition pain was
reported as moderate-to-severe by 48% of the subjects. These ratings are similar to the
previously mentioned studies in subjects with symptomatic experimental teeth, and
higher than what was reported in the studies with asymptomatic subjects. Since the
current study enrolled asymptomatic subjects, we would have expected that our solution deposition pain levels would have been more similar to the other studies with asymptomatic subjects. A possible explanation for this is that there is a similarity between the asymptomatic subjects in our study and the symptomatic subjects in other studies in that they were all undergoing endodontic treatment. Asymptomatic subjects in
other studies evaluating efficacy of anesthesia using an electric pulp tester, for example,
may not have been anticipating pain, and thus their reported levels of solution deposition pain may have been lower. In other words an “asymptomatic” subject in our study may not be the same entity as an “asymptomatic” subject in a dental anesthesia study. It is also important to consider the accuracy of the electric pulp tester. Kitamura et al. (144) reported the Analytic Technology Pulp Tester to be 100% accurate when testing teeth previously determined to be nonvital, and 99% accurate when testing teeth previously determined to be vital (1% false negative, no response). Cooley et al. (143) reported two of thirty teeth having endodontic treatment gave false positives. Dreven et al. (180) found that 100% of normal teeth, 100% of asymptomatic carious or restored teeth, and
73% of teeth with irreversible pulpitis could be instrumented painlessly during operative
90 procedures after an “80” reading with the electric pulp tester was achieved. These studies
demonstrate that while the electric pulp tester has a high level of accuracy, false negative
and positive responses are possible. Accessing the pulp chamber and instrumentation of
root canals during an endodontic procedure is a verifiable test of anesthetic efficacy.
Even though all of the subjects in the current study reported they were asymptomatic on the day they were enrolled in the study, it is important to consider that all of the subjects were in need of endodontic treatment and many of the teeth had been symptomatic at one time (as recounted by the patient in their preoperative clinical history). Some patients presented for treatment with experimental teeth which had already undergone pulpectomy or had previous endodontic treatment, while other patients were presenting for initial root canal therapy. These situations may have implications on how patients perceive and report pain.
Another possible explanation for differences in pain levels for solution deposition is rate of injection. Although rate of solution deposition was reported as one minute per cartridge in all of the previously discussed studies, as it was in the current study, there remains a possibility that the individual clinicians administering the injections may have deposited the solution at faster or slower rates. In such cases, depending on each subject’s perception of pain and other uncontrollable factors, reported pain levels could have been higher or lower than expected. Our study shows that solution deposition in the
IAN block can result in moderate-to-severe pain and further research is needed in order to identify methods to reduce the reported levels of pain.
Mean lidocaine dose for maxillary infiltrations was 2.5 mL in the OraVerse™ group and 2.0 mL in the Sham group, a difference which was not statistically significant
91 (P=0.0984). The mean lidocaine dose for IAN blocks was 4.0 mL in the OraVerse™ group and 3.6 mL in the Sham group. There was no statistically significant difference between the groups (P=0.4903). The mean articaine dose in the maxilla was 0.07 mL in the OraVerse™ group and 0.0 mL in the Sham group, which was not a statistically significant difference (P=0.3277). The mean articaine dose in the mandible
(administered as buccal infiltration) was 0.46 mL in the OraVerse™ group and 0.13 mL in the Sham group. There was not a statistically significant difference between the groups (P=0.0865) (Table 5).
Mean anesthetic dose is an important factor to examine because the amount of
OraVerse™ administered to subjects at the completion of treatment was directly related to the amount of anesthetic initially administered. If the subject required one cartridge of lidocaine to achieve sufficient anesthesia for the procedure to be comfortably completed, the subject received one cartridge of OraVerse™ (or the Sham injection) at the same location that the initial lidocaine injection was given. If the subject required 2 cartridges of lidocaine, he or she received 2 cartridges of OraVerse™ (or 2 Sham injections) at the same location that the initial two lidocaine injections were given. If the subject required
2 cartridges of lidocaine plus a buccal infiltration with articaine, or 2 cartridges of lidocaine plus a buccal infiltration with articaine plus an intraosseous injection, the subject received one cartridge of OraVerse™ at the location of the first lidocaine injection and one cartridge at the location of the buccal articaine infiltration injection (or a sham injection at each of these sites).
Anesthetic success was an important consideration in our study. If a single cartridge (1.8 mL) of 2% lidocaine with 1:100,000 epinephrine did not provide adequate
92 pulpal anesthesia, one or more additional cartridges was given in order to complete the root canal procedure comfortably for the subject. In the cases in which more than two cartridges of anesthetic were necessary, the subjects’ total anesthetic dose exceeded the maximum allowable dose of OraVerse™ (7). The inability to administer equal doses of anesthetic and OraVerse™ with every subject may have affected the mean time to return to normal soft tissue sensation in many of the subjects treated in this study. The administration of more than two cartridges of OraVerse™ has not been studied, and thus two cartridges is the maximum dose recommended (7).
In the maxilla, 41.7% of the subjects in the OraVerse™ group received more than one primary injection with lidocaine, while 15.4% of the subjects in the Sham group received more than one primary injection. Although time of administration of supplemental anesthesia was not recorded, it is likely that many of the maxillary subjects who required more than one primary injection received the second injection toward the end of the appointment. This has important implications on duration of anesthesia and in relation to when the OraVerse™ was administered. For these subjects, the OraVerse™ was administerd much closer to the time of administration of the anesthetic, which may alter the efficacy of the OraVerse™.
