A Thesis. The Degree of Master of Science in the. Graduate School of The Ohio State University. Matthew Joshua Martin, D.D.S.

Transcription

1 ANESTHETIC EFFICACY OF 3.6 ML OF 4% ARTICAINE WITH 1:100,000 EPINEPHRINE COMPARED TO 1.8 ML OF 4% ARTICAINE WITH 1:100,000 EPINEPHRINE AS PRIMARY BUCCAL INFILTRATIONS IN MANDIBULAR POSTERIOR TEETH A Thesis Presented in Partial Fulfillment of the Requirements for The Degree of Master of Science in the Graduate School of The Ohio State University By Matthew Joshua Martin, D.D.S. Graduate Program in Dentistry The Ohio State University 2010 Master s Examination Committee Dr. John M. Nusstein, Advisor Dr. Al Reader Dr. Melissa Drum Dr. F. Michael Beck

2 Copyright by Matthew J. Martin 2010

3 ABSTRACT The purpose of this prospective, randomized, single-blind study was to compare the anesthetic efficacy of 3.6 ml of 4% articaine with 1:100,000 epinephrine to 1.8 ml of 4% articaine with 1:100,000 epinephrine in mandibular buccal infiltration injections given next to the first molar. Using a cross-over design, 86 adult subjects (43 males and 43 females) randomly received two primary buccal mandibular infiltration injections given next to the first molar of 3.6 ml of 4% articaine with 1:100,000 epinephrine and 1.8 ml of 4% articaine with 1:100,000 epinephrine, in two separate appointments, spaced at least one week apart. The second molar through the first premolar were tested with an electric pulp tester every 3 minutes for a total of 90 minutes. The pain of injection and any postoperative discomfort over the next three days was rated by the subjects on a Heft-Parker visual analogue scale. Each test tooth had a higher percentage of 80/80 readings for each test time when the 3.6 ml volume was injected but not all differences reached statistical significance. Anesthetic success was defined as two consecutive 80/80 readings at any point during the testing time. The incidence of anesthetic success was 65.1% and 48.8% of second molars, 75.6% and 52.3% of first molars, 92.9% and 87.1% of second premolars, and 91.9% and 81.4% of first premolars for Group 1 (3.6 ml volume) and Group 2 (1.8 ml volume), respectively: There was no statistically significant difference in anesthetic success ii

4 between Groups 1 and 2 for the second premolar (p=0.1797), but the second molar, first molar, and first premolar were significantly different (p=0.0129, <0.0001, and =0.0234, respectively). The incidence of anesthetic failure was 34.9% and 51.2% in the second molars, 24.4% and 47.7% in the first molars, 7.1% and 12.9% in the second premolars, and 8.1% and 18.6% in the first premolars for Group 1 and Group 2, respectively. There was no statistically significant difference between Groups 1 and 2 for the second premolar (p=0.1797), but the second molar, first molar, and first premolar were significantly different (p=0.0129, <0.0001, and =0.0234, respectively). The percentages of short duration of anesthesia was significantly higher for second molar, first molar, second premolar, and first premolar in Group 2 (1.8 ml volume) compared to Group 1 (3.6 ml volume) (p=0.0215, , <0.0001, and =0.0001, respectively). There were no significant differences between Groups 1 and 2 for any of the four teeth tested for slow onset of anesthesia or for incidences of noncontinuous anesthesia. There were no significant differences in pain ratings between the two volumes for needle insertion, needle placement, or anesthetic deposition. The 3.6 ml volume had significantly higher pain ratings at each post-operative period, but the average pain ratings were still in the mild category. In conclusion, the anesthetic efficacy of 3.6 ml of 4% articaine with 1:100,000 iii

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

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

7 ACKNOWLEDGMENTS I wish to specially thank my advisor, Dr. John Nusstein. Thank you for your hard work, dedication to teaching, and your guidance over the last two years. You are an incredible teacher and mentor, and your passion for endodontics, Ohio State, and your residents shows through in all of your teaching efforts. I will miss the slow afternoons that enabled us to talk about sports and life. I thank Dr. Al Reader for your great humor and love of teaching. Your experience and dedication to our program is an integral part to the success of all who are fortunate enough to attend Ohio State. Thank you for teaching me about how to hire staff people (the elbow test), and for all of your support over the years. You are a huge part of the reason Ohio State Endo has the excellent, and well deserved, reputation it does. I thank Dr. Melissa Drum for helping to teach me everything Endo. Your great personality and love of what you do made residency fun. I hope I ve made Yoda proud with my endodontic knowledge and clinical skills. We need more people like you in education. I am relieved to know that you will continue the great tradition of OSU Endo for the decades to come. I thank Dr. William Meyers for your amazing stories of every historical person in endodontics. Your wisdom, kindness, and dedication to teaching young dental students and residents is inspiring. I hope you continue to shape the minds of students for many more years to come. I thank Dr. Michael Beck for your commitment and support. Thank you for making my life easier and taking the time to explain stats to me. Your continued dedication to the College of Dentistry and specifically the Division of Endodontics is appreciated more than you could ever know. I thank my co-residents Sara Fowler, Kevin Wells, and Mike Simpson. You have become like a dysfunctional family to me over the last two years. I will cherish the time I spent with you for the rest of my life. I hope life continues to bring each of you everything you are searching for. I thank all of the dental students who helped me complete my research including Jonathan Mason, Spencer Fullmer, Matt Balasco, Vivian Kaufman, and Josh Melton. Without your help I would still be pulp testing teeth. vi

