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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 11  |  Issue : 4  |  Page : 189-195

Efficacy of 4% Articaine with 1:100,000 Adrenaline as an Effective Alternative for Achieving Anesthesia during Dental Extraction


Department of Oral and Maxillofacial Surgery, Haldia Institute of Dental Sciences and Research, West Bengal University of Health Sciences, Haldia, West Bengal, India

Date of Submission21-May-2019
Date of Decision17-Aug-2019
Date of Acceptance17-Aug-2019
Date of Web Publication1-Oct-2019

Correspondence Address:
Sucharu Ghosh
Department of Oral and Maxillofacial Surgery, Haldia Institute of Dental Sciences and Research, West Bengal University of Health Sciences, Haldia, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJDS.IJDS_54_19

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  Abstract 


Purpose: The purpose of the study is to ascertain the efficacy of 4% articaine with 1:100,000 adrenaline, its duration of action, onset, the field of anesthesia, check patient compliance and complications (if any) during and postsurgery, and assess the degree of pain. Materials and Methods: Ninety-five patients requiring intra-alveolar tooth extraction in mandibular and maxillary arches. Results: Subjective onset of action for inferior alveolar nerve block was from 59 to 90 s and the objective onset of action was from 68 to 90 s. For posterior superior alveolar nerve blocks, the onset of action was from 42 to 68 s, and for infraorbital nerve blocks, it was from 40 to 52 s. The mean duration of anesthesia was 183.6 ± 6.912 min in case of inferior alveolar nerve blocks, 60.735 ± 3.212 min in posterior superior alveolar nerve blocks, and 43.33 ± 3.497 min in infraorbital nerve blocks. Pain scoring by the patients showed a visual analog scale score of 2 ± in inferior alveolar nerve blocks, 3 ± in posterior superior nerve blocks, and 1 ± in infraorbital nerve block. Conclusion: We recommend 4% articaine with 1:100,000 adrenaline as a better anesthetic, as it was more comfortable the patient with less bleeding, more profound, less time of onset, slightly longer duration of action, and comfortable to the surgeon.

Keywords: Articaine, local anesthesia, nerve block


How to cite this article:
Ghosh A, Basu S, Maity C, Pachisia S, Sahu S, Ghosh S. Efficacy of 4% Articaine with 1:100,000 Adrenaline as an Effective Alternative for Achieving Anesthesia during Dental Extraction. Indian J Dent Sci 2019;11:189-95

How to cite this URL:
Ghosh A, Basu S, Maity C, Pachisia S, Sahu S, Ghosh S. Efficacy of 4% Articaine with 1:100,000 Adrenaline as an Effective Alternative for Achieving Anesthesia during Dental Extraction. Indian J Dent Sci [serial online] 2019 [cited 2019 Oct 17];11:189-95. Available from: http://www.ijds.in/text.asp?2019/11/4/189/268418




  Introduction Top


Horace Wells in 1844, who inhaled nitrous oxide and got his tooth extracted, enjoys the first credit of introducing general anesthesia, the fruits of which is enjoyed very much in the field of dentistry.[1] The discovery of local anesthetics was made with the introduction of Cocaine in 1860.[2] Lignocaine and novocaine were introduced later in 1904 by Lofgren and Lundquist which revolutionized dental practice. Later, newly developed drugs such as articaine, etidocaine, bupivacaine, and mepivacaine were compared against these to check their efficacy.[2],[3]

Articaine hydrochloride by the name Carticaine was first marketed in Germany in 1976. The advantages of this newly developed drug are hidden in its pharmacological actions and most importantly in its structure. It is the only amide-type anesthetic that contains an ester group also, and this allows it to be metabolized by both lungs and liver enzymes as well as by plasma esterases. Thus it produces less tissue toxicity. Substitution of the aromatic ring by the thiophene ring increased the liposolubility of the drug along with its potency. Other features of articaine that allows its advantages over other local anesthetics are its quick onset and long duration of action that allows its single administration to go on for long procedures such as serial extractions or for the extraction of impacted third molars. Its greater field of action and a wide range of penetration makes this local anesthesia work only by a single administration and by providing just a single nerve block instead of several blocks that need to be given in case of the standard drug lignocaine. Thus, patient's satisfaction is more. Since its discovery, various studies have been conducted to check its efficacy so that it can be made into regular use.