For subjects with mandibular experimental teeth, 77.3% of the subjects in the
OraVerse™ group and 80.8% of the subjects in the Sham group received more than one primary injection (Table 5). Although time of administration of supplemental anesthesia in the mandible was not recorded, it is likely that a second anesthetic injection was given earlier in the appointment, especially when the pulp was vital. This may have implications on the efficacy of OraVerse™, since the supplemental injections in the
93 mandible were given further from the OraVerse™ injections when compared to maxillary
teeth.
None of the subjects with maxillary experimental teeth and 2 patients in the Sham
group with mandibular experimental teeth required intraosseous injections. According to
the package insert the maximum recommended dosage of OraVerse™ for adults is two
1.7 mL cartridges (7). Thus, subjects in the OraVerse™ group did not always receive
equivalent doses of anesthetic and OraVerse™. This could have had an effect on
duration of soft tissue anesthesia.
It is important to consider anesthetic success as it is related to total anesthetic
required to achieve adequate numbness in order to complete treatment. In subjects with
maxillary experimental teeth, 41.7% of the subjects in the OraVerse™ group and 15.4%
of the subjects in the Sham group did not have anesthetic success with one cartridge of
2% lidocaine with 1:100,000 epinephrine and required a second infiltration in order to achieve complete anesthesia (Table 5). This represents a 68% overall anesthetic success rate for maxillary infiltrations with 2% lidocaine with 1:100,000 epinephrine. There was one subject in the OraVerse™ group who required an infiltration with 1.7 mL 4% articaine with 1:100,000 epinephrine in addition to the two cartridges of 2% lidocaine with 1:100,000 epinephrine. Individual subject differences may have been magnified due to the small number of subjects in each of these subgroups (OraVerse™/maxilla N=24,
Sham/maxilla N=13).
Evans (8) studied the efficacy of one cartridge of 2% lidocaine with 1:100,000 epinephrine for maxillary infiltrations. The authors reported 62% success with the lidocaine in the maxillary lateral incisor. In maxillary first molars, the success rate of
94 lidocaine was 73%. Gross et al. (37) reported 97% success with 2% lidocaine with
1:100,000 epinephrine infiltrations at the maxillary lateral incisor and 82% success at the
maxillary first molar. Mikesell at al. (38) compared the anesthetic efficacy of 1.8 mL and
3.6 mL volumes. Our overall anesthetic success with maxillary infiltration with one
cartridge of 2% lidocaine with 1:100,000 epinephrine was 68%, which was similar to
what was reported by Evans’ group (8). We did not analyze anesthetic success according
to tooth type. Anesthetic success in our study was lower than what was reported by
Gross et al. (37) and Mikesell et al. (38). Although the subjects in both studies were
asymptomatic, the subjects in our study were undergoing endodontic therapy, which may have contributed to the need for a higher volume of anesthetic. Also, the smaller number of subjects in our treatment groups may have magnified individual subject differences in
anesthetic success.
For subjects in our study who received IAN blocks, 79% overall (77% in the
OraVerse™ group and 81% in the Sham group) required more than one cartridge of 2%
lidocaine with 1:100,000 epinephrine for adequate anesthesia. This represents a 21%
success rate for the IAN block with 1.8 mL 2% lidocaine with 1:100,000 epinephrine.
With two cartridges of lidocaine, anesthetic success in the mandible was 81%. Seven
subjects (32%) in the OraVerse™ group and 2 subjects (8%) in the Sham group required
two cartridges of 2% lidocaine plus a buccal infiltration with 4% articaine with 1:100,000
epinephrine. After buccal infiltration with articaine, anesthetic success in the mandible
was 96%. Two subjects (8%) in the Sham group required mandibular intraosseous
injections with 1.8 mL 2% lidocaine with 1:100,000 epinephrine to achieve adequate numbness.
95 Successful mandibular pulpal anesthesia, as defined as numb (80/80 reading with the electric pulp tester) within fifteen minutes of injection and continuously numb for one hour (22), has been reported to occur in 55% of molars, 60% of premolars, and in only
31% of lateral incisors with normal pulps, using 2% lidocaine with 1:100,000 epinephrine
(14-17, 20-27, 29, 30). Pulpal anesthetic success according to tooth type was not analyzed in the current study. However, the applicability of the above definition of anesthetic success is questionable for the current study design. Although mean procedure times were 67 minutes (Sham group) and 71 minutes (OraVerse™ group) in the maxilla, and 85 minutes (Sham group) and 83 minutes (OraVerse™ group) in the mandible, these times reflect the total time from initial anesthetic injection(s), rubber dam placement, access, canal cleaning and shaping, obturation, placement of temporary, removal of rubber dam, capture of necessary radiographs, and administration of the OraVerse™ or
Sham injection(s). Sixty minutes of pulpal anesthesia was not always necessary to complete each procedure comfortably for the subject. In this study, the most practical definition of successful anesthesia was the ability to perform all of the necessary steps of treatment without the patient experiencing pain.
Matthews et al. (28) evaluated the anesthetic efficacy of the supplemental infiltration injection of 4% articaine with 1:100,000 epinephrine in mandibular posterior teeth diagnosed with irreversible pulpitis when the conventional IAN block failed.
Anesthetic success of the IAN block was determined based upon the patient stopping the operator at any time during treatment and recording access pain as greater than mild
(VAS >54 mm). Similar to our study, twenty-seven out of fifty-five (33%) patients had anesthetic success with the lidocaine IAN block. In the study by Matthews’ group (28),
96 anesthetic success of the supplemental buccal infiltration with 4% articaine with
1:100,000 epinephrine was also determined by the patient stopping the operator and
recording pain as greater than mild (VAS>54 mm). The authors reported articaine
infiltration success rates of 58% for the first molar, 48% for the second molar, and 100%
for the premolars. Although our study did not evaluate success of the supplemental
buccal articaine infiltration according to tooth type, we noted similar increased anesthetic
success after articaine infiltration (96% for all mandibular teeth).
