ANESTHESIA/FACIAL PAIN
Dexmedetomidine Dose-Dependently Enhances Local Anesthetic Action of Lidocaine Kentaro Ouchi, DDS, PhD,* Yoshihisa Koga, MD, PhD,y Shinichi Nakao, MD, PhD,z and Kazuna Sugiyama, DDS, PhDx The combination of a2-adrenoceptor agonists, such as dexmedetomidine (DEX) and clonidine, with local anesthetics has been found to extend the duration of peripheral nerve blocks, probably owing to the resultant local vasoconstriction in the peripheral nerves. However, because the clear elucidation of the effect of DEX requires examination of the local anesthetic effect with DEX alone and the combination of various concentrations of DEX with local anesthetics, we evaluated the local anesthetic effect of various concentrations of DEX alone and with a local anesthetic.
Purpose:
Materials and Methods:
The present study assessed the tail-flick (TF) latencies after injection of the appropriate drug in male Sprague-Dawley rats, using an epidural model that allowed constant pain stimulation intensity, dispersion of the anesthetic, and a precise injection site and dose. Lidocaine alone, lidocaine with 2.5-ppm DEX, lidocaine with 5.0-ppm DEX, lidocaine with 7.5-ppm DEX, and DEX alone were administered at the predetermined dose. The TF latency changes over time were compared using repeated measures analysis of variance (ANOVA). Comparisons among the groups were analyzed using ANOVA followed by a post hoc Dunnett’s multiple comparison test or Tukey’s multiple comparison test.
Results:
The addition of DEX to lidocaine increased the TF latency and dose-dependently prolonged its duration as follows: 0-ppm DEX, 20 minutes; 2.5-ppm, 40 minutes; 5.0-ppm, 40 minutes; and 7.5-ppm, 50 minutes. DEX alone did not change the TF latency.
Conclusions: Our results have demonstrated that DEX dose-dependently enhances the local anesthetic action of lidocaine in a rat TF model. Crown Copyright Ó 2014 Published by Elsevier Inc on behalf of the American Association of Oral and Maxillofacial Surgeons. All rights reserved J Oral Maxillofac Surg 72:474-480, 2014
Dental local anesthetics contain vasoconstrictors, such as epinephrine and felypressin, to enhance the anesthetic effects and reduce bleeding in the surgical field.1 Several reports have warned against the use of local
dental anesthetics containing epinephrine in patients with cardiovascular disease.1-5 Therefore, felypressin, a noncatecholamine vasopressor chemically related to vasopressin, has been used as a safe vasoconstrictor in
*Assistant Professor, Department of Dental Anesthesiology, Field
was the subject of a report published in the Journal of Japanese
of Oral and Maxillofacial Rehabilitation, Kagoshima University
Dental Society of Anesthesiology.
Graduate School of Medical and Dental Sciences, Kagoshima, Japan. yProfessor Emeritus, Department of Anesthesiology, Kinki
Address correspondence and reprint requests to Dr Ouchi: Department of Dental Anesthesiology, Field of Oral and Maxillofacial
University Faculty of Medicine, Higashi-Osaka City, Japan.
Rehabilitation, Kagoshima University Graduate School of Medical
zProfessor and Chairman, Department of Anesthesiology, Kinki
and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544,
University Faculty of Medicine, Higashi-Osaka City, Japan.
Japan; e-mail: [email protected]
xProfessor and Chairman, Department of Dental Anesthesiology,
Received August 16 2013
Field of Oral and Maxillofacial Rehabilitation, Kagoshima University
Accepted September 24 2013
Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Crown Copyright Ó 2014 Published by Elsevier Inc on behalf of the American
This work was supported by the departmental research fund of Kinki University.
Association of Oral and Maxillofacial Surgeons. All rights reserved 0278-2391/13/01231-7$36.00/0
This study was previously presented, in part, at the Annual
http://dx.doi.org/10.1016/j.joms.2013.09.038
Meeting of the Japanese Dental Society of Anesthesiology, October 8, 2010, Yokosuka, Japan, and October 8, 2011, Kobe, Japan, and
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patients with compromised cardiovascular status in Japan and European Union nations.5,6 However, reports have been published that the clinical doses of felypressin are capable of inducing myocardial ischemia during surgery,7 and in a dog study, clinical doses of felypressin caused decreases in the coronary blood flow.8 Hence, a new drug is needed that can replace epinephrine and felypressin for the safe enhancement of the local anesthetic effect in patients with cardiovascular disease. The use of a2-adrenoceptor agonists during anesthesia produces sympatholytic, sedative, analgesic, antihypertensive, bradycardiac, and anesthetic-sparing effects.9,10 The a2-adrenoceptor agonists, dexmedetomidine (DEX) and clonidine, when combined with a local anesthetic agent, have been found to extend the duration of peripheral nerve blocks. This action has been suggested to be due to local vasoconstriction in the peripheral nerves.10-15 We hypothesized that if vasoconstriction is the explanation for the sustained effect of local anesthetics with the addition of DEX, the effect should be dose-dependent. The aim of the present study was to determine whether DEX itself exerts a local anesthesia effect, and the appropriate concentration of DEX to add to a local anesthetic to enhance the potency and duration of action. We examined the local anesthetic effect of various concentrations of DEX both with and without lidocaine, using a sedated tail-flick (TF) and epidural animal model that has been reported to be an appropriate method for assessing the effects of local anesthesia.