8 VITA February 28, Born Peoria, Illinois B.A. Psychology, University of Michigan D.D.S., University of Michigan Specialization in Endodontics Post-Doctoral Certificate, The Ohio State University Major Field: Dentistry Specialization: Endodontics FIELDS OF STUDY vii

9 TABLE OF CONTENTS Page Abstract...ii Dedication...v Acknowledgments..vi Vita vii List of Tables...x List of Figures xii Chapters: 1. Introduction Literature Review 5 Mechanism of Action of Local Anesthetics...5 Pharmacology of Local Anesthetics...8 Articaine...11 Safety of Articaine Efficacy of Articaine..32 Onset and Duration of Articaine...49 Vasoconstrictors.53 Mandibular Buccal Infiltration Injection..57 Effect of Volume on Anesthesia 65 The Electric Pulp Tester.68 The Visual Analogue Scale Materials and Methods Results Discussion of Materials and Methods Discussion of Results Subject Biographical Information 114 Sex Differences in Pain 115 Pain of Injection Pain during needle insertion.118 Pain during needle placement viii

10 Pain during solution deposition 124 Anesthetic Efficacy Frequency of Pulpal Anesthesia Anesthetic Success Anesthetic Failure.149 Onset of Pulpal Anesthesia Duration of Pulpal Anesthesia Slow Onset of Anesthesia, Short Duration of Anesthesia, and Non-continuous Anesthesia..157 Postoperative Pain Summary and Conclusions..174 Appendices A. Tables B. Figures..204 C. Biographical Data 211 D. Medical History Form E. Consent 216 F. HIPAA.223 G. Random code list..227 H. VAS form and raw VAS pain score data.232 I. Electric pulp testing form and raw EPT data References ix

11 LIST OF TABLES Table Page 1. Biographical data for all subjects Mean VAS values (mm) for infiltration injection Mean VAS values (mm) for infiltration by gender Frequency of pain ratings for needle insertion Frequency of pain ratings for needle placement Frequency of pain ratings for solution deposition Between-solution comparisons of percent 80/80 for the second molar Between-solution comparisons of percent 80/80 for the first molar Between-solution comparisons of percent 80/80 for the second premolar Between-solution comparisons of percent 80/80 for the first premolar Adjusted odds ratios for pulpal anesthesia Anesthetic success by group and definition of success Anesthetic failure by tooth and group Mean Onset of pulpal anesthesia by tooth and group Slow onset of anesthesia by group and by tooth Short duration of anesthesia by group and by tooth Non-continuous anesthesia by group and by tooth Mean VAS values (mm) of postoperative discomfort ratings 196 x

12 19. Mean VAS values (mm) of post-op pain ratings by gender Summary of pain ratings for Post-op Day Summary of pain ratings for Post-op Day Summary of pain ratings for Post-op Day Summary of pain ratings for Post-op Day Frequency of subject-reported postoperative complications by day Postoperative complications associated with buccal infiltration injection..203 xi

13 LIST OF FIGURES Figure Page 1. Mean pain ratings by group and stage of injection Second molar pulpal anesthesia by postinjection time First molar pulpal anesthesia by postinjection time Second premolar pulpal anesthesia by postinjection time First premolar pulpal anesthesia by postinjection time Postoperative pain by group and period xii

14 CHAPTER 1 INTRODUCTION Selected portions of the following have been adapted from previous theses by McEntire (1) and Pabst (2) from the Division of Endodontics at The Ohio State University College of Dentistry. Articaine [4-methyl-3 (2[propylamino] propionamido)-2 thiophenecarboxylic acid, methyl ester hydrochloride] was first synthesized in 1969 by H. Rushing et al. (3) and was originally known as carticaine. The drug was approved in 1976 for use in both Germany and Switzerland and in 1984 had its name changed to articaine (3). Approval for use was granted in Canada in 1983 and in the United Kingdom in 1998 (3). In 2000, the FDA approved the drug for use in the United States. The formulation that gained approval was a 4% solution which contained a 1:100,000 concentration of epinephrine. The formulation is known as Septocaine (Septodont, Inc., New Castle, DE) and is now available as either a 4% solution with 1:100,000 epinephrine or a 4% solution with 1:200,000 epinephrine. Successful anesthesia requires a local anesthetic that can produce a loss of sensation in a peripheral area into which it is injected or applied (4). The inferior alveolar nerve block is the most frequently used injection technique for achieving local anesthesia for mandibular restorative and surgical procedures. However, the inferior alveolar nerve block does not always result in successful pulpal anesthesia (5-22). 1

15 Clinical anesthetic studies in endodontics have found failure with the inferior alveolar nerve block occurring between 38% and 81% of the time (19-21). Anesthetic failure rates (a positive response when tested with an electric pulp tester) of 10% to 57% have been reported in experimental studies (8,14,18,19,21-26). (1) Articaine has a reputation for providing improved local anesthetic efficacy. Research has shown that buccal infiltrations of lidocaine and prilocaine solutions are not very effective for pulpal anesthesia in adult mandibular posterior teeth (27). However, articaine has the clinical reputation of penetrating bone allowing successful pulpal anesthesia of mandibular teeth. If this is indeed true, the practitioner could use this injection routinely to anesthetize the mandibular teeth and avoid the lip numbness which comes with an inferior alveolar nerve block. Articaine buccal infiltration injections may also be useful as supplemental injections when the inferior alveolar nerve block fails to achieve pulpal anesthesia. Kanaa et al. (28) compared the pulpal anesthesia produced by one cartridge of 2% lidocaine with 1:100,000 epinephrine to one cartridge of 4% articaine with 1:100,000 epinephrine for mandibular buccal infiltration injections. Success was defined as having two consecutive negative readings with the electric pulp tester at any time during the 30- minute testing period. Articaine had 64.5% success while lidocaine had only 38.7% success in producing mandibular first molar anesthesia. (1) Robertson et al. (29) has reported an increased success rate and faster onset time with an articaine solution, when compared to a lidocaine solution, when used for buccal infiltration injections in mandibular posterior teeth. Anesthetic success (obtaining two consecutive 80 readings during post-injection testing) for articaine and lidocaine were, 2