Patients experiencing pain, for example those diagnosed with irreversible pulpitis, are known to have additional anesthetic difficulties. Based on research conducted at the
Advanced Endodontics Program of The Ohio State University, overall IAN block success
with 2% lidocaine with 1:100,000 epinephrine in patients with irreversible pulpitis ranged from 25%-68% (11, 28, 31-33). Therefore, not all patients will experience pulpal anesthesia after what would appear to be a clinically successful (lip numbness) IAN block. In these cases supplemental injections of anesthetic would be required to work on the tooth. Although the subjects in the current study reported that they were asymptomatic at the time of enrollment in the study, the lower anesthetic success rates
(21%) reported in our study are more consistent with studies involving symptomatic subjects than those that enrolled asymptomatic subjects. Again, the similarity between our subjects and symptomatic subjects is that they were undergoing endodontic treatment.
One might expect a need for a higher volume of anesthetic when performing root canal therapy than when performing pulp testing. As discussed in previous sections, the practical definition of anesthetic success is different for this clinical endodontic study model in which 60 minutes of pulpal anesthesia (as determined by sustained 80/80
97 readings with the electric pulp tester in other anesthetic studies) may be more or less time
than is required to complete endodontic treatment painlessly. Also as previously
discussed, the electric pulp tester used to determine anesthetic success in studies enrolling
asymptomatic volunteers is known to be less than 100% accurate (143-145, 180).
Success of anesthesia also affected the recorded procedure time in this study. In
subjects who required more than one injection to have successful anesthesia, the
procedure time was lengthened because the procedure clock started at the end of
administration of first cartridge of anesthetic and stopped when the entire procedure was
complete. The amount of time the clinician waited for the second and/or third injection
to take effect is included in the procedure time, though this additional time was not
separately recorded. It should also be noted that in general, the clinician waited longer
for a second IAN block to take effect than for a second maxillary infiltration to take
effect. When a mandibular buccal infiltration with articaine was necessary the clinician always waited 5 minutes before proceeding, according to the study protocol. Removal of the rubber dam, administration of the additional cartridge(s) of anesthesia, and replacement of the rubber dam were all considered as part of the procedure time. In the maxilla, 12 subjects (10 in the OraVerse™ group and 2 in the Sham group) required more than one primary injection. In the mandible, 38 subjects (17 in the OraVerse™ group and
21 in the Sham group) required more than one primary injection (Table 5). A lengthened procedure time meant that the OraVerse™ was administered later in comparison to subjects who did not require additional injections. Procedure time, duration of anesthesia, and timing of administration of OraVerse™ is discussed in the following paragraphs.
98 As presented in Table 6, the mean procedure times for the OraVerse™ and Sham
groups were balanced for each jaw. In the maxilla, mean procedure time was 71.4 ± 4.2
minutes in the OraVerse™ group and 66.6 ± 3.3 minutes in the Sham group. In the
mandible, mean procedure time was 83.5 ± 4.7 minutes in the OraVerse™ group and
85.4 ± 3.9 minutes in the Sham group. The OraVerse™ or Sham injection(s) were given
at the completion of each procedure in our study. Completion of endodontic treatment,
and thus the end of the timed procedure in this study, was defined as the time at which all necessary treatment was accomplished, the rubber dam was removed, and the final radiograph was captured. Laviola et al. (12) administered one or two OraVerse™ or placebo injections at the completion of routine restorative or periodontal scaling
procedures in adults, which was between 20 and 70 minutes after the last local anesthetic
injection. Hersh et al. (6) administered OraVerse™ or sham injections at the completion
of routine dental procedures in adults, which were required to be completed within 60
minutes of the local anesthetic injection. Tavares et al. (5) administered OraVerse™ or
sham injections after routine restorative or periodontal maintenance procedures in
children, at 20 to 49 minutes after the last anesthetic injection was given.
Again, it is important to consider that the longer procedure times in our study delayed the administration of the OraVerse™ or sham injection(s). There were additional steps and more time was required for the endodontic procedure itself when compared to the operative or periodontal scaling procedures done in other studies utilizing clinical patients. In many cases in our study there was additional time necessary to provide anesthesia beyond the primary anesthetic injection and to allow it to take effect. Tooth
99 type should also be considered as to its effect on procedure time. Although procedure time by tooth type was not analyzed, one can assume that in most cases a single-rooted anterior tooth with one canal would require less time to treat than a premolar or molar with multiple roots and canals. In addition, the clinician in our study almost always worked without the aide of a dental assistant, which likely increased overall procedure time.
Duration of soft tissue anesthesia and timing of administration of OraVerse™
may influence how OraVerse™ works. Since the OraVerse™ was given at the end of
each procedure, it is important to compare procedure times to the expected duration of
local anesthesia. For example, if the OraVerse™ is given before anesthesia starts to
diminish, or after it has already begun to dissipate, its total perceived effect may be
different. In a series of studies performed by The Ohio State University Advanced
Endodontics Program, the duration of maxillary pulpal anesthesia after infiltration with a
lidocaine solution varied from 31 minutes to 100 minutes, with the majority of studies
showing duration times of less than 60 minutes (35-38). Reader and Nusstein (34) reported that mandibular anesthesia usually persisted for approximately 150 minutes.
