Vol. 33 No. 2 February 2007 Journal of Pain and Symptom Management 203

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1 Vol. 33 No. 2 February 2007 Journal of Pain and Symptom Management 203 Original Article A Double-Blind Comparison of a Supplemental Interligamentary Injection of Fentanyl and Mepivacaine with 1:200,000 Epinephrine for Irreversible Pulpitis Eman A. Elsharrawy, MBBCh, MSc, MD, and Yehia M. Elbaghdady, BDS, MDS, PhD Faculty of Dentistry, October 6 University, Cairo, Egypt Abstract The analgesic efficacy of supplemental interligamentary fentanyl injection for management of endodontic debridement patients was investigated through a randomized, double-blind study. Forty patients who presented with acute symptomatic irreversible pulpitis of the upper first molar tooth participated in the study. Patients were scheduled for endodontic debridement, for which infiltration anesthesia with 1.8 ml of 2% mepivacaine with epinephrine 1:200,000 was the standard primary anesthetic technique. Patients were randomly divided into two equal groups. The first group received supplemental interligamentary injection with 0.4 ml fentanyl 0.05 mg/ml, while the second group received supplemental interligamentary injection with 0.4 ml mepivacaine with epinephrine 1:200,000. The intraligamental-injected drug was given as 0.2 ml on the mesial and 0.2 ml on the distal aspect of the tooth. Results indicated that fentanyl provided relatively greater analgesia, yielding satisfactory relief during different stages of the procedure, including access cavity preparation, pulpotomy, and pulp extirpation. Fentanyl is effective when used in conjunction with local anesthetics to provide adequate analgesia during endodontic debridement, and this finding provides strong evidence that peripheral actions are involved in the analgesia produced by opioid drugs in inflammatory pain. J Pain Symptom Manage 2007;33:203e207. Ó 2007 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Fentanyl, mepivacaine, acute pulpitis, interligamentary injection Address reprint requests to: Eman A. Elsharrawy, MBBCh, MSc, MD, Department of Anesthesiology, October 6 University, 19 Mohamed Elmakref Street, Nasr City, Cairo, Egypt. elsharrawy@ hotmail.com Accepted for publication: July 28, Ó 2007 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. Introduction Increased tissue pressure caused by an inflamed pulp is the major cause of painful dental emergencies. 1 Spontaneous severe pain that persists after removal of the stimulus is the most distressing complaint of the patient. 2 Currently, endodontic debridement is a predictable method to relieve pain 3 and satisfactory anesthesia is necessary to render this treatment. 4 Unfortunately, the administration of a local anesthetic by either nerve block or /07/$esee front matter doi: /j.jpainsymman

2 204 Elsharrawy and Elbaghdady Vol. 33 No. 2 February 2007 infiltration does not always produce satisfactory anesthesia of the dental pulp. 5 This may be distressing for both patient and operator. Techniques of anesthesia other than the standard infiltration and regional block techniques may be used, including the use of periodontal ligament, intraosseus, and intrapulpal injection to achieve pulpal anesthesia. 6 Unfortunately, the administration of a local anesthetic solution does not always produce satisfactory anesthesia of the dental pulp, as the inflammatory process may lower local tissue ph, and the acidic media prevents local anesthetic molecules from dissociation into the unionized, lipid-soluble form and migration through neural sheath to produce its effect. 7 Although opioid drugs may be able to provide analgesia at the site of inflammation, 8,9 few previous studies have investigated peripheral opioid analgesic effects in dental disorders. Hargreaves et al. 10 reported that periodontal ligament injection of morphine in patients with apical periodontitis provided more pain relief than saline placebo administration. Also, Uhle et al. 11 found that periodontal ligament injection of fentanyl provided satisfactory analgesia in patients with inflamed pulps. This randomized, controlled study investigated the efficacy of periodontal ligament injection of fentanyl as a supplementary technique combined with a standard local anesthetic technique in management of endodontic debridement. Material and Methods Forty American Society of Anesthesiologists Class I (ASAI) patients presenting with acute symptomatic irreversible pulpitis of the upper first molar tooth were selected from the outpatient clinic, Faculty of Dentistry, October 6 University. The selected patients complained of severe spontaneous pain and painful, prolonged response to thermal stimuli. The teeth were vital and had sensitivity to percussion. The diagnosis was confirmed by using