16 respectively, as follows: 75% and 45% of the second molars; 87% and 57% for the first molars; 92% and 67% of the second premolars; and 86% and 61% of the first premolars. (1) These results were found to be significantly different (p<0.05) between the solutions with each tooth type (29). Haase and co-workers (30) compared the degree of pulpal anesthesia obtained with 4% articaine with 1:100,000 epinephrine and 2% lidocaine with 1:100,000 epinephrine in buccal infiltrations of the mandibular first molar following an inferior alveolar nerve block. At each appointment all subjects received an inferior alveolar nerve block of 1.8 ml of 4% articaine with 1:100,000 epinephrine. Then after 15 minutes, the subjects received a buccal infiltration injection of either 1.8 ml of 2% lidocaine with 1:100,000 epinephrine or 1.8 ml of 4% articaine with 1:100,000 epinephrine. Anesthetic success for the first molar was 81% with articaine and 65% with lidocaine. This difference was found to be significant (p=0.0075). Anesthetic success was also generally greater with articaine for the second molar, second premolar, and first premolar, however, the differences were not significant (30). (1) Pabst (2) studied the anesthetic efficacy of a repeated infiltration injection of articaine given 25 minutes following a primary articaine infiltration injection in mandibular posterior teeth. The repeated infiltration of articaine increased the anesthetic success (two consecutive 80 readings) from 69.8% to 84.9% in the second molar, from 66.3% to 83.7% in the first molar, from 78.8% to 97.7% in the second premolar and from 80.7% to 92.8% in the first premolar. A repeated injection of articaine significantly (p<0.05) increased the anesthetic success for all teeth when compared to a repeated mock injection. (1) 3

17 Nuzum (207) studied the anesthetic efficacy of a combination labial plus lingual infiltration compared to a labial infiltration in mandibular anterior teeth. This prospective, randomized, single-blinded study included eighty-two subjects that randomly received mandibular lateral incisor infiltrations, either a combination of labial and lingual (totaling 3.6 ml) or labial and mock (totaling 1.8 ml), utilizing 4% articaine with 1:100,000 epinephrine at two separate appointments spaced at least 1 week apart. The labial plus lingual infiltration of articaine increased the anesthetic success (two consecutive 80 readings) from 76% to 98% in the mandibular lateral incisor, from 82% to 99% in the mandibular central incisor and from 74% to 93% for the mandibular canine. The labial plus lingual infiltration injection of articaine significantly (p<0.05) increased the anesthetic success for all teeth when compared to a labial plus mock infiltration injection. No objective study has addressed the addition of an additional volume of articaine to a primary infiltration injection over the mandibular first molar. Therefore, the purpose of this prospective, randomized, single-blinded study was to determine the anesthetic efficacy of an infiltration of a 3.6 ml volume of 4% articaine with 1:100,000 epinephrine in mandibular posterior teeth. 4

18 CHAPTER 2 LITERATURE REVIEW Selected portions of the following have been adapted from previous theses by McEntire (1) and Pabst (2) from the Division of Endodontics at The Ohio State University College of Dentistry. MECHANISM OF ACTION OF LOCAL ANESTHETICS The primary action of a local anesthetic is interference with the excitationconduction process of nerve fibers and endings (31). A nerve fiber has the capability to respond to a stimulus by excitation and to propagate this stimulus along the nerve fiber to its point of termination (47). This conduction of the stimulus is temporarily interfered with by the action of the local anesthetic (31). The electrophysiological properties of the neuronal membrane are a result of the permeability of the membrane to specific electrolytes, as well as the concentration of these electrolytes in the cytoplasmic and extracellular fluid (31). A nerve cell membrane is fully permeable to potassium and chloride ions in its resting state and relatively impermeable to proteins, amino acids, and sodium ions (31,32). As a result of this selective permeability, sodium and chloride ions are concentrated extracellularly. 5

19 Potassium ions and anions other than chloride are concentrated intracellularly. The permeability of the nerve cell membrane combines with the concentrations of cytoplasmic and extracellular electrolytes to determine the electrophysiologic properties of the nerve cell membrane. The electrochemical gradient between the inside and outside of the nerve membrane results in an electrical potential of approximately -70 to -90 mv across the cell membrane (48). Stimulating the nerve results in increased sodium permeability which is facilitated by a transitory widening of the transmembrane channels. This widening allows sodium ions to rapidly diffuse to the interior of the cell resulting in depolarization of the neural cell membrane to a firing threshold of approximately -50 to -60 mv. Upon reaching the firing threshold, sodium permeability increases markedly and a rapid influx of sodium ions occurs across the cell membrane. At the end of the depolarization phase, the electrical potential is actually reversed across the membrane to approximately +40 mv (4,31). Once depolarization is complete, the permeability of the nerve membrane to sodium ions decreases and the high permeability to potassium is restored. This results in movement of sodium ions out, and potassium ions in, by passive diffusion, restoring the normal resting potential of the nerve cell membrane. When the resting potential is achieved, there is a relatively high concentration of sodium ions intracellularly and of potassium ions extracellularly (48). The sodium pump actively transports the excess sodium ions out of the cell. This process is energy dependent. Adenosine triphosphate (ATP) is oxidatively metabolized to provide the necessary energy (32,48). Once the normal ionic gradient is restored, the nerve is again in its resting state. This repolarization process takes approximately 0.7 msec. The nerve cell membrane s normal 6

