Vol. 113 No. 4 April 2012

Vol. 113 No. 4 April 2012 Comparison of 4% articaine with epinephrine (1:100,000) and without epinephrine in inferior alveolar block for tooth extraction: double-blind randomized clinical trial of anesthetic efficacy Peer W. Kämmerer, MD, DMD, 1,a Victor Palarie, DDS, 1,b Monika Daubländer, MD, DDS, PhD, c Constantin Bicer, DDS, d Niloufar Shabazfar, a Dan Brüllmann, DDS, c and Bilal Al-Nawas, MD, DMD, PhD, a Mainz, Germany; and Chisinau, Moldova UNIVERSITY MEDICAL CENTER MAINZ, STATE UNIVERSITY OF MEDICINE AND PHARMACY Objective. The purpose of this clinical prospective, randomized, double-blind study was to compare the anesthetic efficacy of 4% articaine with epinephrine (1:100,000) and without epinephrine in inferior alveolar nerve block anesthesia for extractions of mandibular teeth. Study Design. Eighty-eight patients received intraoral inferior alveolar nerve blocks using 4% articaine with 1:100,000 epinephrine (n 41; group 1) or without epinephrine (n 47; group 2) for extractions of mandibular teeth. The primary objectives were differences in onset as well as in length of soft tissue anesthesia. The amount of anesthetic solution, need of a second injection, pain while injecting, pain during treatment, postoperative pain, and possible complications were surveyed. Results. In both groups, anesthesia was sufficient for dental extractions. In group 1, a significantly faster onset of the anesthetic effect (7.2 min vs. 9.2 min; P.001) and a significantly longer duration of soft tissue anesthesia (3.8 h vs. 2.5 h; P.0001) were seen. There was no significant difference in the amount of anesthetic solution needed, in the need for a second injection, in the injection pain, in pain during treatment, or in postoperative analgesia. In both groups, no complications were seen. Conclusions. To minimize the epinephrine-induced side effects, 4% articaine without epinephrine is a suitable anesthetic agent for dental extractions in the mandible after inferior alveolar nerve block anesthesia. There could be less postoperative discomfort due to the shorter duration of anesthesia without increased postoperative pain. (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;113:495-499) Articaine is a common local anesthetic agent (LA). 1 Its thiophene ring confers greater lipid solubility than lidocaine, which allows enhanced diffusion through nerve sheaths. It also has an increased potency compared with lidocaine. Evidence suggests that it is the LA that best diffuses within soft and hard tissues. 2 The ester side chain of articaine is hydrolyzed by plasma esterases rendering the molecule inactive. This results in a short half-life of 20 minutes compared with 90 minutes for other amides (e.g., lidocaine) that require hepatic clearance. 3 Accordingly, it was suggested that articaine does not possess any relevant side effects or gross toxicity. 4 a Department of Oral and Maxillofacial Surgery, University Medical Center Mainz. b Clinic of Oral and Maxillofacial Surgery, Implantology, and Orthopedic Stomatology, State University of Medicine and Pharmacy, Chisinau. c Department of Oral Surgery, University Medical Center Mainz. d Unit of Oral Surgery, Polyclinic of Stomatology, State University of Medicine and Pharmacy, Chisinau. Received for publication Feb. 10, 2011; returned for revision Mar. 26, 2011; accepted for publication Apr. 29, 2011. 2012 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter doi:10.1016/j.tripleo.2011.04.037 1 The first 2 authors contributed equally to this work. Dental LA are often combined with vasoconstrictors, such as epinephrine, to increase depth and duration of analgesia. 5 They also provide hemostasis and concentrate the agent at the injection site, which results in decrease of systemic toxicity (i.e., dose-dependent depression of the central nervous system) of the corresponding LA. It has been shown that when using articaine, adverse reactions occur mainly due to the amount of vasoconstrictor in the LA solution. 6 Even small doses of epinephrine in LA have an influence on cardiovascular function. 3 Physiologic responses of solutions containing a vasoconstrictor include changes in heart rate and blood pressure. 7-9 Other known side effects are cardiac dysrrhythmia 10 as well as cardiac ischemic changes, 11-13 a further release of endogenous catecholamines, 14 and hypokalemia. 15 Flu-like symptoms 16 and potentiation of adverse drug reactions 17 also have been reported. Although most current literature accepts epinephrine to have a safety range, 18 its threshold of concentration remains unclear. 19,20 It can be concluded that, if the vasoconstrictor-induced physiologic events exceed the normal range, an increase in morbidity or even mortality can be observed. 13 Because LA administration can be as stressful as the operative procedure, an LA with none or at least modest cardiovascular 495