According to Malamed (2), in general, administration of 2% lidocaine with 1:100,000 epinephrine (IAN block) can be expected to produce soft tissue anesthesia for 180-300 minutes. For maxillary procedures in the OraVerse™ group, the mean procedure time was 71.4 minutes with a range of 29 to 118 minutes. In the mandible, procedure time for the OraVerse™ group was 83.5 minutes with a range of 60 to 155 minutes. It is possible that there is a difference in the effect of the OraVerse™ when it is given at 29 minutes,
100 when presumably anesthesia is at its peak, than when the OraVerse™ is given at 155
minutes and the effect of the anesthetic may be beginning to decline. In the studies by
Laviola et al. (12), Tavares et al. (5), and Hersh et al. (6), the OraVerse™ was administered at what could be considered the peak of anesthetic efficacy, between 20 and
70 minutes after anesthetic onset. This may have increased the effectiveness of the
OraVerse™ in reversing the anesthetic effects in terms of time to return to normal sensation.
Data on case completion status was collected in our study to allow for comparison of postoperative tooth pain levels between experimental teeth that had obturation material beyond the radiographic apex, teeth that did not have obturation material beyond the radiographic apex, and teeth that were not obturated. Although there was a significant
difference in case completion status between the treatment groups in the maxilla (Table
6), we do not believe that this had an effect on postoperative tooth pain. The significant
difference is due to and imbalance in the “obturation material beyond the apex” and “not
obturated” categories for maxillary teeth. There were 4 teeth in the OraVerse™ group
and 0 teeth in the Sham group that were not obturated, and 0 teeth in the OraVerse group
and 3 teeth in the Sham group that had obturation material beyond the radiographic apex.
The mean VAS pain scores for all subjects with maxillary experimental teeth were in the
none-to-mild range. There was not a significant difference between the treatment groups
for case completion status for subjects with mandibular experimental teeth (Table 6).
Mean VAS pain scores for subjects with mandibular experimental teeth were in the none-
101 to-mild category. Again, the postoperative pain data shows that case completion status did not have a significant effect on postoperative tooth pain in this study.
Although there were no significant differences in postoperative tooth pain, it is possible that individuals could have had different levels of pain depending on if there was obturation material extended beyond the radiographic apex. According to Seltzer and
Bender (110), following vital pulp extirpation, patients with underfilled root canals report a 14% incidence of pain, 53% of patients with flush-filled canals report pain, and 60% of patients with overfilled canals had pain. Underfilling roots of teeth with necrotic pulps also produced less postoperative pain than flush-filling or overfilling (110). Seltzer et al.
(181) reported that instrumentation short of the apex caused inflammatory changes that were less severe and intense than when teeth were instrumented beyond the apex.
Mean VAS pain values for the OraVerse™ and Sham injections were in the none- to-mild range for all subjects in both groups, genders, and jaws. There was no significant difference between the groups at any stage of the injection (insertion, placement, and deposition) (Table 7). For all subjects with experimental teeth in either the maxilla or mandible, 93% reported pain of OraVerse™ solution deposition as none-to-mild (Table
8).
Again, duration of anesthesia and procedure time were important factors to consider. When evaluating pain of the OraVerse™ or Sham injection, the subjects’ numbness status may have affected their pain reports during any of the three stages of the injection (needle insertion, needle placement, and solution deposition). For subjects who underwent lengthier procedures, it is possible that their level of anesthesia had begun to
102 diminish, and they would have felt increased pain during the OraVerse™ injection.
There were also incidences, the number of which was not recorded, in which subjects
who reported that they were experiencing soft tissue numbness at the end of the
procedure but reported pain at one or more of the three stages of the OraVerse™ and/or
Sham injections. This was an unexpected result in those cases because we would have
expected them to perceive no pain if they were, in fact, still numb. In the maxilla, for
subjects who received the OraVerse™, 75% of the subjects reported no pain at any of the
stages of the injection. Seventy-four percent of the subjects who received Sham
injections in the maxilla reported no pain at any of the three stages of the injection. In the
mandible, 67% of the subjects in the OraVerse™ group, and 81% of the subjects in the
Sham group reported no pain at any stage of the injection.
The results suggest that deposition of OraVerse™ is not significantly more
painful than administration of a sham injection at the same location that the anesthetic
injection was given. This would especially be true if the injection was given at the time
of peak anesthetic effectiveness. Other publications investigating the effectiveness of
OraVerse™ (1, 5, 6, 12) did not report OraVerse™ and sham/placebo injection pain.
When evaluating differences in duration of soft tissue anesthesia between the
OraVerse™ and Sham treatment groups, we felt the most important outcomes to consider
were duration of “numbness” and time to “return to normal sensation” (loss of numbness and tingling). In this study, subjects with maxillary experimental teeth reported duration
of lip/cheek numbness of 99.1 ± 7.8 minutes in the OraVerse™ group and 134.2 ± 10.9
minutes in the Sham group. This represents a 35 minute decrease in duration of lip/cheek
103 numbness for subjects who received OraVerse™. This was a statistically significant
difference (P=0.0145). Return to normal sensation (loss of numbness and tingling) of the
lip/cheek for subjects with maxillary experimental teeth was 135.5 ± 12.1 minutes in the
OraVerse™ group and 223.8 ± 19.1 minutes in the Sham group. There was an 88 minute
decrease in time to return to normal sensation of the lip/cheek for subjects who received
OraVerse™, which was statistically significant (P=0.0007).