20 resting potential of approximately -90 mv is thereby restored (32). (1) The exact mechanism of action of local anesthetics is unknown. The generally accepted theory is that they prevent depolarization by blocking the transmembrane sodium channels. This is believed to be accomplished by either of the following mechanisms: the specific receptor mechanism and/or the membrane expansion mechanism (31-34,49-51). The specific receptor theory is based on four proposed binding sites within the sodium channel to which local anesthetic molecules can attach. Molecules may bind to the inner mouth of the channel pore resulting in a tonic block. Binding to a second site deeper within the pore will result in a use-dependent block (51). The other two proposed sites are located at the gate of the sodium channel and are related to the action of scorpion venom (33). Only the charged, or ionized, forms of the local anesthetic can bind to the first two sites, but this form is unable to cross the nerve membrane (31,49,51). (1) The nonionized, lipid-soluble local anesthetic molecules diffuse across the membrane and are present in high amounts inside the nerve initially. However, the molecules cannot exist only in this nonionized form at the intracellular ph of 7.4, and equilibrium is immediately established between the ionized and nonionized forms within the cell. Approximately 75% of the nonionized molecules are converted to the ionized form. It is this ionized form of the anesthetic molecule that is capable of binding to receptor sites on the sodium channel, thereby decreasing membrane permeability to sodium and preventing the propagation of action potentials (31,32,49). (2) The alternative explanation of local anesthetic action is known as the membrane expansion theory. According to this theory, the anesthetic agent acts by penetrating the 7

21 nerve membrane, resulting in an expansion of the membrane and a decrease in the diameter of the sodium channel, thereby preventing sodium permeability (31,32,50). This theory offers an explanation for the action of anesthetics such as benzocaine that do not exist in an ionized form (32). Local anesthetics consist of an aromatic group (benzoic acid or aniline) with an ester or amide linkage to an intermediate hydrocarbon chain, and a secondary or tertiary amino group (31,34). The local anesthetic s hydrophilic properties are due to the secondary or tertiary amino groups, while the lipophilic properties are derived from the aromatic residue which originates from benzoic acid or aniline (34). The ester or amide linkage between the aromatic residue and the intermediate carbon chain determines the anesthetic s metabolism, allergenicity, and classification (31,51). Each compound s anesthetic properties are dependent on its lipid solubility, protein binding capacity, pka, ph, tissue diffusibility, and intrinsic vasodilating properties (31). (1) The potency of the anesthetic compound is primarily determined by its ability to penetrate the nerve cell membrane, which is directly related to its lipid solubility. Highly lipid-soluble anesthetic compounds can easily penetrate the nerve membrane. Relatively lower concentrations are therefore efficacious (31,32,34). Lidocaine and articaine are considered to be of intermediate potency. Duration of action is primarily determined by the local anesthetic s proteinbinding characteristics. The stronger the binding ability is, the longer the duration will be. Poor protein binding results in a short duration of anesthesia. Lidocaine and articaine are rated as having intermediate duration of action: two to four hours for maxillary infiltration injections and four to five hours for inferior alveolar nerve (IAN) block 8

22 injections (31,33). (1) A chemical compound's pka is defined as the ph at which the ionized and nonionized forms exist in equilibrium. The pka is constant for each specific anesthetic molecule and ranges from a low for mepivacaine at 7.6 to a high for procaine at 9.1 (31,32,34,35). Lidocaine has a pka of 7.9, and articaine has a pka of 7.8. Anesthetic onset time is strongly related to the pka. It is the nonionized form of the drug that penetrates the neuronal membrane (31). At a tissue ph of 7.4, 2-40% of an anesthetic will exist in the nonionized form, depending on the anesthetic s pka. The lower the pka value and the closer it gets to the ph of the injected tissues, the faster the onset time because a larger portion of the particles will be in the nonionized form and can easily penetrate the nerve membrane. Lidocaine and articaine have relatively fast clinical onset times (from one to three minutes for maxillary infiltration injections and one to four minutes for IAN block injections) because their pka s are close to the ph of the injected tissue (31,33,36). Anesthetic compounds can only act on nerve membranes after they diffuse through non-nervous tissue to reach the nerve. Tissue diffusibility has a direct relationship to the rate of onset. Despite their importance, the factors that determine the rate of diffusibility through non-nervous tissues are poorly understood (31). (1) Vasodilator activity of anesthetic compounds influences their potency and duration. Increased blood flow caused by vasodilation results in quicker removal of the anesthetic compound from the injection site, thereby decreasing the amount available to act upon the nerve. With the exception of cocaine, all local anesthetic agents have vasodilator properties (48). (1) Both lidocaine and articaine are potent vasodilators and 9