Materials and Methods ANIMALS
With approval from the Animal Care and Use Committee of Kinki University Faculty of Medicine in April 2010 (approval no. KAME-21-011), 10- to 12-week-old male Sprague-Dawley rats weighing 340 to 420 g (a total of 60 rats both experiments 1 and 2), purchased from Japan SLC (Shizuoka, Japan), were used in the present study. The rats were maintained under controlled conditions (temperature 23 0.5 C, humidity 55%, and a 12/12-hour light/dark cycle) and fed a commercial diet (CE-2, CLEA Japan, Tokyo, Japan), with tap water ad libitum. The experiments were performed from 12:00 to 5:00 PM under controlled conditions (temperature 23 0.5 C). All procedures were conducted at the Life Science Research Institute (Kinki University Faculty of Medicine). The epidural space was cannulated with a Teflonlined polyethylene tube (0.3-mm outer diameter and 0.11-mm inner diameter, Microspinal Catheter, Hakko, Nagano, Japan) using a method reported by Ouchi et al.16 In brief, the rats were anesthetized by inhalation of 2% isoflurane in oxygen with a mask. The epidural space was exposed at the level of the atlanto-occipital
membrane under a stereoscopic microscope, without causing leakage of the cerebrospinal fluid. The catheter was passed through a slit in the atlanto-occipital membrane and inserted caudally for a distance of 11 cm. A preliminary rat dissection experiment had indicated that this was the length of catheter insertion required to reach the L5–L6 intervertebral space from the atlanto-occipital membrane. The other end of the catheter was fixed in the subcutaneous tissue to avoid dislocation of the catheter. One week later, the rats were examined for evidence of sensory or motor dysfunction; those with dysfunction were eliminated from the present study. On completion of both experimental series, all catheterized rats were sacrificed by an epidural injection of 30 mL indigo carmine followed by a lethal dose of pentobarbital injected into the peritoneum. The location of the catheter tip and distribution of the dye in the epidural space were verified after removal of the vertebrae. AGENTS
Lidocaine (lidocaine hydrochloride) was purchased from Astra Zeneca (Osaka, Japan). DEX (Precedex), a specific a2-adrenoceptor agonist, was purchased from Maruishi Pharmaceutical (Osaka, Japan). All drugs were dissolved and diluted with saline. TF TEST
A TF measuring device (model 7360, Ugo Basile, Varese, Italy) was used to measure the TF latency after epidural administration of the study drugs. The stimulator consisted of an infrared power source (8 V, 50 W, Halogen ‘‘Bellaphot,’’ model 64607, Osram Licht AG, Munich, Germany) with an adjustable intensity (maximum 20 W) from 10 in to 99 in 1-digit increments. The rats were placed in a plastic box (22 6.5 6.5 cm). The rats were sedated by inhalation of 1.0% isoflurane for 20 minutes, with monitoring of the rats to assess their inspired gas concentration. An area on the ventral surface of the distal 5 cm to 6 cm of the tail was placed over a 0.5-cm hole in an aluminum box, and an infrared radiant (IR) bulb was placed beneath the hole. In each trial, different points at 5mm intervals on the tail were exposed to the IR bulb, and a 10-second cutoff was used to minimize the risk of tissue damage. The rectal temperature of the anesthetized rats was measured using a thermocouple and was maintained at 36 to 38 C by a thermal plate connected to a feedback warmer placed beneath the box. EXPERIMENT 1: EVALUATION OF EFFECT OF ADMINISTRATION OF VARIOUS DEX CONCENTRATIONS ON LOCAL ANESTHETIC EFFECT OF EPIDURAL LIDOCAINE
A total of 48 rats that had been implanted with an epidural catheter were randomly divided into 4 groups
476 (n = 12 each) as follows: 2% lidocaine alone (0-ppm), 2.5-ppm DEX with 2% lidocaine (2.5-ppm), 5.0-ppm DEX with 2% lidocaine (5.0-ppm), and 7.5-ppm DEX with 2% lidocaine (7.5-ppm). The TF latency was used to calculate the maximum possible effect (MPE) of the local anesthetic according to the following formula: %MPE = [(test latency)(baseline latency)/(cutoff time)(baseline latency)] 100. After epidural injection of 30 mL of the respective test drugs, the TF latency was tested in each rat at 10-minute intervals for 60 minutes (Fig 1). The TF latency was then evaluated as the %MPE. EXPERIMENT 2: EVALUATION OF LOCAL ANESTHESIA EFFECT OF DEX ALONE
A total of 12 rats implanted with an epidural catheter were evaluated. After epidural injection of 30 mL of 5.0-ppm DEX alone (this was the concentration of DEX shown to produce effective enhancement of the local anesthetic action of lidocaine in experiment 1), each rat was tested at 10-minute intervals for 60 minutes (Fig 1). The TF latency was then evaluated as the %MPE. STATISTICAL ANALYSIS
The TF latency changes over time were compared using repeated measures analysis of variance (ANOVA), and the comparisons among the groups were analyzed using ANOVA followed by a post hoc Dunnett’s multiple comparison test or Tukey’s multiple comparison test, as indicated. Statistical analysis was performed using Prism 5 for Windows, version 5.01 (GraphPad Software, San Diego, CA). The significance level was set at P < .05.
DEXMEDETOMIDINE ENHANCES LOCAL LIDOCAINE ACTION
7.5-ppm groups. In the 0-ppm group, the TF latency (%MPE) increased significantly from immediately after injection until 20 minutes thereafter compared with the baseline values (P < .05). In the 2.5-ppm group, the TF latency increased significantly from immediately after until 40 minutes after the injection compared with baseline (P < .05). In the 5.0-ppm group, the TF latency increased significantly from immediately after until 40 minutes after the injection compared with baseline (P < .05). In the 7.5-ppm group, the TF latency increased significantly from immediately after until 50 minutes after the injection compared with baseline (P < .05; Fig 2). Measurement of the diachronic TF latency showed that the increase in the duration of TF latency was different for the different concentrations of DEX (Table 1). The magnitude of TF latency (assessed as the %MPE) was also different for the various DEX concentration groups. In the 2.5-ppm group, the increase in TF latency was significantly different during the 20 to 40 minutes after epidural drug administration compared with that in the 0-ppm group (P < .05). In the 5.0-ppm group, the increase was also significantly different during the 20- to 40-minute period compared with that in the 0-ppm group (P < .05) and at 40 minutes compared with that in the 2.5-ppm group (P < .05). In the 7.5-ppm group, the increase in TF latency was significantly different during the 20- to 50-minute postinjection period compared with that in the 0-ppm group (P < .05), at 40 to 50 minutes compared with that in the 2.5-ppm group (P < .05), and at 50 to 60 minutes compared with that in the 5.0-ppm group (P < .05; Table 2).
Results EXPERIMENT 1: EVALUATION OF EFFECT OF ADMINISTRATION OF VARIOUS DEX CONCENTRATIONS ON LOCAL ANESTHETIC EFFECT OF LIDOCAINE
No significant difference was found in the baseline TF latency among the 0-ppm, 2.5-ppm, 5.0-ppm, and
EXPERIMENT 2: EVALUATION OF LOCAL ANESTHETIC EFFECT OF DEX ALONE
The course of TF latency (%MPE) did not show any significant changes during the observation period when 5.0-ppm DEX was epidurally injected alone, without lidocaine (Fig 3).
FIGURE 1. Experimental schedule. In experiment 1, rats in the 0-ppm, 2.5-ppm, 5.0-ppm, and 7.5-ppm groups received an epidural injection of 30 mL 2% lidocaine alone, 2.5-ppm DEX with 2% lidocaine, 5.0-ppm DEX with 2% lidocaine, or 7.5-ppm DEX with 2% lidocaine, respectively. In experiment 2, the rats received an epidural injection of 30 mL of 5.0-ppm DEX alone. After epidural injection, the TF latency in each rat was tested at 10-minutes intervals for 60 minutes. Ouchi et al. Dexmedetomidine Enhances Local Lidocaine Action. J Oral Maxillofac Surg 2014.