Aim and objectives

The main objectives of the study were as follows:

  1. To ascertain the efficacy of 4% articaine with 1:100,000 adrenaline during intra-alveolar tooth extractions in maxillary and mandibular arches
  2. To carefully assess its action during and postadministration and to check its clinical parameters such as onset and the field of anesthesia by both subjective and objective ways
  3. To note its effect in patients with any systemic conditions
  4. To check if the patient suffered any complication during and postsurgery
  5. To assess the degree of pain.



  Materials and Methods Top


Written informed consent was obtained from all patients prior to the commencement of the study procedure. The Ethical Committee of the Haldia Institute of Dental Sciences and Research reviewed the study protocols and granted ethical clearance. The sample size comprises 95 patients (50 males, 45 females, mean age 27.8 years, ranging from 18 to 52 years) who needed intra-alveolar tooth extraction in mandibular and maxillary arches.

Inclusion criteria

The inclusion criteria were as follows:

  1. Patients willing to give consent to participate in the study
  2. Patients aged 18–60 years
  3. Patients with ASA status I and having normal hematological status
  4. No history of complication during extractions or surgery
  5. Lactating mothers, patients with local infection were also included in this study.


Exclusion criteria

The exclusion criteria were:

  1. Patients not willing to give consent to participate in this study
  2. Patients with systemic diseases or conditions such as chronic obstructive pulmonary disease, cardiac problem, liver disease, or taking any medication that may alter the outcome of the study
  3. History of allergy to any of the medications that will be administered or prescribed
  4. Any oral habits that may alter the outcome of the study
  5. Not willing to follow-up.


Out of 95 patients, 40 patients needed mandibular tooth extraction [Figure 1] and were given inferior alveolar nerve block and 55 patients needed a maxillary tooth extraction. Posterior superior alveolar nerve block was given in 34 patients and infraorbital nerve block was given to 21 patients as per the region to be anesthetized in maxillary tooth extraction [Figure 2].
Figure 1: The procedure of inferior alveolar nerve block

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Figure 2: Pie chart showing the distribution of nerve blocks among patients

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Patients who needed extraction of mandibular molars were only given inferior alveolar nerve block; a long buccal block was not given. Moreover, as for patients who needed extraction of maxillary molars, the greater palatine block was not given; only posterior superior nerve block was given.

Hypersensitivity reactions were checked before administration, however, two patients experienced vasovagal attack and their data were later considered as a failure. The patients were immediately put on Trendelenburg position and vitals monitored.

The amount of anesthetic agent injected, the onset and duration of anesthesia, and postinjection complications were recorded for all patients. The intraoperative pain was scored with a visual analog scale (VAS).[4] Patients who required reanesthetization were also noted.


  Results Top


The onset of action

The subjective onset of action for inferior alveolar nerve block is ranging from 59 to 90 s with a mean value of 71.45 ± 9.58 s [Figure 3], and the objective onset of action was found to be ranging from 68 to 90 s with a mean value of 79.875 ± 5.52 s [Figure 4].
Figure 3: The subjective onset of inferior alveolar nerve block

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Figure 4: The objective onset of inferior alveolar nerve block

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For posterior superior alveolar nerve blocks, the onset of action was recorded to be ranging from 42 to 68 s with a mean value of 51.80 ± 4.80 s [Figure 5], and for infraorbital nerve blocks, it was found to be ranging from 40 to 52 s with a mean value of 43.33 ± 3.497 s [Figure 6].
Figure 5: Onset of posterior superior alveolar nerve block

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Figure 6: Onset of infraorbital nerve block

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Two out of 34 patients in the group of maxillary molar tooth extraction needed greater palatine nerve block [Figure 7].
Figure 7: Pie chart showing number of patients requiring greater palatine nerve block