23 would be ineffective and more toxic if given as plain solutions (32). Therefore, in order to improve duration and safety, a vasoconstrictor such as epinephrine is added to the anesthetic cartridges. In contrast, other anesthetics, such as prilocaine, are less potent and can be given safely as plain solutions. Local anesthetic compounds exist in cartridges in the form of hydrochloride salt solutions (31,48). These preparations have a ph of 4.5 to 6.0 (4). Not only does such a low ph improve water solubility, but stability of the local anesthetic is also increased. Epinephrine and other vasoconstrictors become progressively unstable as ph increases; therefore, solutions with vasoconstrictors are required to have a ph in the range of 3.3 to 5.5 (52). Within this range, vasoconstrictor concentration will be within USP regulated levels for up to a year, whereas solutions with a ph much higher than this will deteriorate in several hours (52). Therefore, this ph is most optimal for storage. Because the compounds have pka values greater than these ph values, most of the solutions are in the ionized form. Once injected, however, fluid buffers of the surrounding tissues quickly neutralize the acidic local anesthetic solution. This increases the ph of the anesthetic solution and increases the amount of free base (nonionized) anesthetic available to diffuse through the nerve sheath (31,32). (2) Various instances of local anesthetic toxicity have been reported. The earliest and most common response to a local anesthetic overdose is central nervous system excitation. Initially, a feeling of light-headedness or dizziness occurs. Auditory and visual disturbances may also be noted. The patient may become disoriented and develop slurred speech, tremors, muscle twitching and generalized convulsions. Generalized central nervous system depression follows, with loss of consciousness and respiratory 10

24 arrest. At even higher doses, the cardiovascular depressant effects of local anesthetics, such as decreased myocardial contractility, decreased peripheral resistance, hypotension, and circulatory collapse, will also result (53). (1) ARTICAINE Carticaine [4-methyl-3(2[propylamino] propionamido)-2 thiophenecarboxylic acid, methyl ester hydrochloride] was first synthesized in 1969 by Rushing et al. when experimenting with thiophene derivatives (3). The drug was approved for use in both Germany and Switzerland in 1976 and had its name changed from carticaine to articaine in 1984 (3). Approval for use was granted in Canada in 1983 and in the United Kingdom in 1998 (3). In Germany, articaine accounts for 90% of all local anesthetics used (54). In Canada, a 1993 survey showed that articaine was the most frequently used local anesthetic, accounting for almost 38% of all dental injections (55). In Canada, a 2007 survey showed that articaine accounted for 44.2% of all dental injections (209). Pogrel reported that articaine sales accounted for approximately 25% of the U.S. market in 2003 (208). Malamed estimated that articaine accounted for 26% of the U.S. market in 2005 (211). Articaine s action is similar to that of other currently available local anesthetics. Like other amide local anesthetics (e.g. lidocaine), articaine blocks sodium and potassium channels in the nerve membrane to such an extent that the nerve resting membrane potential cannot reach the electrical threshold needed to fire an action potential (56). This prevents the nerve from sending a signal to the brain (57). The epinephrine in dental cartridges produces localized vasoconstriction which slows absorption of the articaine. 11

25 This ensures prolonged maintenance of an active tissue concentration of the anesthetic while minimizing the systemic absorption of both active compounds (56). (1) In 2000, the Food and Drug Administration (FDA) approved articaine for use in the United States. The articaine formulation that gained approval in the United States was a 4% solution which contained a 1:100,000 concentration of epinephrine. The formulation is known as Septocaine (Septodont, Inc., New Castle DE). Septocaine is distributed in a 1.7 ml dental cartridge and contains many components with specific functions: articaine hydrochloride 40 mg/ml as the local anesthetic, epinephrine tartrate mg/ml for vasoconstriction, sodium chloride 1.6 mg/ml for isotonicity, sodium metabisulphite 0.5 mg/ml as an antioxidant for the vasoconstrictor, and distilled water 1.0 ml volume for injection (3). Sodium chloride is added to the cartridge to make the solution isotonic with the tissues of the body and sterile water is added to the cartridge to provide the correct volume of solution. A small bubble of nitrogen gas is also included in the cartridge during manufacturing to prevent oxygen from being trapped in the cartridge and potentially destroying the vasoconstrictor (32). (1) Sodium metabisulfate is a chemical added as an antioxidant whenever a vasoconstrictor is present, including articaine preparations. People allergic to bisulfites (most often steroid-dependent asthmatics) may develop allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes (68). Sodium metabisulfate is not present in dental anesthetics without a vasoconstrictor. The overall prevalence of sulfite sensitivity in the general population is unknown. (1) Original articaine formulations contained a bacteriostatic agent, an antifungal agent, and methylparaben as an antioxidant preservative for the local anesthetic. Methylparaben has a high potential for allergenicity 12

26 and it was not until 1994 that methylparaben was removed from articaine formulations sold in Canada. A similar methylparaben-free formula is sold in the United States (58). (1) Berlin (69) reported that although the 4% articaine with 1:100,000 epinephrine solution is supplied in a cartridge labeled 1.7 ml, the volume is 1.8 ml. Weaver (67) also acknowledged that articaine anesthetic cartridges actually contain 1.8 ml of solution. The FDA requires the manufacturer to indicate the solution as a 1.7 ml cartridge because some anesthetic cartridges were found to occasionally contain slightly less than 1.8 ml of solution (67). Therefore, the apparent difference in anesthetic volume between the two solutions is very likely not different at all. (1) Articaine has been available since 1984 in Europe and Canada in two formulations: 4% articaine with 1:100,000 epinephrine and 4% articaine with 1:200,000 epinephrine. Articaine is now available in the United States with 1:200,000 epinephrine. The basic ingredients are the same, but the higher concentration of epinephrine in the 1:100,000 epinephrine formulation may provide a longer duration of analgesia (75 minutes vs. 45 minutes with the 1:200,000 epinephrine formulations) (32). (2) Several studies have recently shown no differences in anesthetic efficacy, onset, or duration between the two formulations (44-46). Articaine is classified as an amide, similar to lidocaine and all other local anesthetics currently available in dentistry. Articaine has a molecular weight of and has an intermediate chain with a trivalent bonded nitrogen attached to a carboxylic acid (3). Articaine, however, differs from all other amide local anesthetics in that it is derived from thiophene. Therefore, the molecule does not contain a benzene ring as do 13