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FIGURE 2. Effect of various concentrations of DEX administered with the local anesthetic lidocaine. *P < .05 compared with baseline; +P < .05 compared with the 0-ppm group; #P < .05 compared with the 2.5-ppm group; $P < .05 compared with the 5.0-ppm group. Closed squares, open squares, closed circles, and open circles show the TF latency from baseline (before administration) to 60 minutes after epidural drug administration in the 0-ppm, 2.5-ppm, 5.0-ppm, and 7.5-ppm groups, respectively. In the 0-ppm group, TF latency increased significantly immediately after injection compared with baseline (P < .05), with the increase lasting 20 minutes. In the 2.5-ppm group, TF latency increased significantly immediately after injection compared with baseline (P < .05), with the increase lasting 40 minutes and significantly different from 20 to 40 minutes after injection compared with that in the 0-ppm group (P < .05). In the 5.0-ppm group, TF latency increased significantly immediately after injection compared with baseline (P < .05), with the increase lasting for 40 minutes and significantly different during the 20- to 40-minute postinjection period compared with that in the 0-ppm group (P < .05) and at 40 minutes compared with that in the 2.5-ppm group (P < .05). In the 7.5-ppm group, TF latency increased significantly immediately after injection compared with baseline (P < .05), with the increase lasting 50 minutes and significantly different at 20 to 50 minutes after injection compared with that in the 0-ppm group (P < .05), at 40 to 50 minutes compared with that in the 2.5-ppm group (P < .05), and at 50 to 60 minutes compared with that in the 5.0-ppm group (P < .05). Ouchi et al. Dexmedetomidine Enhances Local Lidocaine Action. J Oral Maxillofac Surg 2014.
EPIDURAL CATHETER POSITION
On completion of the experimental series, the rats were sacrificed. In all rats, the tip of the catheter had been placed caudal to the lumbar vertebrae at the L4–L6 level.
Discussion New drugs that can replace epinephrine and felypressin for the safe enhancement of the local anesthetic effect in patients with cardiovascular diseases are required. a2-Adrenoceptor agonists, such as DEX, which produce sympatholytic, sedative, analgesic, antihypertensive, and bradycardiac effects when combined with a local anesthetic agent, have been found to extend the duration of the local anesthetic effect by causing local vasoconstriction. We hypothesized that if the local anesthetic reinforcement action of DEX depends on local vasoconstriction, prolongation of the local anesthetic effect should be concentrationdependent. In the present study, we examined the local anesthetic effect of various concentrations of DEX administered with and without lidocaine, using a sedated TF and epidural animal model that has been reported to be an appropriate method for assess-
ing the effect of local anesthesia. Our results have demonstrated that DEX dose-dependently enhanced the local anesthetic action of lidocaine. Evaluating the effectiveness of local anesthetics necessitates an in vivo model to precisely detect the amount of pain relief achieved after noxious stimulation.16 Various animal models have been used to examine the different clinical effects and durations of various local anesthetic agents. Noxious stimulation can be achieved using various methods, including Table 1. DURATION OF INCREASED TF LATENCY
DEX Concentration (ppm) 0 2.5 5.0 7.5
Duration (min) 20 40 40 50
In each concentration group, the TF latency (%MPE) increased significantly from immediately after injection until the point shown compared with the baseline values (P < .05). Ouchi et al. Dexmedetomidine Enhances Local Lidocaine Action. J Oral Maxillofac Surg 2014.
478
DEXMEDETOMIDINE ENHANCES LOCAL LIDOCAINE ACTION
Table 2. TF LATENCY AT 20 TO 50 MINUTES AFTER EPIDURAL DRUG ADMINISTRATION
DEX Concentration (ppm) Measurement Point (min)
0
2.5
5.0
7.5
20
25.6
72.5
100.0
100.0
30
12.4
67.6
100.0
100.0
40
4.6
27.8
80.6
96.6
50
1.8
2.2
17.4
72.7
P < .05 0-ppm vs 2.5-ppm 0-ppm vs 5.0-ppm 0-ppm vs 7.5-ppm 0-ppm vs 2.5-ppm 0-ppm vs 5.0-ppm 0-ppm vs 7.5-ppm 0-ppm vs 2.5-ppm 0-ppm vs 5.0-ppm 0-ppm vs 7.5-ppm 2.5-ppm vs 5.0-ppm 2.5-ppm vs 7.5-ppm 0-ppm vs 7.5-ppm 2.5-ppm vs 7.5-ppm 5.0-ppm vs 7.5-ppm
TF latency was increased for 20 to 50 minutes; the response to TF stimulation differed with different concentrations of DEX. Ouchi et al. Dexmedetomidine Enhances Local Lidocaine Action. J Oral Maxillofac Surg 2014.
with a pinprick; however, these types of methods have not always been constant in intensity.14 Furthermore, they can damage the skin of the animal and possibly lead to increased difficulty in evaluating the effectiveness of the local anesthesia. Additionally, subcutaneous injection and infiltration anesthesia are methods associated with imprecise administration sites and dosages and, from an anatomic viewpoint, lead to imprecise effectiveness. In addition, in conscious animals, repetitive stimulation for pain assessment will result in hypersensitive responses.17 A radiant heat intensity of 161.5 mW/cm2 will result in a constant skin temperature of 44 C to 50 C and stimulates the C-polymodal nociceptors. The TF method used in the present study has been established as a method to measure sensory blocks.16,18 In contrast to subcutaneous injections and infiltration anesthesia, epidural anesthesia enables precise administration of the required dose at the appropriate site using an indwelling catheter. Learning,
which also will inevitably occur from cues and will affect the response, can be controlled by sedatives. The learning effect was controlled using 1% isoflurane, which does not affect the TF latency.18 Inhalation of 1% isoflurane has been shown to exclude the influence of supraspinal structures on nociception, providing a reliable TF latency for repeated TF testing.18 Other similar studies that have evaluated the clinical effects of local anesthetics by measuring the escape response to noxious stimulation in vivo have been hindered by the learning effect and imprecise pain stimulation and administration methods. The TF and epidural model used in the present study had the following advantages: pain stimulation was achieved by application of radiant heat of a constant intensity (161.5 mW/cm2), diminution of the TF latency was inhibited by suppression of the learning effect, and drug administration using an epidural catheter allowed precise control of the injection site and dosage. Furthermore, the TF and epidural model
FIGURE 3. Local anesthetic effect of DEX administered alone at a concentration of 5.0 ppm. Black squares show the change in TF latency from baseline (before administration) to 60 minutes after epidural administration of 30 mL of 5.0-ppm DEX alone. The course of TF latency (%MPE) did not change significantly during the experiment. Ouchi et al. Dexmedetomidine Enhances Local Lidocaine Action. J Oral Maxillofac Surg 2014.