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Duration of anesthesia

The mean duration of anesthesia was 183.6 ± 6.912 min [Figure 8] in case of inferior alveolar nerve blocks and was found to be 60.735 ± 3.212 min [Figure 9] and 43.33 ± 3.497 min [Figure 10] in posterior superior alveolar and infraorbital nerve blocks consecutively.
Figure 8: Duration of anesthesia in case of inferior alveolar nerve blocks

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Figure 9: Duration of anesthesia in case of posterior superior alveolar nerve blocks

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Figure 10: Duration of anesthesia in case of infraorbital nerve blocks

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Need for reanesthetization

One of 40 patients in the group of mandibular molar extraction needed reanesthesia. None of the patients in the group of maxillary tooth extraction needed to be reanesthetized.

Pain

Subjective intraoperative pain scoring by the patients showed mean VAS score of 2 ± in case of inferior alveolar nerve blocks [Figure 11], 3 ± in cases of posterior superior nerve blocks [Figure 12], and 1 ± in infraorbital nerve blocks [Figure 13].
Figure 11: Visual analog scale score in alveolar nerve blocks

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Figure 12: Visual analog scale score in posterior superior nerve blocks

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Figure 13: Visual analog scale score in infraorbital nerve blocks

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Postoperative complications

Two of the 40 patients who were subjected to inferior alveolar nerve block suffered from paresthesia.


  Discussion Top


Since its introduction in 1969, articaine has gradually become available in Europe. Its chemical structure, different to that of other local anesthetics due to the substitution of the aromatic ring with a thiophene ring, and presence of an additional ester ring provides articaine with increased liposolubility and intrinsic potency, as well as greater plasma protein binding versus other commonly used local anesthetics such as prilocaine or mepivacaine. These differential characteristics are in turn clinically reflected by a shorter latency and increased the duration of anesthesia, as well as superior bony tissue diffusion.[5]

The onset of action of an anesthetic agent depends on several factors, such as the intrinsic factor of the drug substance used and the particular anesthetic technique employed. On the other hand, latency is directly influenced by the corresponding pKa value; smaller pKa value being responsible for shorter latency. Accordingly, 4% articaine having the pKa value of 7.8 would present a shorter latency when compared with other anesthetics such as lidocaine (pKa = 7.9). Moore et al.[6] reported 4% articaine HCl with 1:100,000 as 4.2 ± 2.8 min and for 4% articaine HCl with 1:200,000 as 4.7 ± 2.6 min. Colombini et al.[7] stated 149.50 ± 14.29 s for articaine. Rebolledo et al.[5] reported 53.03 s (0.93 min) for articaine versus 75.04s (1.25 min) for lidocaine. The long period of analgesia for articaine explained by Gregorio et al.[8] stated that the onset of action of articaine was 1.66 ± 0.13 min. In our study, the mean time of onset for subjective symptoms for inferior alveolar nerve block was 71.45 ± 9.58 s and objective symptoms 79.875 ± 5.52 s. For posterior superior alveolar nerve blocks, the mean onset of action was 51.80 ± 4.80 s, and for infraorbital nerve blocks, it was found to be 43.33 ± 3.497 s.

Equal analgesic efficacy along with lower systemic toxicity (i.e. a wide therapeutic range) allows the use of articaine in higher concentrations than other amide-type local anesthetics.[9] This is advantageous with respect to the required bone penetration, and hence, it is possible to inject smaller volumes, thereby minimizing the injection-induced pain. In our study, none of the patients in the group of mandibular tooth extractions needed long buccal nerve block, and only 2 of 34 patients in the group of posterior maxillary tooth extraction needed greater palatine nerve block.

Duration of anesthesia is proportional to its degree of protein binding. However, the duration of the effect of the local anesthetic is also dependent on the injection site or concentration of vasoconstrictor present in the anesthetic solution, among other factors. Articaine presents one of the greatest protein binding percentages of all amide local anesthetics, comparable only to ultra-long-action substances such as bupivacaine, ropivacaine, and etidocaine. This, in turn, implies a longer duration of the anesthetic effect.[5] In our study, the mean duration of anesthesia was recorded 183.6 ± 6.912 min in case of inferior alveolar nerve blocks and was found to be 60.735 ± 3.212 min and 43.33 ± 3.497 min in posterior superior alveolar and infraorbital nerve blocks consecutively.