Hersh et al. (6) reported median recovery times of the maxillary lip of 50 minutes
for subjects who received OraVerse™ and 133 minutes for subjects in the sham group, a statistically significant 83-minute difference (P<0.0001). Tavares et al. (5) reported a 75- minute reduction in time to return of normal lip sensation in pediatric subjects who received OraVerse™, as analyzed by the stratified log-rank test with the mandibular or maxillary location as the stratification factor. This was a statistically significant difference (P<0.0001). Laviola et al. (12) found a 115-minute reduction in time to recovery of normal lip sensation for subjects who received equivalent doses of 2% lidocaine with 1:100,000 epinephrine and OraVerse™ in the maxilla. There was a statistically significant difference between the groups (P<0.0001). Our results are similar to previous research investigating the efficacy of OraVerse™ for reversal of local anesthesia in maxillary soft tissue.
In the current study, mean duration of mandibular lip numbness was 120.5 ± 8.3 minutes in the OraVerse™ group and 144.7 ± 7.4 minutes in the Sham group. This 24 minute reduction in duration of mandibular lip anesthesia represents a statistically significant difference between the groups (P=0.0348). Time to return to normal sensation
104 (loss of numbness and tingling) of the mandibular lip was 170 ± 11.9 minutes in the
OraVerse™ group and 217.3 ± 10.8 minutes in the Sham group. This represents a statistically significant 47 minute reduction in time to recovery of normal sensation for subjects in the OraVerse™ group with mandibular experimental teeth (P=0.0054). Hersh et al. (6) found an 85 minute reduction in median time to recovery of normal mandibular lip sensation for subjects who received equivalent doses of 2% lidocaine with 1:100,000 epinephrine and OraVerse™. This reduction in time was statistically significant
(P<0.0001). Froum et al. (179) reported overall mean time to return to normal sensation of the mandibular lip of 50.6 minutes for subjects who received either two cartridges of
2% lidocaine with 1:100,000 epinephrine, two cartridges of 4% articaine with 1:200,000 epinephrine, or one cartridge of each of these anesthetics, plus an equivalent dosage of
OraVerse™. The authors reported a shorter mean time to recovery of normal mandibular lip sensation than was found in the current study (50.6 minutes and 170 minutes, respectively). Froum’s group did not use a sham or placebo injection control group.
Fernandez et al. (62) reported mean mandibular lip anesthesia duration of 192 minutes and mean time to return to normal lip sensation of 220 minutes after administration of 1.8 mL of 2% lidocaine with 1:100,000 epinephrine. This was similar to the duration of numbness and time to return to normal sensation found in the Sham group in our study
(Table 12).
In the current study, mean duration of tongue numbness was 106.1 ± 7.5 minutes for subjects in the OraVerse™ group and 120.9 ± 6.3 minutes for subjects in the Sham group. There was not a statistically significant difference between the groups
105 (P=0.1382). Return to normal sensation of the tongue was 141.9 ± 10.5 minutes in the
OraVerse™ group and 169.4 ± 8.9 minute in the Sham group, a 27.5-minute reduction in time to return to normal sensation for the OraVerse™ group. While the difference between the groups was not statistically significant (P=0.0649), individual patients may appreciate a nearly 30 minute faster return to normal sensation and function. Hersh et al.
(6) reported median recovery times for the tongue with subjects in the OraVerse™ and sham groups of 60 minutes and 125 minutes, respectively. This 65-minute reduction in median recovery time for OraVerse™ subjects was considered statistically significant
(P<0.0001). Laviola et al. (12) found that subjects who received equivalent doses of 2% lidocaine with 1:100,000 epinephrine and OraVerse™ had median times to recovery of normal tongue sensation of 60.5 minutes, while subjects who received 2% lidocaine with
1:100,000 epinephrine and placebo had median times to recovery of normal tongue sensation of 115 minutes. This 54.5-minute difference was statistically significant
(P<0.0001). Tavares et al. (5) reported median time to recovery of normal tongue sensation of 45 minutes for pediatric subjects in the OraVerse™ group and 112.5 minutes for pediatric subjects in the sham group. Subjects received equivalent doses of 2% lidocaine with 1:100,000 epinephrine and OraVerse™. The statistically significant
(P=0.0003) 67.5-minute difference represents a 60% reduction in time to recovery of normal tongue sensation for the OraVerse™ group. Froum et al. (179) reported average time to return to normal sensation of the tongue of 60.5 minutes in subjects who received either 2% lidocaine, 4% articaine, or a combination of the two anesthetics, and equivalent doses of OraVerse™ in the mandible. The authors reported a shorter mean time to recovery of normal tongue sensation than was found in the current study (60.5 minutes
106 and 141.9 minutes, respectively). Froum’s group did not use a sham or placebo injection
control group. The difference in time to return to normal tongue sensation between the
OraVerse™ and Sham groups in our study (27.5 minutes) was comparable to what was
reported by Hersh et al. (6) (32 minutes). Larger differences in time to recovery of
normal tongue sensation were reported by Laviola et al. (12) and Tavares et al. (5).
The timing of administration of OraVerse™ may have affected time to return to
normal sensation. Longer mean procedure times in our study when compared to other
studies (5, 6, 12) may have delayed administration of OraVerse™ to a point where soft
tissue anesthesia was already beginning to decline. Thus, the overall effect of
OraVerse™ may have been less evident than if it had been given earlier during treatment,
at the height of anesthesia efficacy. For example, if the OraVerse™ had been
administered at 30-60 minutes after the initial anesthetic injection, the recovery time may have been more significantly shortened. However, this may have also led to the loss of anesthesia during the endodontic procedure, causing the subjects undue pain, and thus requiring the administration of additional anesthetic in order to complete the endodontic treatment comfortably.