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allowed us to detect the effect of local anesthesia onset and regression and the local anesthetic continuation action of the additive agent, all improvements compared with conventional methods. Therefore, in the present study, we used the rat TF and epidural model to examine the local anesthetic effects of DEX. In the present study, the results from experiment 1 indicated that the addition of DEX to the local anesthetic dose-dependently enhanced the local anesthetic action of lidocaine and prolonged its duration. Two possible mechanisms have been proposed for this action. The first is vasoconstriction around the site of injection, resulting in delay in the absorption of the local anesthetic and prolongation of the local anesthetic effect.12 DEX is a selective a2-adrenoceptor agonist. a2-Adrenoceptors can be subdivided into 4 subtypes: a2A, a2B, a2C, and a2D. The a2A-, a2B-, and a2C-adrenoceptors have been well identified pharmacologically and have been shown to cause vasoconstriction.19-21 Hence, it is possible that DEX interfered with the absorption of the injected lidocaine by inducing vasoconstriction. The other possible mechanism for the enhancement and prolongation of the local anesthetic action by DEX is its direct effect on peripheral nerve activity. DEX has been demonstrated to directly inhibit the peripheral nerve action.22,23 In experiment 2 of our study, when DEX was administered alone at the concentration shown in experiment 1 to effectively enhance local anesthetic action, no local anesthetic effects were observed. Therefore, we did not observe a direct effect of DEX on peripheral nerve activity in our study. However, a direct action of DEX has been reported on isolated sciatic nerve fibers in vitro and with exposure of the sciatic nerve fiber to DEX in vivo. A possible explanation for this discrepancy is that epidural anesthesia blocks the spinal root domain in the epidural space, which includes the loose connective tissue, lipids, and the Batson venous plexus.24 Therefore, the action resulting from the application of DEX directly to the nerve fiber possibly differs from that due to its epidural administration, which requires penetration of the extradural space and dura. However, for clinical purposes, the action of DEX as a local anesthetic additive is likely to be obvious, even with epidural administration, because the drugs can effectively percolate through the loose connective tissue, lipids, and the Batson venous plexus. The results of the present study suggest that DEX enhances the local anesthetic action of lidocaine by vasoconstriction by way of a2A-, a2B-, and a2C-adrenoceptors around the site of injection. This also suggests that the vasoconstriction effect of DEX is dose-dependent. It would be interesting to know the concentration of DEX that has action equal to that of epinephrine, because epinephrine has usually been used as the additive for local anesthesia. Therefore, we compared
the effect of DEX on TF latency in the present study with that of previous report on the effect of epinephrine (1:80,000) on TF latency performed using the same model used in our study.16 The previously reported %MPE, resulting from the addition of epinephrine, of approximately 100% in 20 minutes, 60% in 30 minutes, and 25% in 40 minutes, was similar to that seen with the addition of 2.5-ppm DEX in the present study (approximately 100% in 20 minutes, 80% in 30 minutes, and 30% in 40 minutes). The present study, using a sedated TF and epidural animal model, demonstrated that DEX dose-dependently enhances the local anesthetic action of lidocaine. However, before applying these results to clinical use, it is necessary to demonstrate similar effects in humans. In addition, the pH of the local anesthetic would be likely to change if DEX were simply added to the local anesthetic preparation, because the pH of DEX is different from that of local anesthetic preparations. Therefore, it is necessary to maintain the quality control of the preparation for clinical use. In conclusion, our results have demonstrated that DEX dose-dependently enhanced the local anesthetic action of lidocaine. Our results suggest that DEX interferes with the absorption of the injected lidocaine by vasoconstriction. Furthermore, the addition of DEX at a concentration of 2.5 ppm produced enhancement of the local anesthetic effect similar to that with addition of 1:80,000 epinephrine. This finding suggests that it is possible to safely achieve a local anesthetic effect equal to that of 1:80,000 epinephrine, without using epinephrine or felypressin, by the addition of 2.5-ppm DEX to the local anesthetic.
References 1. Yagiela JA: Vasoconstrictor agents for local anesthesia. Anesth Prog 42:116, 1995 2. Meechan JG, Parry G, Rattray DT, Thomason JM: Effects of dental local anaesthetics in cardiac transplant recipients. Br Dent J 192: 161, 2002 3. Ichinohe T, Igarashi O, Kaneko Y: The influence of propranolol on the cardiovascular effects and plasma clearance of epinephrine. Anesth Prog 38:217, 1991 4. Sims PG, Kates CH, Moyer DJ, et al: Anesthesia in outpatient facilities. J Oral Maxillofac Surg 70:e31, 2012 5. Anderson LD, Reagan SE: Local anesthetics and vasoconstrictors in patients with compromised cardiovascular systems. Gen Dent 41:161, 1993 6. Inagawa M, Ichinohe T, Kaneko Y: Felypressin, but not epinephrine, reduces myocardial oxygen tension after an injection of dental local anesthetic solution at routine doses. J Oral Maxillofac Surg 68:1013, 2010 7. Himuro H, Aono K, Honda T, et al: A case of coronary artery spasm during oral surgery under general anesthesia. Anesth Pain Control Dent 1:215, 1992 8. Agata H, Ichinohe T, Kaneko Y: Felypressin-induced reduction in coronary blood flow and myocardial tissue oxygen tension during anesthesia in dogs. Can J Anaesth 46:1070, 1999 9. Ebert TJ, Hall JE, Barney JA, et al: The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology 93:382, 2000
480 10. Talke P, Richardson CA, Scheinin M, Fisher DM: Postoperative pharmacokinetics and sympatholytic effects of dexmedetomidine. Anesth Analg 85:1136, 1997 11. Eisennach JC, Kock MD, Klimscha W: a2-Adrenergic agonists for regional anesthesia: A clinical review of clonidine. Anesthesiology 85:655, 1996 12. Singelyn FJ, Gouverneur JM, Robert A: A minimum dose of clonidine added to mepivacaine prolongs the duration of anesthesia and analgesia after axillary brachial plexus block. Anesth Analg 83:1046, 1996 13. Eledjam JJ, Deschodt J, Viel EJ, et al: Brachial plexus block with bupivacaine: Effects of added alpha-adrenergic agonists: Comparison between clonidine and epinephrine. Can J Anaesth 38:870, 1991 14. Yoshitomi T, Kohjitani A, Maeda S, et al: Dexmedetomidine enhances the local anesthetic action of lidocaine via an alpha-2A adrenoceptor. Anesth Analg 107:96, 2008 15. Patil PM, Patil SP: Is clonidine an adequate alternative to epinephrine as a vasoconstrictor in patients with hypertension? J Oral Maxillofac Surg 70:257, 2012 16. Ouchi K, Sekine J, Koga Y, et al: Establishment of an animal model of epidural anesthesia and sedative tail-flick test for evaluating local anesthetic effects in rats. Exp Anim 62:137, 2013 17. King TE, Joynes RL, Grau JW: Tail-flick test II: The role of supraspinal systems and avoidance learning. Behav Neurosci 111:754, 1997
DEXMEDETOMIDINE ENHANCES LOCAL LIDOCAINE ACTION 18. Takasugi Y, Fuyuta M, Sugiura J, et al: The effect of sub-MAC anesthesia and the radiation setting on repeated tail flick testing in rats. Exp Anim 57:65, 2008 19. Duka I, Gavras I, Johns C, et al: Role of the postsynaptic alpha(2)adrenergic receptor subtypes in catecholamine-induced vasoconstriction. Gen Pharmacol 34:101, 2000 20. Snapir A, Koskenvuo J, Toikka J, et al: Effects of common polymorphisms in the alpha1A-, alpha2B-, beta1- and beta2adrenoreceptors on haemodynamic responses to adrenaline. Clin Sci (Lond) 104:509, 2003 21. Chotani MA, Mitra S, Su BY, et al: Regulation of alpha(2)adrenoceptors in human vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 286:H59, 2004 22. Kosugi T, Mizuta K, Fujita T, et al: High concentrations of dexmedetomidine inhibit compound action potentials in frog sciatic nerves without alpha(2) adrenoceptor activation. Br J Pharmacol 160:1662, 2010 23. Brummett CM, Hong EK, Janda AM, et al: Perineural dexmedetomidine added to ropivacaine for sciatic nerve block in rats prolongs the duration of analgesia by blocking the hyperpolarization-activated cation current. Anesthesiology 115:836, 2011 24. Hogan QH: Lumbar epidural anatomy: A new look by cryomicrotome section. Anesthesiology 75:767, 1991
Dexmedetomidine Dose-Dependently Enhances Local Anesthetic Action of Lidocaine Kentaro Ouchi, DDS, PhD,* Yoshihisa Koga, MD, PhD,y Shinichi Nakao, MD, PhD,z and Kazuna Sugiyama, DDS, PhDx The combination of a2-adrenoceptor agonists, such as dexmedetomidine (DEX) and clonidine, with local anesthetics has been found to extend the duration of peripheral nerve blocks, probably owing to the resultant local vasoconstriction in the peripheral nerves. However, because the clear elucidation of the effect of DEX requires examination of the local anesthetic effect with DEX alone and the combination of various concentrations of DEX with local anesthetics, we evaluated the local anesthetic effect of various concentrations of DEX alone and with a local anesthetic.