ORAL AND MAXILLOFACIAL SURGERY OOOO 496 Kämmerer et al. April 2012 effects (as less vasoconstrictor as possible) would be preferable. 6,13,21-24 Owing to its low systemic toxicity, routine use of articaine without vasoconstrictor can be considered. Of course, this has to be limited to cases in which the duration of treatment is short and the epinephrine-induced hemostasis may not be necessary, such as conservative treatment or less complicated dental extractions. The primary objectives of the present study were to compare the differences in time of onset and length of soft tissue anesthesia of 4% articaine with (1:100,000) epinephrine and 4% articaine without epinephrine when used in inferior alveolar nerve block for dental extractions. The secondary objectives were to compare descriptively the amount of anesthetic solution, the need of a second injection, pain while injecting, pain during treatment, postoperative pain, and other possible complications. MATERIALS AND METHODS Eighty-eight patients (male 43, female 45) in need of single tooth extraction owing to caries and/or periodontitis in the mandible were included in this prospective, randomized, double-blinded, confirmatory analysis study. 25 The study took place at the State University of Medicine and Pharmacy of Moldova between January 2009 and December 2009 after approval by the local Ethics Committee. Equal randomization was achieved with the use of a computer-generated random number list. Inclusion criteria for the study were all patients who required single tooth extractions in the mandibular arch. Signed inform consent was obtained from every patient included in the study. The exclusion criteria were as follows: cardiovascular instability, including unstable angina pectoris, recent myocardial infarction ( 6 months), refractory dysrrythmias, untreated or uncontrolled hypertension, uncontrolled diabetes mellitus, sulfite sensitivity or allergy to any part of the solution, steroid-dependent asthma, pheochromacytoma, tricyclic antidepressant treatment, and history of psychiatric illness. Patients requiring open surgical extractions and with infected teeth were excluded from the study. The mean age of patients was 36.7 years (range 18-80, SD 12.6). Twenty-six patients (29.5%) had tooth pain before treatment, of which 18 patients (20%) took pain medication (ibuprofen 17, aspirin 1). Concomitant diseases were hypertension (n 3), carcinoma in remission (n 2), hepatitis (n 2), epilepsy (n 1), hypothyroidism (n 1), and migraine (n 1). In each patient, 1 tooth in the mandible was extracted. The affected teeth were #38 (n 18), #46 (n 15), #48 (n 13), #47 (n 12), #36 (n 9), #7 (n 8), #45 (n 6), #35 (n 3), #34 (n 2), and #44 (n 2). All patients were examined clinically and radiographically (panoramic x-ray). No presence of acute or chronic oral infections was seen. In all cases, articaine 4% was given as local anesthetic. In 41 cases (40.2%, group 1) an epinephrine adjuvant of 1:100,000 (Ultracaine D-S Forte; Sanofi-Aventis, Frankfurt, Germany) was used. Forty-seven patients (46%, group 2) received articaine solution without epinephrine (Ultracaine D; Sanofi- Aventis). A dental nurse gave the different solutions in identical syringes (2 ml) marked with the patient s randomization number only. The blinding was rendered when evaluating the data. The same LA was used in second and repeated injections. Treatment protocol In all cases, an inferior alveolar nerve block with direct access of the cannula to the injection site was administered as previously described. 