In the current study, we found a 40.6 minute reduction in duration of maxillary gingival numbness for subjects who received OraVerse™ when compared to those that received the Sham injection. There was a statistically significant difference between the groups (P=0.0036). There was a 46.8 minute reduction in time to return to normal sensation of the maxillary gingiva for subjects in the OraVerse™ group when compared to the Sham group, and this was a statistically significant difference between the groups
107 (P=0.0128). The only gender difference noted in our study occurred in subjects with mandibular experimental teeth when reporting gingival numbness. Females in the
OraVerse™ group reported a 3.3 minute reduction in duration of mandibular gingival numbness when compared to the females in the Sham group. This difference was not significant (P=0.6829). Males in the OraVerse™ group reported a 46.6 minute reduction in duration of mandibular gingiva numbness when compared to males in the Sham group, which was statistically significant (P=0.0073). There was not a gender difference in time to return to normal mandibular gingival sensation. Subjects in the OraVerse™ group experienced a 41.4 minute reduction in time to return to normal mandibular gingival sensation when compared to the Sham group. There was a statistically significant difference between the groups (P=0.0164) (Table 13).
Analysis of the female subjects with mandibular experimental teeth is inconclusive as to why there was an apparent difference in their perception and subsequent report of gingival numbness when compared to their male cohorts. Individual variances in anatomy and perception of the numbness sensation may account for the differences in how the subjects reported numbness. Perhaps the female individuals in either group had slight variances in how they perceived or understood “numb” and
“tingly,” and thus started reporting “tingly” sooner than the male subjects in the other treatment group. If we had enrolled a greater number of subjects in both groups, a significant difference in duration of mandibular gingival numbness may have been detected. The clinical significance or importance of gingival anesthesia may also be lost on patients who appear to be more aware or concerned about lip/cheek and tongue
108 numbness, as gingival anesthesia is not as relevant to the ability to function (eat, drink, talk) normally as lip and tongue anesthesia are.
Duration of gingival anesthesia may be difficult for the subjects to discern when compared to lip and tongue. Gross et al. (37) noted that “Perhaps, the smaller amount of anesthetic solution available in the gingiva (compared with the soft tissues of the cheek at the injection site) may account for the shorter duration of numbness compared with the lip.” Other studies on the effectiveness of OraVerse™ for reversal of local anesthesia (5,
6, 12) did not report on the effect of OraVerse™ on maxillary or mandibular gingiva.
With regard to mandibular lip and tongue anesthesia, there is a larger difference in
return to normal sensation in the studies done by Hersh et al. (6), Tavares et al. (5), and
Laviola et al. (12) when compared to the results of our study. These groups compared
median time to recovery of normal sensation, while we compared adjusted mean time to
return to normal sensation. This makes direct comparison of the differences found in
each study more difficult. As in our study, the OraVerse™ or sham/placebo was given at
the end of each procedure in these studies. However, they were doing routine restorative
and periodontal maintenance care, and all reported shorter procedure times in comparison
to our procedure times. Therefore the OraVerse™/Sham injections were given sooner
than in our study. By doing this the time to return to normal sensation is sooner and there
is a larger difference when compared to the sham injection. Hersh et al. (6) reported the
median elapsed time between their administration of the local anesthetic and of the study
drug was 44 minutes for subjects in the OraVerse™ group and 47.5 minutes for subjects
in the sham group.
109 Our mean procedure times for the two treatment groups were longer than procedure times in other studies (5, 6, 12) for several reasons. In our study each patient was treated by the co-investigator without the aide of a dental assistant. Many subjects presented for initial root canal treatment and the procedure was completed in one appointment. This meant that there was a more frequent need for additional anesthetic injections in order to complete the endodontic treatment painlessly. In these cases, additional procedure time was required to remove and replace the rubber dam, administer the anesthetic, and allow for the anesthetic to take effect before continuing treatment.
These parameters of the study likely contributed to relatively long procedure times.
Although there was not a significant difference in procedure time between the two treatment groups, longer average procedure times delayed administration of the
OraVerse™. Consequently, the administration of OraVerse™ in our study occurred closer to the time when recession of soft tissue anesthesia would have been beginning to occur. Hersh et al. (3) found that after an IAN block with 1.8 mL of 2% lidocaine with
1:100,000 epinephrine, peak lip and tongue anesthesia occurred at 30 to 45 minutes post- injection with recession of anesthesia beginning between 90 and 120 minutes. If maximum efficacy of OraVerse™ is dependent on administration within an optimum timeframe, this timeframe may have passed by the time the OraVerse™ was administered during many of the procedures performed in this study.
Goebel et al. (4) found that the addition of epinephrine to 2% lidocaine provided local vasoconstrictor effects, slowing the rate of lidocaine’s systemic absorption. The mechanism of action of OraVerse™ is vasodilation, thus accelerating clearance of lidocaine from the oral tissues into the circulatory system (7). Moore et al. (1) suggested
110 that the administration of OraVerse™ 30 minutes after injection with 2% lidocaine with
1:100,000 epinephrine reversed the epinephrine-induced delay in absorption, allowing more rapid absorption of the lidocaine from the tissue. It may be possible that the effectiveness of OraVerse™ is related to the amount of epinephrine available in the tissue at the time of administration.