Purpose:
Materials and Methods:
The present study assessed the tail-flick (TF) latencies after injection of the appropriate drug in male Sprague-Dawley rats, using an epidural model that allowed constant pain stimulation intensity, dispersion of the anesthetic, and a precise injection site and dose. Lidocaine alone, lidocaine with 2.5-ppm DEX, lidocaine with 5.0-ppm DEX, lidocaine with 7.5-ppm DEX, and DEX alone were administered at the predetermined dose. The TF latency changes over time were compared using repeated measures analysis of variance (ANOVA). Comparisons among the groups were analyzed using ANOVA followed by a post hoc Dunnett’s multiple comparison test or Tukey’s multiple comparison test.
Results:
The addition of DEX to lidocaine increased the TF latency and dose-dependently prolonged its duration as follows: 0-ppm DEX, 20 minutes; 2.5-ppm, 40 minutes; 5.0-ppm, 40 minutes; and 7.5-ppm, 50 minutes. DEX alone did not change the TF latency.
Conclusions: Our results have demonstrated that DEX dose-dependently enhances the local anesthetic action of lidocaine in a rat TF model. Crown Copyright Ó 2014 Published by Elsevier Inc on behalf of the American Association of Oral and Maxillofacial Surgeons. All rights reserved J Oral Maxillofac Surg 72:474-480, 2014
Dental local anesthetics contain vasoconstrictors, such as epinephrine and felypressin, to enhance the anesthetic effects and reduce bleeding in the surgical field.1 Several reports have warned against the use of local
dental anesthetics containing epinephrine in patients with cardiovascular disease.1-5 Therefore, felypressin, a noncatecholamine vasopressor chemically related to vasopressin, has been used as a safe vasoconstrictor in
*Assistant Professor, Department of Dental Anesthesiology, Field
was the subject of a report published in the Journal of Japanese
of Oral and Maxillofacial Rehabilitation, Kagoshima University
Dental Society of Anesthesiology.
Graduate School of Medical and Dental Sciences, Kagoshima, Japan. yProfessor Emeritus, Department of Anesthesiology, Kinki
Address correspondence and reprint requests to Dr Ouchi: Department of Dental Anesthesiology, Field of Oral and Maxillofacial
University Faculty of Medicine, Higashi-Osaka City, Japan.
Rehabilitation, Kagoshima University Graduate School of Medical
zProfessor and Chairman, Department of Anesthesiology, Kinki
and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544,
University Faculty of Medicine, Higashi-Osaka City, Japan.
Japan; e-mail: [email protected]
xProfessor and Chairman, Department of Dental Anesthesiology,
Received August 16 2013
Field of Oral and Maxillofacial Rehabilitation, Kagoshima University
Accepted September 24 2013
Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Crown Copyright Ó 2014 Published by Elsevier Inc on behalf of the American
This work was supported by the departmental research fund of Kinki University.
Association of Oral and Maxillofacial Surgeons. All rights reserved 0278-2391/13/01231-7$36.00/0
This study was previously presented, in part, at the Annual
http://dx.doi.org/10.1016/j.joms.2013.09.038
Meeting of the Japanese Dental Society of Anesthesiology, October 8, 2010, Yokosuka, Japan, and October 8, 2011, Kobe, Japan, and
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patients with compromised cardiovascular status in Japan and European Union nations.5,6 However, reports have been published that the clinical doses of felypressin are capable of inducing myocardial ischemia during surgery,7 and in a dog study, clinical doses of felypressin caused decreases in the coronary blood flow.8 Hence, a new drug is needed that can replace epinephrine and felypressin for the safe enhancement of the local anesthetic effect in patients with cardiovascular disease. The use of a2-adrenoceptor agonists during anesthesia produces sympatholytic, sedative, analgesic, antihypertensive, bradycardiac, and anesthetic-sparing effects.9,10 The a2-adrenoceptor agonists, dexmedetomidine (DEX) and clonidine, when combined with a local anesthetic agent, have been found to extend the duration of peripheral nerve blocks. This action has been suggested to be due to local vasoconstriction in the peripheral nerves.10-15 We hypothesized that if vasoconstriction is the explanation for the sustained effect of local anesthetics with the addition of DEX, the effect should be dose-dependent. The aim of the present study was to determine whether DEX itself exerts a local anesthesia effect, and the appropriate concentration of DEX to add to a local anesthetic to enhance the potency and duration of action. We examined the local anesthetic effect of various concentrations of DEX both with and without lidocaine, using a sedated tail-flick (TF) and epidural animal model that has been reported to be an appropriate method for assessing the effects of local anesthesia.