The profoundness of anesthesia was made by means of a VAS in which the patient was instructed to score intraoperative pain intensity. Subjective intraoperative pain scoring by the patients showed mean VAS score of 2± in case of inferior alveolar nerve blocks, 3± in cases of posterior superior nerve blocks, and 1± in infraorbital nerve blocks.

Gregorio et al.[8] reported the intraoperative analgesia evoked by articaine may be explained by its ability to readily diffuse through tissues due to the presence of thiophene group in the molecule which increases liposolubility. Sumer et al.[10] reported that painfulness of local anesthetic injections may be related to the pH of the injected solutions. Local anesthetic solutions with low pH have been thought to cause a burning sensation, and thus more pain than anesthetics with more neutral pH.

The pH of lidocaine is 5–5.5 while that of articaine is 4.4–5.2 and prilocaine was 3.5–5.2 and concluded that there were no significant differences among the anesthetic solutions for injection pain.

Inferior alveolar nerve block has the highest failure rate of about 10%–15% and positive aspiration rate,[11] yet in our study, the nerve block was successful for most of the patients. 1 out of 40 patients in the group of mandibular molar extraction needed reanesthesia but that was found to be due to the patient's apprehensiveness of the procedure. None of the patients in the group of maxillary tooth extraction needed to be reanesthetized. For maxillary extractions, the posterior superior alveolar block was all that was required for all upper molars and infraorbital nerve block for premolars and nasopalatine block for anterior teeth. Greater palatine nerve block was not required. This shows the efficacy of articaine, as it has a wide field of action and it also reduces systemic toxicity.

In both the Norwegian “Felleskatalogen” and the manufactures recommendation for usage, articaine is not recommended for children under 4 years of age as the documentation of safety in this group is sparsely, and that controlled trials must be carried out [Table 1]. A retrospective report showed, however, that articaine had been successfully administered to children <4 years of age, and that articaine is likely safe for children under 4 years of age, and that the pharmacokinetic profile of articaine is very similar for children and adults.[12],[13]
Table 1: The maximum recommended doses for articaine at different weights (Felleskatalogen, 2003)

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However, it is important to be careful when the local anesthetic is administered in a sedated child since there is a higher risk of adverse reactions to occur, and that there is a direct link between adverse reactions and local anesthesia volumes.[12],[14] It is also important to remember that articaine is in a 4% solution, and that maximum dose for children is the same as for adults; 7 mg/kg (0.175 ml/kg). For simple procedures, the recommendation is 0.04 ml/kg, and for complicated procedures, 0.07 ml/kg (Felleskatalogen, 2003). It is important to have in mind that when you administer the local anesthetic to children with a small weight, the maximum dose can easily be reached.

Moreover, due to the better bone penetration property, children undergoing dental treatment in the posterior mandibular area can be anesthetized with local infiltrations, except extraction where the mandibular block is indicated. Furthermore, infiltrations are more suited for difficult and handicapped children, and it can be safely administered in a reluctant child. Since the tongue is not affected, the risk of postoperative bites is reduced.[15],[16]

Concerning local anesthesia, most of our knowledge of pharmacokinetics is based almost entirely on investigations in young individuals.[17] The only local anesthetic agent that is tested extensively in elderly patients, is lidocaine.[18]

However, there are no statistical differences in Cmax and Tmax or t1/2 between young and older individuals.[18] This is a very important finding, indicating that there might be an age-independent plasma esterase function. This is in contrast to other amide local anesthetics, which is primarily metabolized in the liver, which has a capacity that decreases with age. There is a significant decrease in CL (drug clearance) and volume of distribution by steady state method of articaine in elderly, related to the decrease in lean body mass and increase in body fat.[18]

Considered that articaine shows an age-independent metabolism, there should be no reason to change the dosage in elderly patients. However, it is important to remember that articaine is a high serum protein-bounded drug, and changes in binding to serum are also a factor that could affect pharmacokinetics in the elderly.