Time of administration in our study occurred at the completion of the procedure, which was longer for subjects with mandibular experimental teeth than those with maxillary experimental teeth (Table 6). Length of procedure could also have been related to tooth type since in general, molar teeth required more time to complete than anterior teeth. Mandibular buccal infiltrations with articaine and intraosseous injections with lidocaine may also have increased duration of mandibular lip anesthesia. Froum et al.
(179) reported longer time to recovery of normal soft tissue sensation in subjects who received 4% articaine with 1:200,000 epinephrine than in subjects who received 2% lidocaine with 1:100,000 epinephrine and equal doses of OraVerse™. In such instances in our study where articaine infiltrations and intraosseous injections were required, one cartridge of OraVerse™ was given at the site of the initial IAN block, and one was given at the site of the buccal articaine infiltration in an attempt to reverse soft tissue at two of the injection sites. However, this was done at the cost of using less OraVerse™ at the
IAN block location. Perhaps if we had given three cartridges of OraVerse™ (two as
IAN blocks, and one as a buccal infiltration) in these cases, the reversal effect of the
OraVerse™ would have been more pronounced. Limitations on the maximum allowable dose of OraVerse™, according to the drug prescribing information (7), prevented the
111 clinician from being able to administer equal doses of anesthetic and OraVerse™ in every
case. Also, the time of administration of OraVerse™ relative to time of administration of
the local anesthetic was longer in comparison to other studies on the effectiveness of
OraVerse™ for local anesthesia reversal (5, 6, 12). This may have had an influence on
mean time to recovery of normal soft tissue sensation in our study.
We found that the greatest reduction in time to recovery of normal soft tissue
sensation occurred in maxillary lip/cheek sensation (88.3 minute difference) when
compared to return to normal sensation of the mandibular lip, tongue, and maxillary or
mandibular gingiva (Tables 11-13 and Figures 1 and 2). Laviola et al. (12) found that the
effect of OraVerse™ on recovery of normal lip sensation was more pronounced in the
maxilla than in the mandible. It is not known whether normal maxillary soft tissue
sensation can be expected to recover more quickly than mandibular soft tissue sensation
after the administration of 2% lidocaine with 1:100,000 epinephrine. We suggest that an
important factor to consider is that when giving an infiltration, the bolus of anesthetic
remains in the soft tissue, which may result in more anesthetic with epinephrine available
for the OraVerse™ to have an effect on. This in turn could result in a greater overall
reduction in time to return to normal sensation compared to subjects who received an
IAN block. We also suspect that the greater reduction in time to return to normal sensation in the maxillary lip/cheek in our study may be due to these subjects perceiving maxillary lip/cheek sensation differently, perhaps more easily, than the other soft tissue sites that were examined.
112 We found that mean VAS values for postoperative injection site pain were within
the none-to-mild range for all subjects in both groups, genders, and jaws (Table 14). In
the maxilla there was a slight general increase in postoperative injection site pain at the
60-minute time interval for both groups and genders (Figure 3). The trend then decreased
toward the 90-minute interval, increasing again in the interval between 120-180 minutes,
and then generally decreasing toward the 360-minute postoperative mark. In the mandible, the trends for each group and gender are more variable, but remain within the none-to-mild range (Figure 4). Laviola et al. (12) reported increased postoperative pain at maxillary and mandibular injection sites at 60 minutes postoperatively. The authors suggested that this may reflect injection site pain that was unmasked by early reversal of the anesthetic. Subjects reported weak pain which was not considered clinically significant. Tavares et al. (5) reported only one subject in the sham group with severe injection site pain. The incidence of subjects who experienced no intraoral pain was similar in both the OraVerse™ and sham groups. The authors state that their data shows that the OraVerse™ injection was not associated with more intraoral pain than the sham injection, and our results confirm this conclusion.
In the current study, we found that mean VAS pain values of postoperative tooth discomfort were in the none-to-mild range (Table 15). In the study by Hersh et al. (6), the majority of subjects in both treatment groups who received injections in the mandible experienced either no or mild oral pain, which includes both injection site and treatment site (tooth) pain. Less than 10% of the subjects in both groups who received mandibular injections reported having moderate oral pain. In the maxilla, 91% of their subjects had
113 none or mild postoperative oral pain. Less than 10% of their subjects in both groups who
received maxillary injections reported moderate postoperative oral pain.
All of the subjects enrolled in our study had asymptomatic experimental teeth, and thus we expected that they would experience less postoperative pain relative to symptomatic patients. Mattscheck et al. (56) studied the factors associated with posttreatment pain in patients undergoing root canal retreatment and initial root canal treatment. Patients who reported higher pretreatment pain levels had significantly increased post-treatment pain (P<0.05) up to 24 hours after the procedure. Pretreatment pain level was found to influence post-treatment pain level more than whether patients underwent retreatment or initial treatment, the type of obturation material originally used, or what the pretreatment diagnosis was.
Our findings suggest that the additional injection of OraVerse™ did not significantly increase postoperative pain at the injection site or in the experimental tooth.
These findings are consistent with other studies on the effectiveness of OraVerse™ for the reversal of soft tissue anesthesia.
We found the most frequent subject-reported postoperative complication was intraoral swelling (Table 16). At 30 and 60 minutes postoperatively, 4.3% of the subjects who received OraVerse™ reported intraoral swelling. Perhaps these patients experienced local tissue swelling due to the additional volume of solution injected during administration of the OraVerse™. The incidences of these and the other subject-reported postoperative complications were infrequent and considered not clinically significant.
Hersh et al. (6) stated the most frequently reported adverse events for all subjects were
114 injection site pain, postprocedural pain, and headache. Tavares et al. (5) reported injection site pain, transient increase in blood pressure, and postprocedural pain as the most common adverse events. Laviola et al. (12) reported injection site pain, one case of aphthous stomatitis, and two mild tongue disorders. Our findings are similar when compared to these studies.