26 An additional buccal nerve block to obtain vestibular soft tissue anesthesia was administered. The required amount of local anesthetic was estimated clinically via patients characteristics (body weight and constitution). Two milliliters was available in each syringe. The duration of injection was standardized to 1 minute per syringe. Dental extraction was performed after full anesthesia, tested with a probe on the vestibular mucosa and oral gingiva and on the tooth itself each minute after injection, and after subjective symptoms of numbness by the patient. If a patient declared full numbness (i.e., soft tissue anesthesia), the onset was subsequently tested. Time taken to reach complete anesthesia was evaluated with a stop watch. The injection as well as the treatment was performed by 2 experienced dentists. Repeated injections were given if the patient reported pain during treatment. Need of a second injection and injected amount of LA were noted for each patient. After extraction, the gingiva was adapted over the alveolae with sutures. After treatment, the subjective efficiency of anesthesia by means of pain while injecting and pain during treatment were collected via questionnaire. Pain was rated by visual analog scale (VAS) from 0 (no pain) to 10 (worst pain). Patients were recommended to take 1 tablet of paracetamol (1,000 mg) 6 hours after operation. 27 Patients were instructed to monitor the time of fading of soft tissue anesthesia as well as unexpected bleeding events ( 30 minutes of bleeding, excessive bleeding). The patients were contacted via telephone on the first postoperative day. Fading of soft tissue anesthesia with exact time, the postoperative pain (VAS), and possible bleeding complications were documented. Statistics A prior calculation showed a sample size of 27 in each group to be sufficient to achieve a study power of 90%. The primary objectives were differences in soft tissue anesthesia, measured from onset to full anesthesia

OOOO ORIGINAL ARTICLE Volume 113, Number 4 Kämmerer et al. 497 Fig. 1. Boxplots comparing the time until full anesthetic effect between group 1 (with epinephrine 1:100,000) and group 2 (without epinephrine). Without epinephrine, the time was significant longer (P.001). Fig. 2. Boxplots comparing the duration of anesthetic effect between group 1 (with epinephrine 1:100,000) and group 2 (without epinephrine). Without epinephrine, the duration was significant shorter (P.0001). (min) as well as length of anesthesia (min). Here, a Fisher test was used to examine the statistical significance of the differences. Because of multiple testing, a Bonferroni correction was used. Therefore, a difference was seen to be statistically significant if P.025. The further analyses were regarded as explorative, and the P values of the corresponding tests are presented for descriptive reasons only. To compare amount of anesthetic solution (ml), pain while injecting (VAS), pain during treatment (VAS), and postoperative pain (VAS), 2-tailed 2 -tests were used. Differences in need of a second injection were calculated with Fisher exact test. All analyses were performed with SPSS version 16.0 (SPSS, Chicago, IL). RESULTS The mean time of extraction from beginning of total anesthesia to end of the operation with sutures was 14.4 minutes (SD 13.92 min). In all cases the operation was finished successfully. Primary objectives In group 1, the mean time between injection and full anesthetic effect was 7.2 minutes (SD 2.97 min). In group 2, it took 9.2 minutes (SD 2.7 min). In group 1, the effect could be seen significantly earlier (P.001; Fig. 1) and the mean duration of anesthesia was 3.8 hours (SD 0.57 h), whereas in group 2, the duration was significantly shorter (2.5 h; SD 0.97 h; P.0001; Fig. 2). Secondary objectives In group 1, 1.86 ml (SD 0.17 ml) of LA was primarily injected, whereas in group 2, 1.94 ml (SD 0.23 ml) was used. There was no significant difference between the 2 groups (P.202). In 70 cases (79.5%; group 1: n 34 (82.9%); group 2: n 36 (76.6%)) a single injection was seen to be sufficient. No significant difference between the groups was detected (P.461). For injection pain, in group 1, the mean VAS score was 2.56 (SD 1.41), and in group 2 it was 2.72 (SD 1.84). The difference was not significant (P.647). For pain during treatment, a mean VAS score of 0.8 (SD 1.54) was evaluated in group 1. In group 2, a mean VAS score of 0.79 (SD 1.08) was seen. There was no significant difference between the 2 groups (P.95). For postoperative pain, a mean VAS score of 0.4 (SD 0.5) was evaluated in group 1. In group 2, a mean VAS score of 0.3 (SD 0.4) was observed. This difference was not significant (P.96). DISCUSSION To our knowledge, this is the first study comparing 4% articaine with (1:100,000) and without vasoconstrictor after inferior alveolar nerve block in a clinical situation, such as tooth extraction. A reduction of the vasoconstrictor epinephrine for block anesthesia may be favorable to minimize potential side effects. 