27 other amide local anesthetics but instead contains a thiophene ring (3). A second molecular difference between articaine and other amide local anesthetics is the extra ester linkage incorporated into the articaine molecule (3). Borchard et al. (59) studied the action of local anesthetics on myelinated nerve fibers. He stated that a lower concentration of the thiophene derivative (articaine) was sufficient to block an action potential, compared to benzene derivatives (all other amide anesthetics). (1) Degradation of articaine is initiated primarly in the plasma by plasma esterase hydrolysis of the carboxylic acid and ester groups to yield free carboxylic acid (56,60). A small amount is also metabolized in the liver by hepatic microsomal enzymes. Articainic acid is the primary metabolite (60). (2) Additional metabolites including articainic acid glucoronide have been detected in animal studies (3). In contrast to lidocaine, which has known active metabolites, it is unclear whether articainic acid has biologic activity (3). This is important because an active metabolite may cause toxicity and may lead to undesirable side-effects (3). Van Oss et al. (61) administered articainic acid intravenously to a single volunteer to determine the clinical effects and pharmacokinetics of the major metabolite of articaine. They found no change in electrocardiography, blood pressure, or heart rate in this subject. Though the study had only one subject, it provided evidence that the metabolite may be inactive, unlike the metabolites found after breakdown of lidocaine. The other metabolite, articainic acid glucoronide, also appears to be inactive (3). (1) High performance liquid chromatography has been used to determine the concentrations of articaine and its metabolite articainic acid in the serum. Oertel and 14

28 Rahn (62) studied the clinical pharmacokinetics of articaine and found that the maximum drug concentration of articaine is reached about 10 to 15 minutes after submucosal injection of an 80 mg, 4% articaine solution, irrespective of the addition of epinephrine. They also found the mean maximum plasma drug concentration to be about 400 μg/l for articaine with 1:200,000 epinephrine, and 580 μg/l for articaine without epinephrine. Oertel and Rahn (62) concluded that the rapid breakdown of articaine to its inactive metabolite articainic acid results in a very low systemic toxicity, giving articaine a wide therapeutic range. They also concluded that articaine can be safely administered using repeated doses because the use of articaine in higher doses is safer than other amide-type local anesthetics (62). Isen et al. (3) also concluded that re-injection with articaine is safe after 30 minutes should the patient require additional local anesthetic, since the majority of the initial dose would already be metabolized. If more lidocaine were administered 30 minutes after the first injection, it would be additive to the first dose because its half-life is 3 times longer than articaine. (1) Biotransformation of articaine occurs in both the plasma (hydrolysis by plasma cholinesterase) and the liver (hepatic microsomal enzymes) (56). It has been shown that a higher percentage of articaine is metabolized in the blood than in the liver. Van Oss (60) found protein binding of articaine in patients varied between 50% and 70% while protein binding of the metabolite articainic acid varied between 60% and 90% (60). Isen (3) states that 90% to 95% of articaine is metabolized in the blood and only 5% to 10% is broken down by the microsomal P450 enzyme system in the liver (3). The half-life of articaine has been reported to be as low as 20 minutes (60), while the half-life of lidocaine is approximately 90 minutes (63). Oertel and Rahn (62) studied the clinical 15

29 pharmacokinetics of articaine and also found the elimination half-life to be 20 minutes. Jakobs et al. (64) evaluated the pharmacokinetics of both 2% and 4% articaine in children and found plasma half-lives of 18.5 and 23.6 minutes, respectively. Muller et al. (65) studied the pharmacokinetics of articaine in mandibular nerve block anesthesia using 2 ml of 4% articaine with 1:200,000 epinephrine in 10 alert patients and 10 patients under general anesthesia. Blood samples from peripheral veins showed a half-life of approximately 20 minutes. Muller concluded that compared to other local anesthetics, whose plasma half-lives may vary between 1 and 3.6 hours, the 20 minute value found for articaine was very low. The reason for such a short half-life is explained, in part, by its structure. Plasma esterases can degrade articaine due to its ester group. This is a rapid process compared to the microsomal P450 enzyme system of the liver (2). Articaine is eliminated via the kidneys (56). Van Oss et al. (60) found 2-5% of articaine is excreted unchanged, 30-70% as articainic acid, and 4-15% as articainic acid glucoronide. Renal clearance of articaine ranges from 12 to 28 ml/min and that of articainic acid ranges from 84 to 160 ml/min (60). (1) Potocnik and co-authors (66) compared the effectiveness of 2% and 4% lidocaine, 3% mepivacaine, and 2% and 4% articaine solution in blocking the action potential of rat sensory nerves. After application of an anesthetic solution and stimulation of the nerve with a supramaximal electrical stimulus, a complete disappearance of the compound action potential of the C fibers, but not of the A fibers, was observed in all the experimental groups. Both 2% and 4% articaine more effectively depressed the compound action potential of the A fibers than did other anesthetic solutions (66). (2) 16