Materials and Methods ANIMALS
With approval from the Animal Care and Use Committee of Kinki University Faculty of Medicine in April 2010 (approval no. KAME-21-011), 10- to 12-week-old male Sprague-Dawley rats weighing 340 to 420 g (a total of 60 rats both experiments 1 and 2), purchased from Japan SLC (Shizuoka, Japan), were used in the present study. The rats were maintained under controlled conditions (temperature 23 0.5 C, humidity 55%, and a 12/12-hour light/dark cycle) and fed a commercial diet (CE-2, CLEA Japan, Tokyo, Japan), with tap water ad libitum. The experiments were performed from 12:00 to 5:00 PM under controlled conditions (temperature 23 0.5 C). All procedures were conducted at the Life Science Research Institute (Kinki University Faculty of Medicine). The epidural space was cannulated with a Teflonlined polyethylene tube (0.3-mm outer diameter and 0.11-mm inner diameter, Microspinal Catheter, Hakko, Nagano, Japan) using a method reported by Ouchi et al.16 In brief, the rats were anesthetized by inhalation of 2% isoflurane in oxygen with a mask. The epidural space was exposed at the level of the atlanto-occipital
membrane under a stereoscopic microscope, without causing leakage of the cerebrospinal fluid. The catheter was passed through a slit in the atlanto-occipital membrane and inserted caudally for a distance of 11 cm. A preliminary rat dissection experiment had indicated that this was the length of catheter insertion required to reach the L5–L6 intervertebral space from the atlanto-occipital membrane. The other end of the catheter was fixed in the subcutaneous tissue to avoid dislocation of the catheter. One week later, the rats were examined for evidence of sensory or motor dysfunction; those with dysfunction were eliminated from the present study. On completion of both experimental series, all catheterized rats were sacrificed by an epidural injection of 30 mL indigo carmine followed by a lethal dose of pentobarbital injected into the peritoneum. The location of the catheter tip and distribution of the dye in the epidural space were verified after removal of the vertebrae. AGENTS
Lidocaine (lidocaine hydrochloride) was purchased from Astra Zeneca (Osaka, Japan). DEX (Precedex), a specific a2-adrenoceptor agonist, was purchased from Maruishi Pharmaceutical (Osaka, Japan). All drugs were dissolved and diluted with saline. TF TEST
A TF measuring device (model 7360, Ugo Basile, Varese, Italy) was used to measure the TF latency after epidural administration of the study drugs. The stimulator consisted of an infrared power source (8 V, 50 W, Halogen ‘‘Bellaphot,’’ model 64607, Osram Licht AG, Munich, Germany) with an adjustable intensity (maximum 20 W) from 10 in to 99 in 1-digit increments. The rats were placed in a plastic box (22 6.5 6.5 cm). The rats were sedated by inhalation of 1.0% isoflurane for 20 minutes, with monitoring of the rats to assess their inspired gas concentration. An area on the ventral surface of the distal 5 cm to 6 cm of the tail was placed over a 0.5-cm hole in an aluminum box, and an infrared radiant (IR) bulb was placed beneath the hole. In each trial, different points at 5mm intervals on the tail were exposed to the IR bulb, and a 10-second cutoff was used to minimize the risk of tissue damage. The rectal temperature of the anesthetized rats was measured using a thermocouple and was maintained at 36 to 38 C by a thermal plate connected to a feedback warmer placed beneath the box. EXPERIMENT 1: EVALUATION OF EFFECT OF ADMINISTRATION OF VARIOUS DEX CONCENTRATIONS ON LOCAL ANESTHETIC EFFECT OF EPIDURAL LIDOCAINE
A total of 48 rats that had been implanted with an epidural catheter were randomly divided into 4 groups
476 (n = 12 each) as follows: 2% lidocaine alone (0-ppm), 2.5-ppm DEX with 2% lidocaine (2.5-ppm), 5.0-ppm DEX with 2% lidocaine (5.0-ppm), and 7.5-ppm DEX with 2% lidocaine (7.5-ppm). The TF latency was used to calculate the maximum possible effect (MPE) of the local anesthetic according to the following formula: %MPE = [(test latency)(baseline latency)/(cutoff time)(baseline latency)] 100. After epidural injection of 30 mL of the respective test drugs, the TF latency was tested in each rat at 10-minute intervals for 60 minutes (Fig 1). The TF latency was then evaluated as the %MPE. EXPERIMENT 2: EVALUATION OF LOCAL ANESTHESIA EFFECT OF DEX ALONE
A total of 12 rats implanted with an epidural catheter were evaluated. After epidural injection of 30 mL of 5.0-ppm DEX alone (this was the concentration of DEX shown to produce effective enhancement of the local anesthetic action of lidocaine in experiment 1), each rat was tested at 10-minute intervals for 60 minutes (Fig 1). The TF latency was then evaluated as the %MPE. STATISTICAL ANALYSIS
The TF latency changes over time were compared using repeated measures analysis of variance (ANOVA), and the comparisons among the groups were analyzed using ANOVA followed by a post hoc Dunnett’s multiple comparison test or Tukey’s multiple comparison test, as indicated. Statistical analysis was performed using Prism 5 for Windows, version 5.01 (GraphPad Software, San Diego, CA). The significance level was set at P < .05.
DEXMEDETOMIDINE ENHANCES LOCAL LIDOCAINE ACTION
7.5-ppm groups. In the 0-ppm group, the TF latency (%MPE) increased significantly from immediately after injection until 20 minutes thereafter compared with the baseline values (P < .05). In the 2.5-ppm group, the TF latency increased significantly from immediately after until 40 minutes after the injection compared with baseline (P < .05). In the 5.0-ppm group, the TF latency increased significantly from immediately after until 40 minutes after the injection compared with baseline (P < .05). In the 7.5-ppm group, the TF latency increased significantly from immediately after until 50 minutes after the injection compared with baseline (P < .05; Fig 2). Measurement of the diachronic TF latency showed that the increase in the duration of TF latency was different for the different concentrations of DEX (Table 1). The magnitude of TF latency (assessed as the %MPE) was also different for the various DEX concentration groups. In the 2.5-ppm group, the increase in TF latency was significantly different during the 20 to 40 minutes after epidural drug administration compared with that in the 0-ppm group (P < .05). In the 5.0-ppm group, the increase was also significantly different during the 20- to 40-minute period compared with that in the 0-ppm group (P < .05) and at 40 minutes compared with that in the 2.5-ppm group (P < .05). In the 7.5-ppm group, the increase in TF latency was significantly different during the 20- to 50-minute postinjection period compared with that in the 0-ppm group (P < .05), at 40 to 50 minutes compared with that in the 2.5-ppm group (P < .05), and at 50 to 60 minutes compared with that in the 5.0-ppm group (P < .05; Table 2).
Results EXPERIMENT 1: EVALUATION OF EFFECT OF ADMINISTRATION OF VARIOUS DEX CONCENTRATIONS ON LOCAL ANESTHETIC EFFECT OF LIDOCAINE
No significant difference was found in the baseline TF latency among the 0-ppm, 2.5-ppm, 5.0-ppm, and
EXPERIMENT 2: EVALUATION OF LOCAL ANESTHETIC EFFECT OF DEX ALONE
The course of TF latency (%MPE) did not show any significant changes during the observation period when 5.0-ppm DEX was epidurally injected alone, without lidocaine (Fig 3).
FIGURE 1. Experimental schedule. In experiment 1, rats in the 0-ppm, 2.5-ppm, 5.0-ppm, and 7.5-ppm groups received an epidural injection of 30 mL 2% lidocaine alone, 2.5-ppm DEX with 2% lidocaine, 5.0-ppm DEX with 2% lidocaine, or 7.5-ppm DEX with 2% lidocaine, respectively. In experiment 2, the rats received an epidural injection of 30 mL of 5.0-ppm DEX alone. After epidural injection, the TF latency in each rat was tested at 10-minutes intervals for 60 minutes. Ouchi et al. Dexmedetomidine Enhances Local Lidocaine Action. J Oral Maxillofac Surg 2014.