According to literature, articaine has potential to cause methemoglobinemia, neuropathies, paresthesia,[5],[19],[20],[21],[22],[23] hypersensitivity,[24] and allergy.[25],[26] Malamed et al.[27],[28] reported an overall incidence of adverse events in the combined studies was 22% for articaine and 20% lidocaine of which paresthesia was 0.9%, hypoesthesia 0.7%, headache 0.55%, infection 0.45%, and rash and pain 0.3%. Potocnik et al.[29] reported that although 4% articaine is more effective, they suggested that it may be worth considering replacing the 4% articaine with 2% articaine solution as the risk of an intravenous injection of the anesthetic solution during the induction of inferior alveolar nerve block and the possibility that the 4% articaine solution may increase the incidence of nonsurgical paresthesia. In our study, two patients experienced inferior alveolar nerve paresthesia who were anesthetized by articaine. Rebolledo et al.[5] reported that there is insufficient evidence to believe the underlying cause to be the type of anesthetic used. We, therefore, consider that further studies are needed to establish such a possible relationship.


  Conclusion Top


Articaine is an uncommon but potent anesthetic drug. Although authors have reported some adverse effects of articaine in our study, articaine was found to be comfortable the patient with less bleeding, more profound, less time of onset, slightly longer duration of action, and comfortable to the surgeon. Hence, we recommended 4% articaine with 1:100,000 adrenaline as practically a better anesthetic.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Haridas RP. Horace wells' demonstration of nitrous oxide in Boston. Anesthesiology 2013;119:1014-22.  Back to cited text no. 1
    
2.
Redman M. Cocaine: What is the crack? A Brief history of the use of cocaine as an anesthetic. Anesth Pain Med 2011;1:95-7.  Back to cited text no. 2
    
3.
Strichartz GR, Berde CB. Local anesthetics. In: Miller RD, editor. Miller's Anesthesia. New York: Churchill Livingstone; 2005. p. 573-603.  Back to cited text no. 3
    
4.
Miller MD, Ferris DG. Measurement of subjective phenomena in primary care research: The visual analogue scale. Fam Pract Res J 1993;13:15-24.  Back to cited text no. 4
    
5.
Rebolledo AS, Molina ED, Aytís LB, Escoda CG. Comparative study of the anesthetic efficacy of 4% articaine versus 2% lidocaine in inferior alveolar nerve block during surgical extraction of impacted lower third molars. Med Oral Patol Oral Cir Bucal 2007;12:E139-44.  Back to cited text no. 5
    
6.
Moore PA, Boynes SG, Hersh EV, DeRossi SS, Sollecito TP, Goodson JM, et al. The anesthetic efficacy of 4 percent articaine 1:200,000 epinephrine: Two controlled clinical trials. J Am Dent Assoc 2006;137:1572-81.  Back to cited text no. 6
    
7.
Colombini BL, Modena KC, Calvo AM, Sakai VT, Giglio FP, Dionísio TJ, et al. Articaine and mepivacaine efficacy in postoperative analgesia for lower third molar removal: A double-blind, randomized, crossover study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;102:169-74.  Back to cited text no. 7
    
8.
Gregorio LV, Giglio FP, Sakai VT, Modena KC, Colombini BL, Calvo AM, et al. Acomparison of the clinical anesthetic efficacy of 4% articaine and 0.5% bupivacaine (both with 1:200,000 epinephrine) for lower third molar removal. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;106:19-28.  Back to cited text no. 8
    
9.
Oertel R, Rahn R, Kirch W. Clinical pharmacokinetics of articaine. Clin Pharmacokinet 1997;33:417-25.  Back to cited text no. 9
    
10.
Sumer M, Misir F, Celebi N, Muǧlali M. A comparison of injection pain with articaine with adrenaline, prilocaine with phenylpressin and lidocaine with adrenaline. Med Oral Patol Oral Cir Bucal 2008;13:E427-30.  Back to cited text no. 10
    