30 SAFETY OF ARTICAINE Articaine has a maximum safe dose of 7 mg/kg for uncompromised patients. Articaine has a maximum milligram dose of 500 mg for an average, healthy, 70 kg adult (67). A 1.7 ml cartridge of 4% articaine contains almost twice the amount of drug (68 mg) as a 1.8 ml cartridge of 2% lidocaine (36 mg). The maximum number of cartridges of articaine that a patient can be safely given would therefore be about half the number of cartridges that the same patient could receive if lidocaine were selected (67). At a body weight of 70 kg, an average adult s maximum dose would be 490 mg of articaine, which translates into 7.2 cartridges of 4% articaine with 1:100,000 epinephrine (67). (1) The rapid breakdown of articaine and the apparent inactivity of its metabolites imply that it may be a safer anesthetic than other currently available anesthetics, including lidocaine. In his editorial on articaine, Weaver (67) noted the excellent safety record for articaine worldwide. Weaver stated that although lidocaine and other amides have been implicated in a number of pediatric deaths, there are few reports of overdose mortalities attributed to articaine. He raised the question: is articaine inherently safer despite its higher concentration? Weaver attributed articaine s reputation of safety to possible underreporting of overdose reactions and acknowledged that the mg/kg maximum dose for articaine may be very conservative. In addition, Weaver also stated that dentists in those countries in which articaine is commonly used may meticulously calculate the maximum recommended dose for each patient; these dentists avoid high blood levels of articaine by spreading out their injections over the entire appointment; and these dentists have better training and are better able to recognize and appropriately treat overdose reactions. Weaver (67) stated that articaine is safe and effective when 17

31 used in appropriate doses for dental patients. (1) Cardiovascular Safety Malamed et al. (70) investigated the safety of articaine compared to lidocaine in adult dental patients. A total of 1325 patients undergoing general dental procedures were evaluated for adverse effects of the injected anesthetic solutions. The subjects were randomized in a 2:1 ratio to maximize trials with articaine. Subjects received comparable volumes of articaine and lidocaine for both simple and complex procedures, but higher mg/kg doses of articaine in both types of procedures due to the higher concentration of articaine at 4% versus lidocaine being 2%. Safety was evaluated by measuring vital signs before administration of the anesthetic, at 1 and 5 minutes post-administration, and at the end of the procedure. Information about any adverse events was also collected by follow-up telephone calls both 24 hours and 7 days after the procedure. The incidence of adverse events was 22% (191 of 882 patients) for the articaine group and 20% (89 of 443 patients) for the lidocaine group. One patient in the lidocaine group had to discontinue the study due to chest pain and dizziness. No deaths were reported associated with either anesthetic in this study. The most common adverse event in the articaine group was postprocedural pain (13%). Other reported adverse events associated with articaine included headache (4%), facial edema (1%), infection (1%), gingivitis and paresthesia (1%). The most commonly reported adverse events which were considered by the investigator to be drug-related were paresthesia (0.9%), hypoesthesia (0.7%), headache (0.55%), infection (0.45%), rash (0.3%), and pain (0.3%). Heart rate and respiratory rates increased slightly at 1 and 5 minutes but by post-procedural times had decreased slightly below the baseline 18

32 values. Adverse events reported for lidocaine were similar to those reported for articaine. However, one case of mouth infection and one case of mouth ulceration rated at severe intensity were reported from the articaine group. Malamed et al. (70) concluded that 4% articaine with 1:100,000 epinephrine had a low risk of toxicity that appeared comparable to other local anesthetics. (1) Simon et al. (71) investigated differences between three anesthetics during intravenous regional anesthesia in a double-blind randomized clinical trial. Thirty patients received either 0.5% articaine, 0.5% lidocaine, or 0.5% prilocaine intravenously, and differences in side effects and maximum drug concentrations were evaluated. The plasma drug concentration was evaluated by high performance liquid chromatography. The peak levels were found immediately after release of the tourniquet and gradually decreased over time. The maximum concentrations were 1.85, 8.5, and 4.4 μg/ml for articaine, lidocaine, and prilocaine, respectively. Articaine had the lowest peak concentration of the three local anesthetics when used for intravenous regional anesthesia. The authors speculate that the low plasma levels of articaine may be a result of hydrolysis by plasma esterase. In addition, no signs of local anesthetic toxicity of the cardiovascular or central nervous system were seen when using articaine. (1) Hidding and Khoury (63) evaluated the safety of 4% articaine with 1:100,000 epinephrine and 4% articaine with 1:200,000 epinephrine when used for an inferior alveolar block. With the 4% articaine with 1:100,000 epinephrine, 7.6% of the patients experienced an increase in blood pressure equal to or greater than 20 mm Hg as compared to 4% articaine with 1:200,000 epinephrine where 6.3% of the subjects experienced a similar increase. There were no differences among the groups with respect 19