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FIGURE 2. Effect of various concentrations of DEX administered with the local anesthetic lidocaine. *P < .05 compared with baseline; +P < .05 compared with the 0-ppm group; #P < .05 compared with the 2.5-ppm group; $P < .05 compared with the 5.0-ppm group. Closed squares, open squares, closed circles, and open circles show the TF latency from baseline (before administration) to 60 minutes after epidural drug administration in the 0-ppm, 2.5-ppm, 5.0-ppm, and 7.5-ppm groups, respectively. In the 0-ppm group, TF latency increased significantly immediately after injection compared with baseline (P < .05), with the increase lasting 20 minutes. In the 2.5-ppm group, TF latency increased significantly immediately after injection compared with baseline (P < .05), with the increase lasting 40 minutes and significantly different from 20 to 40 minutes after injection compared with that in the 0-ppm group (P < .05). In the 5.0-ppm group, TF latency increased significantly immediately after injection compared with baseline (P < .05), with the increase lasting for 40 minutes and significantly different during the 20- to 40-minute postinjection period compared with that in the 0-ppm group (P < .05) and at 40 minutes compared with that in the 2.5-ppm group (P < .05). In the 7.5-ppm group, TF latency increased significantly immediately after injection compared with baseline (P < .05), with the increase lasting 50 minutes and significantly different at 20 to 50 minutes after injection compared with that in the 0-ppm group (P < .05), at 40 to 50 minutes compared with that in the 2.5-ppm group (P < .05), and at 50 to 60 minutes compared with that in the 5.0-ppm group (P < .05). Ouchi et al. Dexmedetomidine Enhances Local Lidocaine Action. J Oral Maxillofac Surg 2014.
EPIDURAL CATHETER POSITION
On completion of the experimental series, the rats were sacrificed. In all rats, the tip of the catheter had been placed caudal to the lumbar vertebrae at the L4–L6 level.
Discussion New drugs that can replace epinephrine and felypressin for the safe enhancement of the local anesthetic effect in patients with cardiovascular diseases are required. a2-Adrenoceptor agonists, such as DEX, which produce sympatholytic, sedative, analgesic, antihypertensive, and bradycardiac effects when combined with a local anesthetic agent, have been found to extend the duration of the local anesthetic effect by causing local vasoconstriction. We hypothesized that if the local anesthetic reinforcement action of DEX depends on local vasoconstriction, prolongation of the local anesthetic effect should be concentrationdependent. In the present study, we examined the local anesthetic effect of various concentrations of DEX administered with and without lidocaine, using a sedated TF and epidural animal model that has been reported to be an appropriate method for assess-
ing the effect of local anesthesia. Our results have demonstrated that DEX dose-dependently enhanced the local anesthetic action of lidocaine. Evaluating the effectiveness of local anesthetics necessitates an in vivo model to precisely detect the amount of pain relief achieved after noxious stimulation.16 Various animal models have been used to examine the different clinical effects and durations of various local anesthetic agents. Noxious stimulation can be achieved using various methods, including Table 1. DURATION OF INCREASED TF LATENCY
DEX Concentration (ppm) 0 2.5 5.0 7.5
Duration (min) 20 40 40 50
In each concentration group, the TF latency (%MPE) increased significantly from immediately after injection until the point shown compared with the baseline values (P < .05). Ouchi et al. Dexmedetomidine Enhances Local Lidocaine Action. J Oral Maxillofac Surg 2014.
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DEXMEDETOMIDINE ENHANCES LOCAL LIDOCAINE ACTION
Table 2. TF LATENCY AT 20 TO 50 MINUTES AFTER EPIDURAL DRUG ADMINISTRATION
DEX Concentration (ppm) Measurement Point (min)
0
2.5
5.0
7.5
20
25.6
72.5
100.0
100.0
30
12.4
67.6
100.0
100.0
40
4.6
27.8
80.6
96.6
50
1.8
2.2
17.4
72.7
P < .05 0-ppm vs 2.5-ppm 0-ppm vs 5.0-ppm 0-ppm vs 7.5-ppm 0-ppm vs 2.5-ppm 0-ppm vs 5.0-ppm 0-ppm vs 7.5-ppm 0-ppm vs 2.5-ppm 0-ppm vs 5.0-ppm 0-ppm vs 7.5-ppm 2.5-ppm vs 5.0-ppm 2.5-ppm vs 7.5-ppm 0-ppm vs 7.5-ppm 2.5-ppm vs 7.5-ppm 5.0-ppm vs 7.5-ppm
TF latency was increased for 20 to 50 minutes; the response to TF stimulation differed with different concentrations of DEX. Ouchi et al. Dexmedetomidine Enhances Local Lidocaine Action. J Oral Maxillofac Surg 2014.
with a pinprick; however, these types of methods have not always been constant in intensity.14 Furthermore, they can damage the skin of the animal and possibly lead to increased difficulty in evaluating the effectiveness of the local anesthesia. Additionally, subcutaneous injection and infiltration anesthesia are methods associated with imprecise administration sites and dosages and, from an anatomic viewpoint, lead to imprecise effectiveness. In addition, in conscious animals, repetitive stimulation for pain assessment will result in hypersensitive responses.17 A radiant heat intensity of 161.5 mW/cm2 will result in a constant skin temperature of 44 C to 50 C and stimulates the C-polymodal nociceptors. The TF method used in the present study has been established as a method to measure sensory blocks.16,18 In contrast to subcutaneous injections and infiltration anesthesia, epidural anesthesia enables precise administration of the required dose at the appropriate site using an indwelling catheter. Learning,
which also will inevitably occur from cues and will affect the response, can be controlled by sedatives. The learning effect was controlled using 1% isoflurane, which does not affect the TF latency.18 Inhalation of 1% isoflurane has been shown to exclude the influence of supraspinal structures on nociception, providing a reliable TF latency for repeated TF testing.18 Other similar studies that have evaluated the clinical effects of local anesthetics by measuring the escape response to noxious stimulation in vivo have been hindered by the learning effect and imprecise pain stimulation and administration methods. The TF and epidural model used in the present study had the following advantages: pain stimulation was achieved by application of radiant heat of a constant intensity (161.5 mW/cm2), diminution of the TF latency was inhibited by suppression of the learning effect, and drug administration using an epidural catheter allowed precise control of the injection site and dosage. Furthermore, the TF and epidural model
FIGURE 3. Local anesthetic effect of DEX administered alone at a concentration of 5.0 ppm. Black squares show the change in TF latency from baseline (before administration) to 60 minutes after epidural administration of 30 mL of 5.0-ppm DEX alone. The course of TF latency (%MPE) did not change significantly during the experiment. Ouchi et al. Dexmedetomidine Enhances Local Lidocaine Action. J Oral Maxillofac Surg 2014.