22 Owing to the low toxicity of articaine, even without the use of epinephrine, it seems to be reasonable for treatments with short duration in oral surgery. Significant differences were detected in time of onset and duration of action. The onset described in literature 24 as well as the anesthetic duration of 4% articaine with 1:100,000 epinephrine in inferior alveolar nerve block anesthesia 28,29 are in accordance with our results. It has been shown that vasoconstrictor concentration may influence anesthetic diffusion owing to a slower absorption rate. 30 This explains the longer time of onset

ORAL AND MAXILLOFACIAL SURGERY OOOO 498 Kämmerer et al. April 2012 as well as the shorter duration of 4% articaine without vasoconstrictor, though this fact does not seem to exist for infiltration anesthesia. 31 In our study, the mean duration of anesthesia was enough for a tooth extraction in both groups. It could be shown that there are no differences in amount of LA, in the need for a second injection and in anesthetic success rate [pain while injecting (with different ph values), pain during treatment, and postoperative pain] between the 2 groups. In an experimental setting, Petrikas et al. 32 described that articaine without vasoconstrictor has no prospects in application in endodontology due to its lacking pulp anesthesia. In an experimental trial, Moore et al. 31 observed an unsatisfactory success rate of articaine without epinephrine. It has to be kept in mind that neither pulpal anesthesia nor the duration of pulpal anesthesia were tested separately in the present study. All pain measurements were done subjectively considering soft tissue anesthesia. Accordingly, higher ratings of success may be possible. Clinically satisfactory results for anesthesia for tooth extraction were obtained with both solutions, and no significant differences between them were seen in the present study. No adverse reactions were observed by the surgeon or reported by the patients the day after surgery. This finding is in accordance with the known low allergenic and toxic potential of articaine. 6 However, it has to be kept in mind that a follow-up period of 1 day may be too short to observe later complications. Because the amount of LA used in inferior alveolar nerve block in both groups is normal 24,29 and the subjective pain experiences were not different, a further use of 4% articaine without epinephrine may be recommended for this clinical situation. CONCLUSIONS Differences between the 2 solutions were seen in terms of time of onset as well as in duration of anesthesia. Four percent articaine solution without epinephrine does not seem to influence the clinical efficacy in terms of several anesthetic properties (need of second injection, injection pain, intra- and postoperative pain). Because the duration of the LA without epinephrine is shorter and postoperative pain is the same, this could add to increased patient comfort after treatment. Therefore, it is possible to successfully use the 4% articaine without epinephrine formulation for dental extractions in the mandible after inferior alveolar nerve block. REFERENCES 1. 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. 2. Vree TB, Gielen MJ. Clinical pharmacology and the use of articaine for local and regional anaesthesia. Best Pract Res Clin Anaesthesiol 2005;19:293-308. 3. Becker DE, Reed KL. Essentials of local anesthetic pharmacology. Anesth Prog 2006;53:98-108; Quiz:9-10. 4. Leuschner J, Leblanc D. Studies on the toxicological profile of the local anaesthetic articaine. Arzneim Forschung 1999; 49:126-32. 5. Jastak JT, Yagiela JA. Vasoconstrictors and local anesthesia: a review and rationale for use. J Am Dent Assoc;19883:623-30. 6. Santos CF, Modena KC, Giglio FP, et al. Epinephrine concentration (1:100,000 or 1:200,000) does not affect the clinical efficacy of 4% articaine for lower third molar removal: a doubleblind, randomized, crossover study. J Oral Maxillofac Surg 2007;65:2,445-52. 7. Cheraskin E, Prasertsuntarasai T. Use of epinephrine with local anesthesia in hypertensive patients. IV. Effect of tooth extraction on blood pressure and pulse rate. J Am Dent Assoc 1959; 58:61-8. 