ice tests. No analgesic drugs were permitted prior to the study. The selected patients signed informed consent and the study was performed after approval of the local ethics committee. The selected patients were divided randomly into two equal groups. Patients were assigned their study numbers sequentially as they entered the study. A computer-generated randomization code determined whether mepivacaine or fentanyl was assigned to each patient. Intraligamental injection solutions were prepared prior to the study. Fentanyl cartridges were prepared by removing the rubber plungers from the standard anesthetic cartridges, which were then emptied, washed with tap water, autoclaved, and filled with fentanyl at a concentration of 0.05 mg/ml. All cartridges were blinded by masking the name of drug contained and labeling the cartridge with a random digit number written on white opaque tape. Only the patient s number was an identifier. The patients rated their pain intensity before administration of anesthesia on a fivepoint scale where 0: no pain, 1: mild pain, 2: moderate pain, 3: severe pain, and 4: worst pain that cannot be tolerated. Baseline heart rate, blood pressure, and oxygen saturation were recorded using a noninvasive vital sign monitor (Omni-Trak SVS). All the selected patients received infiltration anesthesia with 1.8 ml of 2% mepivacaine with 1:200,000 epinephrine as a standard primary anesthetic technique. In double-blind fashion, half the patients then received intraligamental supplementary injection with 0.4 ml fentanyl 0.05 mg/ml, and half received intraligamental supplementary injection with 0.4 ml of 2% mepivacaine with 1: 200,000 epinephrine. The injection was delivered as 0.2 ml on the mesial aspect of the tooth, and 0.2 ml on the distal aspect, using a high-pressure ligamaject syringe (Hammacher HAS ) with a 30-gauge needle. If there was no back pressure during the injection, the needle was repositioned, and the injection was repeated until back pressure was obtained. Patients rated their pain intensity during different stages of the procedure: access cavity preparation, pulpotomy, and pulp extirpation. If the patient could not communicate verbally, pain was rated by the number of fingers extended. Safety was detected by continuous monitoring of the patient. Prior to discharge, each patient and the dentist made a global assessment of the efficacy and quality of the anesthesia (poor-satisfactory-excellent). Analysis of the data was performed using the Statistical Package for the Social Sciences. The Mann-Whitney test was used to compare

3 Vol. 33 No. 2 February 2007 Supplementary Interligamentary Injection of Fentanyl 205 the two groups. P-values of #0.05 and #0.001 were used to indicate significant and highly significant differences, respectively. Results Demographic details of the patients revealed no significant differences between the two groups regarding age and sex (Table 1). The fentanyl group reported a highly significant decrease in pain intensity (P < 0.001) during access cavity preparation (mean [M] standard error [SE] ¼ ), pulpotomy (M SE ¼ ), and pulp extirpation (M SE ¼ ) compared to the baseline pain intensity (M SE ¼ ). Also, the mepivacaine group reported a highly significant decrease in pain intensity (P # 0.001) during access cavity preparation (M SE ¼ ), pulpotomy (M SE ¼ ), and pulp extirpation (M SE ¼ ) compared to the baseline pain intensity (M SE ¼ ). On comparing the two groups, there was no significant difference regarding the initial pain intensity (P ¼ ), while highly significant differences were detected between the two groups during different stages of the procedure involving access cavity preparation, pulpotomy, and pulp extirpation (Table 2). The fentanyl group reported a highly significant decrease in pain intensity (P # 0.001) when compared to the mepivacaine group during the different stages of the procedure. All the patients administered fentanyl considered the anesthesia to be excellent and denied feeling any pain. On the other hand, 18 of 20 patients in the local anesthesia group reported some discomfort during the procedure. Two of them considered the anesthesia was poor and the remaining 16 patients considered the anesthesia was adequate. Only 2 of Group First group (Fentanyl) Second group (Mepivacaine) Table 1 Demographic Data of the Patients in the Two Groups Age (mean SD) ; range, 25e ; range, 28e37 Sex (Male:Female) 11:9 12:8 the 20 rated the anesthesia as excellent. The blinded endodontic doctor who gave the intraligamental supplementary injection considered patients in the fentanyl group to be more relaxed and cooperative. There were no clinically or statistically significant hemodynamic changes throughout the study, as presented in Table 3. There were no reported adverse effects in either group. Discussion Opioid drugs have been used in conjunction with local anesthetics in such techniques as spinal and epidural anesthesia. For example, spinal opioids and local anesthetics have been shown to act synergistically at the spinal level when combined with local anesthetics, 12e14 and intra-articular injection of local anesthetics and opioids provided pain control in arthroscopic anterior cruciate ligament reconstruction. 