33 to changes in blood pressure or heart rate. One subject who received 4% articaine with 1:100,000 epinephrine experienced diplopia after injection, which resolved after 15 minutes. (1) Daublander et al. (54) investigated the incidence of complications associated with local anesthetic use in dentistry. Articaine was reported to have been administered in over 90% of all local anesthetic injections in Germany, with a low incidence of complications. In this study, 2731 patients receiving local anesthesia were evaluated for complications associated with the administration of articaine in an oral surgery clinic in Germany. The overall incidence of complications was 4.5%, with the incidence higher for at-risk patients (5.7%) than non-risk patients (3.5%). Severe complications, including seizure and bronchospasm, occurred in only two cases, a 0.07% incidence. The most frequently observed complications were dizziness, tachycardia, agitation, nausea, and tremor. These were transient and did not require treatment. Moller (72) examined the cardioelectrophysiologic effects of articaine in comparison to those of bupivacaine and lidocaine in isolated rabbit heart preparations. The effects of the three local anesthetics on action potentials from the Purkinje fiber and ventricular muscle tissues were determined. Moller et al. found that articaine, at ten times its observed clinical blood concentration, was significantly less cardiodepressive than bupivacaine at only five times its observed clinical blood concentration. (1) Elad et al. (73) studied the cardiovascular safety profiles of 4% articaine with 1:200,000 epinephrine versus 2% lidocaine with 1:100,000 epinephrine in cardiovascular patients. The study was a prospective, randomized, double blinded study in which 50 patients received 1.8 ml of each anesthetic at separate appointments. There were no 20

34 adverse clinical effects. There were also no statistically significant differences between the two groups in heart rate, systolic or diastolic blood pressure, or oxygen saturation (73). (1) Children Articaine has been shown to be safe in children over 4 years of age. Articaine is not recommended for children under the age of 4 because, according to the articaine product monograph (68), no data exists to support its use. However, recent clinical studies have shown articaine to be safe even in children under 4 years of age (64,74). Wright et al. (75) evaluated the use of articaine administered in children under 4 years old in a retrospective survey of dental records from 2 pediatric dental offices in Ontario, Canada. Two hundred and eleven children (59 also receiving preoperative sedation with chloral hydrate, hydroxyzine hydrochloride, and nitrous-oxide) from 12 months to 48 months of age who received articaine as a maxillary infiltration or mandibular block were evaluated for any observed or reported adverse reactions. The 211 patients received a combined total of 240 doses of articaine without any reported adverse effects. (1) Jakobs et al. (64) measured the serum levels of articaine at multiple time intervals after administration of the drug. The study was carried out on a total of 27 children, aged 3 to 12 years, undergoing general anesthesia. Venous blood samples were gathered before local anesthesia and then 2, 5, 10, and 20 minutes after infiltration with either 2% articaine with 1:200,000 epinephrine or 4% articaine with 1:200,000 epinephrine. It was observed that the pharmacokinetic profile of articaine was similar to 21

35 that observed in adults. The maximum serum concentration in the children was 1060 μg/ml for the 2% articaine group and 1382 μg/ml for the 4% articaine group. These values are consistent with the results of a study by Kirsch et al. (76), in which maximum serum concentrations in adults were approximately 1170 μg/ml after injection of 240 mg of articaine. The T max (time to maximum plasma concentration) values were 7.44 minutes in the 2% group and 7.78 in the 4% group. These values were comparable with investigations of pharmacokinetic characteristics of articaine in adults. Muller (65) found average T max values to vary between 16.9 and 17.7 minutes in adults. Jakobs et al. (64) claims that the T max values in children are distinctly earlier and the plasma clearance is distinctly increased in comparison to adults. Jakobs et al. found no particular adverse events, side-effects, or untoward incidents. Jakobs et al. concluded that there is no reason to adjust the mg/kg dose limit for children as compared to adults. However, it is important to remember that for a small child (15 kg or approximately 30 pounds) the toxic dose can be reached with less than two cartridges of a 4% articaine solution (3). (1) Malamed and Gagnon (77) investigated the safety of articaine compared to lidocaine for pediatric dental patients. Subjects aged 4 to 13 years undergoing general dental procedures were evaluated for any adverse effects of the injected anesthetic solutions. Fifty subjects were randomized in a 2.5:1 ratio to maximize information gathered about articaine. Subjects received comparable volumes of articaine and lidocaine for both simple and complex procedures, but higher mg/kg doses of articaine in both types of procedures due to the higher concentration of articaine at 4% versus lidocaine at 2%. Safety was evaluated by measuring vital signs before administration, at 22

36 1 and 5 minutes post-administration of the medication, and at the end of the procedure. Information about any adverse events was also collected during telephone call follow-up both 24 hours and 7 days after the procedure. At least one minor adverse event was reported by 8% of the articaine subjects and by 10% of the lidocaine subjects. The adverse events noted were post-procedural pain (2%), headache (2%), injection site pain (2%), and accidental injury/lip bite (2%). There were no serious adverse events. One patient received more than the recommended maximum dosage of 7.0 mg/kg of articaine and reported no adverse effects. Mean supine blood pressure values increased slightly from baseline after administration of articaine, but the changes were not clinically significant and were not associated with any adverse events. Malamed et al. (77) concluded that 4% articaine with 1:100,000 epinephrine is safe when administered by injection to children at least 4 years of age. (1) Adewumi et al. (78) reported the incidence of adverse reactions following the use of 4% articaine in children. Follow-up phone interviews were conducted with the parents of 2 to 14 year-olds at 3, 5, 24 and 48 hours regarding prolonged paresthesia, soft tissue injury and pain. The incidence of prolonged paresthesia was 40% at 3 hours postinjection and 11% at 5 hours postinjection. Soft tissue injury occurred in 14% of the patients at 3 hours postinjection and was the highest in children under 7 years old. Twenty percent of the children reported post procedural pain at 3 and 5 hours posttreatment (78). (1) Pregnant, Elderly and Medically Compromised Patients Malamed et al. (77) advised caution with the use of articaine in patients with 23