8. Goldstein DS, Dionne R, Sweet J, et al. Circulatory, plasma catecholamine, cortisol, lipid, and psychological responses to a real-life stress (third molar extractions): effects of diazepam sedation and of inclusion of epinephrine with the local anesthetic. Psychosom Med 1982;44:259-72. 9. Mochizuki M, Yokota S, Murata Y, et al. Changes in heart rate and blood pressure during dental procedures with local anesthesia. Anesth Prog 1989;36:234-5. 10. Ryder W. The electrocardiogram in dental anaesthesia. J Anesth 1970;25:46-62. 11. Hasse AL, Heng MK, Garrett NR. Blood pressure and electrocardiographic response to dental treatment with use of local anesthesia. J Am Dent Assoc 1986;113:639-42. 12. Vanderheyden PJ, Williams RA, Sims TN. Assessment of ST segment depression in patients with cardiac disease after local anesthesia. J Am Dent Assoc 1989;119:407-12. 13. Elad S, Admon D, Kedmi M, et al. The cardiovascular effect of local anesthesia with articaine plus 1:200,000 adrenalin versus lidocaine plus 1:100,000 adrenalin in medically compromised cardiac patients: a prospective, randomized, double blinded study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:725-30. 14. Edmondson HD, Roscoe B, Vickers MD. Biochemical evidence of anxiety in dental patients. BMJ 1972;4:7-9. 15. Kubota Y, Toyoda Y, Kubota H, Asada A. Epinephrine in local anesthetics does indeed produce hypokalemia and ECG changes. Anesth Analg 1993;77:867-8. 16. Petitpain N, Goffinet L, Cosserat F, Trechot P, Cuny JF. Recurrent fever, chills, and arthralgia with local anesthetics containing epinephrine-metabisulfite. J Clin Anesth 2008;20:154. 17. Goulet JP, Perusse R, Turcotte JY. Contraindications to vasoconstrictors in dentistry: part III. Pharmacologic interactions. Oral Surg Oral Med Oral Pathol 1992;74:692-7. 18. Cioffi GA, Chernow B, Glahn RP, Terezhalmy GT, Lake CR. The hemodynamic and plasma catecholamine responses to routine restorative dental care. J Am Dent Assoc 1985;111:67-70. 19. Niwa H, Sugimura M, Satoh Y, Tanimoto A. Cardiovascular response to epinephrine-containing local anesthesia in patients with cardiovascular disease. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:610-6. 20. Bader JD, Bonito AJ, Shugars DA. A systematic review of cardiovascular effects of epinephrine on hypertensive dental patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;93:647-53. 21. Yagiela JA. Adverse drug interactions in dental practice: interactions associated with vasoconstrictors. Part V of a series. J Am Dent Assoc 1999;130:701-9.

OOOO ORIGINAL ARTICLE Volume 113, Number 4 Kämmerer et al. 499 22. Lipp M, Dick W, Daublander M, Fuder H, Stanton-Hicks M. Exogenous and endogenous plasma levels of epinephrine during dental treatment under local anesthesia. Reg Anesth 1993;18:6-12. 23. Meechan JG, Jastak JT, Donaldson D. The use of epinephrine in dentistry. J Can Dent Assoc 1994;60:825-8; 31-4. 24. Tofoli GR, Ramacciato JC, de Oliveira PC, Volpato MC, Groppo FC, Ranali J, et al. Comparison of effectiveness of 4% articaine associated with 1:100,000 or 1:200,000 epinephrine in inferior alveolar nerve block. Anesth Prog 2003;50:164-8. 25. Schulz KF, Altman DG, Consort MD. Statement: updated guidelines for reporting parallel group randomised trials. BMC Med 2010;8:18. 26. Malamed SF. Handbook of local anesthesia. 4th ed. St. Louis; Mosby;1997. 27. Kämmerer PW, Al-Nawas B. The surgical removal of wisdom teeth. Quintessenz 2010;61:1329-36. 28. Sierra-Rebolledo A, Delgado-Molina E, Berini-Aytis L, Gay- Escoda C. 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. 29. Lemay H, Albert G, Helie P, et al. Ultracaine in conventional operative dentistry. J Can Dent Assoc 1984;50:703-8. 30. Lima-Júnior JL, Dias-Ribeiro E, de Araújo TN, Ferreira-Rocha J, Honfi-Júnior ES, Sarmento CF, et al. Evaluation of the buccal vestibule-palatal diffusion of 4% articaine hydrochloride in impacted maxillary third molar extractions. Med Oral Patol Oral Cir Bucal 2009;14:E129-32. 31. Hersh EV, Moore PA, Papas AS, Goodson JM, Navalta LA, et al, for the Soft Tissue Anesthesia Recovery Group. The anesthetic efficacy of 4 percent articaine 1:200,000 epinephrine: two controlled clinical trials. J Am Dent Assoc 2006;137:1572-81. 32. Petrikas A, Egorova VA, Ermilova KV. Articaine and adrenaline combinations efficacy for dental anesthesia. In: Stomatologiia (Mosk); 2009;88:24-6. Reprint requests: Peer W. Kämmerer, MD, DMD Department of Oral and Maxillofacial Surgery University Medical Center Mainz Augustusplatz 2 55131 Mainz Germany peer.kaemmerer@unimedizin-mainz.de