115 CHAPTER 7
SUMMARY AND CONCLUSIONS
The purpose of this prospective, randomized, single-blind study was to evaluate
the reversal of soft tissue anesthesia in endodontic patients. Ninety-five healthy male and female adult patients from the The Ohio State University Advanced Endodontics Clinic with asymptomatic teeth in need of endodontic treatment participated in the study. All of the subjects received local anesthesia according to the study’s protocol and in sufficient amounts so as to allow the clinician to complete the endodontic treatment comfortably for
each subject.
Overall mean VAS pain values were in the none-to-mild category for all three
phases of the initial anesthetic injection in the maxilla for both treatment groups. Female
subjects with maxillary experimental teeth in both treatment groups reported mild-to-
moderate pain for solution deposition. There was not a statistically significant difference
between genders or treatment groups for any phase of the initial injection in the maxilla.
In the mandible, overall mean pain for needle insertion and needle placement was
in the none-to-mild category. Females in the OraVerse™ group reported moderate pain
for needle placement, but there was not a significant difference between the genders or
groups. Male and female subjects reported moderate solution deposition pain in the
mandible. Solution deposition was the most painful stage of the initial injection for both
116 genders and groups in both jaws, however there was not a statistically significant
difference between any of the categories.
There was not a statistically significant difference between the treatment groups
in each jaw for mean lidocaine dose, mean articaine dose, or number of subjects who
required intraosseous anesthesia. Thirty-two percent of the subjects who received
anesthesia in the maxilla required more than one primary anesthetic injection. Seventy-
nine percent of the subjects who received IAN blocks required more than one primary
anesthetic injection.
For treatment time there was not a significant difference between the groups.
Mean procedure time for maxillary teeth was 71.4 ± 4.2 minutes in the OraVerse™ group
and 67 ± 3.3 minutes in the Sham group. Mean procedure time for mandibular teeth was
83.5 ± 4.7 minutes in the OraVerse™ group and 85.4 ± 4 minutes in the Sham group. In the maxilla, 81% of the experimental teeth were not obturated beyond the radiographic apex, 8% had obturation material beyond the radiographic apex, and 11% were not obturated. In the mandible, 75% of the treated teeth were not obturated beyond the radiographic apex, 19% had obturation material beyond the radiographic apex, and 6% were not obturated. There was a significant difference in case completion status between the treatment groups in the maxilla only.
Following treatment, each subject was administered either OraVerse™ or Sham injection(s) at the same location as the initial anesthetic injection(s). Overall mean VAS values for needle insertion, needle placement, and solution deposition were in the none- to-mild category for both genders and groups in both jaws. There was not a significant
117 difference between treatment groups or genders in either jaw. None of the subjects in
either group, gender, or jaw reported severe pain at any stage of the injection.
The subjects were trained how to monitor and report soft tissue numbness,
tingling sensation, and normal sensation. Soft tissue sensation was recorded every 15
minutes for 5 hours following the OraVerse™/Sham injection(s). Subjects were also asked to record VAS pain levels for the treated tooth and for the site of the primary and
OraVerse™/Sham injection(s) at 30, 60, 90, 120, 180, 240, and 360 minutes
postoperatively. Eighty-five of the enrolled subjects returned their data collection forms
for analysis. Forty-six of these subjects had received the OraVerse™ while 37 had received the Sham injection(s).
Subjects in the OraVerse™ group experienced an 88 minute decrease in mean time to return to normal maxillary lip/cheek sensation and a 47 minute decrease in mean time to return to normal maxillary gingival sensation. There was a statistically significantly shorter mean duration of numbness and mean time to return to normal maxillary soft tissue sensation for subjects who received the OraVerse™ injection(s).
Subjects who received OraVerse™ injection(s) experienced a 47 minute decrease in mean time to return to normal mandibular lip sensation. In the mandible, there was a statistically significant decrease in mean duration of lip numbness and mean time to return to normal lip sensation for subjects in the OraVerse™ group. Subjects who received OraVerse™ reported a 27-minute decrease in mean time to return to normal tongue sensation. There was not a statistically significant difference between the
OraVerse™ and Sham groups for mean duration of tongue numbness and mean time to return to normal tongue sensation. Although this is not statistically significant, a nearly
118 30 minute faster return to normal function and sensation may be of significant benefit to
an individual patient.
The only gender differences in duration of anesthesia were found in the
mandibular gingiva. Males in the OraVerse™ group reported a 46 minute decrease in
mean duration of mandibular gingival numbness, which was statistically significant.
Females in the OraVerse™ group reported a 6 minute decrease in mean duration of
mandibular gingival numbness, which was not statistically significant. There was an
overall 41 minute decrease in mean time to return to normal mandibular gingival sensation in the OraVerse™ group, which was statistically significant.
Mean VAS pain values for injection site were in the none-to-mild category for both genders and jaws in both treatment groups for all postoperative time periods.
Although injection site pain levels were generally higher in the OraVerse™ group than in the Sham group, there was not a significant difference between the groups with regard to injection site pain.
Mean VAS pain values for postoperative tooth pain were in the none-to-mild category for both genders and jaws in both treatment groups at all postoperative time periods. In general, postoperative tooth pain was higher for subjects in the OraVerse™ group; however, there was not a significant difference between the OraVerse™ and Sham groups with regard to postoperative tooth pain.
Few subjects reported postoperative complications, and none of the subjects had signi