15 Opioid drugs are not commonly used in conjunction with local anesthetics in dentistry 16 and few studies have evaluated peripheral analgesic effects when opioids are injected through periodontal ligament. 10,11 This study was designed to investigate peripheral opioid effects when the opioid is combined with a local anesthetic during the treatment of inflammatory dental pain. The choice of patients with acute symptomatic irreversible pulpitis undergoing endodontic debridement was based on the fact that the inflamed pulp and its consequences are the major causes of painful dental emergencies, and the administration of a local anesthetic solution does not always produce satisfactory anesthesia. 5 In this double-blind, randomized trial, the addition of a very small dose of fentanyl significantly increased analgesia, yielding a degree of pain relief that is clinically meaningful. The findings confirm the importance of peripheral opioid actions in inflammatory pain and suggest the value of this approach for the clinic. Patients with acute symptomatic irreversible pulpitis complain of severe, spontaneous pain, which persists after removal of the stimulus; this pain increases when the patient is in the lying position. 2 Pain is a perception that results from activation of a specific set of receptors by noxious stimuli. Thermal receptors

4 206 Elsharrawy and Elbaghdady Vol. 33 No. 2 February 2007 Time Table 2 Comparison of Pain Intensity Scores Among the Two Groups During the Different Stages of the Endodontic Debridement Mepivacaine PDL Fentanyl PDL n Median Q-Range n Median Q-Range Adjusted P-Value Baseline e e Access cavity preparation e e Pulpotomy e e Pulp extirpation e e PDL ¼ periodontal ligament. respond to temperature changes; mechanoreceptors respond to pressure, tension, and stretch; and chemoreceptors respond to substances released during the inflammatory process, such as prostaglandins, histamine, and bradykinin. 17 The irritants that intensify the inflammatory reactions in acute pulpitis are bacteria, their metabolites, and deposition products of the affected dentine. 2 The satisfactory provision of dental treatment relies on achieving excellent pain control. However, any anesthetic approach must meet certain criteria, especially adequate depth of anesthesia and minimal discomfort during the treatment. 18 A previous study reported that the administration of a local anesthetic solution does not always produce satisfactory anesthesia of the dental pulp. 5 This is in agreement with our study, in which 18 of 20 patients in the local anesthesia group reported some discomfort during the procedure. The explanation for this is that local anesthetic drugs diffuse through the membranes in the form of lipidsoluble uncharged base. At a low ph, less drug dissociates to liberate base and, therefore, higher concentrations are needed to permit diffusion through the nerve sheath to the axons. 7 Inflammatory pain after tissue destruction may be more responsive to peripherally administered opioids. 8,19 These drugs have been used as analgesic medications for management of moderate-to-severe pain. 20 Opioid receptors are present in the central nervous system, but have also been discovered in peripheral primary afferent nerve fibers. 9 With the discovery of peripheral opioid analgesic mechanisms, it is possible to administer these drugs through topical application. 19 Recent clinical studies reported that topical opioids are effective in relieving inflammatory pain. 8,21 Uhle et al. have shown that 10 mg fentanyl delivered via the periodontal ligament injection in inflamed teeth provided significantly greater analgesia than a saline placebo. Our study suggests that 20 mg fentanyl injected through the periodontal ligament provided a greater amount of analgesia than mepivacaine, which continued during different stages of the endodontic debridement procedure. A potential explanation for this prolonged effect is that opioid kinetics are affected by changes in ph. A decrease in Table 3 Hemodynamic Assessment (mean ± SD) Variable Baseline Access Cavity Preparation Pulpotomy Pulp Extirpation Systolic blood pressure First group Second group Diastolic blood pressure First group Second group Heart rate First group Second group Oxygen saturation First group Second group First group ¼ fentanyl group; Second group ¼ mepivacaine group.