11.
Malamed SF. Handbook of Local Anaesthesia. 4th ed. St. Louis: Mosby; 1997.  Back to cited text no. 11
    
12.
Wright GZ, Weinberger SJ, Friedman CS, Plotzke OB. Use of articaine local anesthesia in children under 4 years of age a retrospective report. Anesth Prog 1989;36:268-71.  Back to cited text no. 12
    
13.
Jakobs W, Ladwig B, Cichon P, Ortel R, Kirch W. Serum levels of articaine 2% and 4% in children. Anesth Prog 1995;42:113-5.  Back to cited text no. 13
    
14.
Weaver JM. Articaine, a new local anesthetic for American dentists: Will it supersede lidocaine? Anesth Prog 1999;46:111-2.  Back to cited text no. 14
    
15.
Dudkiewicz A, Schwartz S, Laliberté R. Effectiveness of mandibular infiltration in children using the local anesthetic ultracaine (articaine hydrochloride). J Can Dent Assoc 1987;53:29-31.  Back to cited text no. 15
    
16.
Wright GZ, Weinberger SJ, Marti R, Plotzke O. The effectiveness of infiltration anesthesia in the mandibular primary molar region. Pediatr Dent 1991;13:278-83.  Back to cited text no. 16
    
17.
Nordenram A, Danielsson K. Local anaesthesia in elderly patients. An experimental study of oral infiltration anaesthesia. Swed Dent J 1990;14:19-24.  Back to cited text no. 17
    
18.
Oertel R, Ebert U, Rahn R, Kirch W. The effect of age on pharmacokinetics of the local anesthetic drug articaine. Reg Anesth Pain Med 1999;24:524-8.  Back to cited text no. 18
    
19.
Yagiela JA. Local anesthetics: A century of progress. Anesth Prog 1985;32:47-56.  Back to cited text no. 19
    
20.
Kaufman E, Goharian S, Katz Y. Adverse reactions triggered by dental local anesthetics: A clinical survey. Anesth Prog 2000;47:134-8.  Back to cited text no. 20
    
21.
Campbell JR, Maestrello CL, Campbell RL. Allergic response to metabisulfite in lidocaine anesthetic solution. Anesth Prog 2001;48:21-6.  Back to cited text no. 21
    
22.
Finder RL, Moore PA. Adverse drug reactions to local anesthesia. Dent Clin North Am 2002;46:747-57, 10.  Back to cited text no. 22
    
23.
Hillerup S, Jensen R. Nerve injury caused by mandibular block analgesia. Int J Oral Maxillofac Surg 2006;35:437-43.  Back to cited text no. 23
    
24.
Malanin K, Kalimo K. Hypersensitivity to the local anesthetic articaine hydrochloride. Anesth Prog 1995;42:144-5.  Back to cited text no. 24
    
25.
Daubländer M, Müller R, Lipp MD. The incidence of complications associated with local anesthesia in dentistry. Anesth Prog 1997;44:132-41.  Back to cited text no. 25
    
26.
Baluga JC. Allergy to local anesthetics in dentistry. Myth or reality? Rev Alerg Mex 2003;50:176-81.  Back to cited text no. 26
    
27.
Malamed SF, Gagnon S, Leblanc D. Efficacy of articaine: A new amide local anesthetic. J Am Dent Assoc 2000;131:635-42.  Back to cited text no. 27
    
28.
Malamed SF, Gagnon S, Leblanc D. Articaine hydrochloride: A study of the safety of a new amide local anesthetic. J Am Dent Assoc 2001;132:177-85.  Back to cited text no. 28
    
29.
Potocnik I, Tomsic M, Sketelj J, Bajrovic FF. Articaine is more effective than lidocaine or mepivacaine in rat sensory nerve conduction block in vitro. J Dent Res 2006;85:162-6.  Back to cited text no. 29
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13]
 
 
    Tables

  [Table 1]



 

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