5 Vol. 33 No. 2 February 2007 Supplementary Interligamentary Injection of Fentanyl 207 ph leads to ionization of more fentanyl in the interstitial compartment, which will interact with more opioid receptors on the cell membrane, producing an enhanced opioid effect. 22 In conclusion, the periodontal ligament injection of fentanyl as a supplemental technique to the standard local infiltration anesthesia is an effective and reliable technique in the management of endodontic debridement patients. It confirms the importance of peripheral opioid actions and can be used in conjunction with local anesthetics to provide adequate analgesia in the presence of inflammation when local anesthetics become insufficient. References 1. Goodell GG, Gallagher FJ, Nicoll BK. Comparison of a controlled injection pressure system with a conventional technique. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90(1):88e Langeland K. Management of the inflamed pulp associated with deep carious lesion. J Endod 1981;7:169e Keiser K. Strategies for managing the endodontic pain patient. Tex Dent J 2003;120(3):250e Nettis E, Napoli G, Ferrannini A, Tursi A. The incremental challenge test in the diagnosis of adverse reaction to local anesthetics. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;91(4): 402e Meechan JG. Supplementary routes to local anaesthesia. Int Endod J 2002;35(11):885e Wong JK. Adjuncts to local anesthesia: separating fact from fiction. J Can Dent Assoc 2001;67(7): 391e Stabile P, Reader A, Gallatin E, Beck M, Weaver J. Anesthetic efficacy and heart rate effects of the intraosseous injection of 1.5% etidocaine (1:200,000 epinephrine) after an inferior alveolar nerve block. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89(4):407e Ballas SK. Treatment of painful sickle cell leg ulcers with topical opioids. Blood 2002;99(3): 1096e Joris JL, Dubner R, Hargreaves KM. Opioid analgesia at peripheral sites: a target for opioids released during stress and inflammation? Anesth Analg 1987;66(12):1277e Hargreaves K, Keating K, Cathers SJ, Dionne R. Analgesic effects of morphine after PDL injection in endodontic patients. J Dent Res 1991;70:445e Uhle RA, Reader AI, Nist R, et al. Peripheral opioid analgesia in teeth with symptomatic inflamed pulps. Anesth Prog 1997;44(3):90e Kuusniemi KS, Pihlajamaki KK, Pitkanen MT, Helenius HY, Kirvela OA. The use of bupivacaine and fentanyl for spinal anesthesia for urologic surgery. Anesth Analg 2000;91(6):1452e Choi DH, Ahn HJ, Kim MH. Bupivacained sparing effect of fentanyl in spinal anesthesia for cesarean delivery. Reg Anesth Pain Med 2000;25(3): 240e Goel S, Bhardwaj N, Grover VK. Intrathecal fentanyl added to intrathecal bupivacaine for day case surgery: a randomized study. Eur J Anaesthesiol 2003;20(4):294e Tetzlaff JE, Dilger JA, Abate J, Parker RD. Preoperative intra-articular morphine and bupivacaine for pain control after outpatient arthroscopic anterior cruciate ligament reconstruction. Reg Anesth Pain Med 1999;24(3):220e Norholt SE. Treatment of acute pain following removal of mandibular third molars. Use of the dental pain model in pharmacological research and development of a comparable animal model. Int J Oral Maxillofac Surg 1998;27(Suppl 1):1e Lantz GC. Regional anesthesia for dentistry and oral surgery. J Vet Dent 2003;20(3):181e Yonchak T, Reader A, Beck M, Meyers WJ. Anesthetic efficacy of unilateral and bilateral inferior alveolar nerve blocks to determine cross innervation in anterior teeth. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92(2):132e Twillman RK, Long TD, Cathers TA, Mueller DW. Treatment of painful skin ulcers with topical opioids. J Pain Symptom Manage 1999; 17(4):288e Jaffe JH, Martin WR. Opioid analgesics and antagonists. In: Gilman AG, Rall TW, Nics AS, et al, eds. Goodman and Gilman s the pharmacological basis of therapeutics, 8th ed. Elmsford, NY: Pergamon Press, 1990: Machelska H, Mousa SA, Brack A, et al. Opioid control of inflammatory pain regulated by intercellular adhesion molecule-1. J Neurosci 2002;22(13): 5588e Lullmann H, Martins BS, Peters T. ph-dependent accumulation of fentanyl, lofentanil, and alfentanil by beating guinea pig atria. Br J Anaesth 1985;57(10):1012e1017.