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allowed us to detect the effect of local anesthesia onset and regression and the local anesthetic continuation action of the additive agent, all improvements compared with conventional methods. Therefore, in the present study, we used the rat TF and epidural model to examine the local anesthetic effects of DEX. In the present study, the results from experiment 1 indicated that the addition of DEX to the local anesthetic dose-dependently enhanced the local anesthetic action of lidocaine and prolonged its duration. Two possible mechanisms have been proposed for this action. The first is vasoconstriction around the site of injection, resulting in delay in the absorption of the local anesthetic and prolongation of the local anesthetic effect.12 DEX is a selective a2-adrenoceptor agonist. a2-Adrenoceptors can be subdivided into 4 subtypes: a2A, a2B, a2C, and a2D. The a2A-, a2B-, and a2C-adrenoceptors have been well identified pharmacologically and have been shown to cause vasoconstriction.19-21 Hence, it is possible that DEX interfered with the absorption of the injected lidocaine by inducing vasoconstriction. The other possible mechanism for the enhancement and prolongation of the local anesthetic action by DEX is its direct effect on peripheral nerve activity. DEX has been demonstrated to directly inhibit the peripheral nerve action.22,23 In experiment 2 of our study, when DEX was administered alone at the concentration shown in experiment 1 to effectively enhance local anesthetic action, no local anesthetic effects were observed. Therefore, we did not observe a direct effect of DEX on peripheral nerve activity in our study. However, a direct action of DEX has been reported on isolated sciatic nerve fibers in vitro and with exposure of the sciatic nerve fiber to DEX in vivo. A possible explanation for this discrepancy is that epidural anesthesia blocks the spinal root domain in the epidural space, which includes the loose connective tissue, lipids, and the Batson venous plexus.24 Therefore, the action resulting from the application of DEX directly to the nerve fiber possibly differs from that due to its epidural administration, which requires penetration of the extradural space and dura. However, for clinical purposes, the action of DEX as a local anesthetic additive is likely to be obvious, even with epidural administration, because the drugs can effectively percolate through the loose connective tissue, lipids, and the Batson venous plexus. The results of the present study suggest that DEX enhances the local anesthetic action of lidocaine by vasoconstriction by way of a2A-, a2B-, and a2C-adrenoceptors around the site of injection. This also suggests that the vasoconstriction effect of DEX is dose-dependent. It would be interesting to know the concentration of DEX that has action equal to that of epinephrine, because epinephrine has usually been used as the additive for local anesthesia. Therefore, we compared
the effect of DEX on TF latency in the present study with that of previous report on the effect of epinephrine (1:80,000) on TF latency performed using the same model used in our study.16 The previously reported %MPE, resulting from the addition of epinephrine, of approximately 100% in 20 minutes, 60% in 30 minutes, and 25% in 40 minutes, was similar to that seen with the addition of 2.5-ppm DEX in the present study (approximately 100% in 20 minutes, 80% in 30 minutes, and 30% in 40 minutes). The present study, using a sedated TF and epidural animal model, demonstrated that DEX dose-dependently enhances the local anesthetic action of lidocaine. However, before applying these results to clinical use, it is necessary to demonstrate similar effects in humans. In addition, the pH of the local anesthetic would be likely to change if DEX were simply added to the local anesthetic preparation, because the pH of DEX is different from that of local anesthetic preparations. Therefore, it is necessary to maintain the quality control of the preparation for clinical use. In conclusion, our results have demonstrated that DEX dose-dependently enhanced the local anesthetic action of lidocaine. Our results suggest that DEX interferes with the absorption of the injected lidocaine by vasoconstriction. Furthermore, the addition of DEX at a concentration of 2.5 ppm produced enhancement of the local anesthetic effect similar to that with addition of 1:80,000 epinephrine. This finding suggests that it is possible to safely achieve a local anesthetic effect equal to that of 1:80,000 epinephrine, without using epinephrine or felypressin, by the addition of 2.5-ppm DEX to the local anesthetic.
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480 10. Talke P, Richardson CA, Scheinin M, Fisher DM: Postoperative pharmacokinetics and sympatholytic effects of dexmedetomidine. Anesth Analg 85:1136, 1997 11. Eisennach JC, Kock MD, Klimscha W: a2-Adrenergic agonists for regional anesthesia: A clinical review of clonidine. Anesthesiology 85:655, 1996 12. Singelyn FJ, Gouverneur JM, Robert A: A minimum dose of clonidine added to mepivacaine prolongs the duration of anesthesia and analgesia after axillary brachial plexus block. Anesth Analg 83:1046, 1996 13. Eledjam JJ, Deschodt J, Viel EJ, et al: Brachial plexus block with bupivacaine: Effects of added alpha-adrenergic agonists: Comparison between clonidine and epinephrine. Can J Anaesth 38:870, 1991 14. Yoshitomi T, Kohjitani A, Maeda S, et al: Dexmedetomidine enhances the local anesthetic action of lidocaine via an alpha-2A adrenoceptor. Anesth Analg 107:96, 2008 15. Patil PM, Patil SP: Is clonidine an adequate alternative to epinephrine as a vasoconstrictor in patients with hypertension? J Oral Maxillofac Surg 70:257, 2012 16. Ouchi K, Sekine J, Koga Y, et al: Establishment of an animal model of epidural anesthesia and sedative tail-flick test for evaluating local anesthetic effects in rats. Exp Anim 62:137, 2013 17. King TE, Joynes RL, Grau JW: Tail-flick test II: The role of supraspinal systems and avoidance learning. Behav Neurosci 111:754, 1997
DEXMEDETOMIDINE ENHANCES LOCAL LIDOCAINE ACTION 18. Takasugi Y, Fuyuta M, Sugiura J, et al: The effect of sub-MAC anesthesia and the radiation setting on repeated tail flick testing in rats. Exp Anim 57:65, 2008 19. Duka I, Gavras I, Johns C, et al: Role of the postsynaptic alpha(2)adrenergic receptor subtypes in catecholamine-induced vasoconstriction. Gen Pharmacol 34:101, 2000 20. Snapir A, Koskenvuo J, Toikka J, et al: Effects of common polymorphisms in the alpha1A-, alpha2B-, beta1- and beta2adrenoreceptors on haemodynamic responses to adrenaline. Clin Sci (Lond) 104:509, 2003 21. Chotani MA, Mitra S, Su BY, et al: Regulation of alpha(2)adrenoceptors in human vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 286:H59, 2004 22. Kosugi T, Mizuta K, Fujita T, et al: High concentrations of dexmedetomidine inhibit compound action potentials in frog sciatic nerves without alpha(2) adrenoceptor activation. Br J Pharmacol 160:1662, 2010 23. Brummett CM, Hong EK, Janda AM, et al: Perineural dexmedetomidine added to ropivacaine for sciatic nerve block in rats prolongs the duration of analgesia by blocking the hyperpolarization-activated cation current. Anesthesiology 115:836, 2011 24. Hogan QH: Lumbar epidural anatomy: A new look by cryomicrotome section. Anesthesiology 75:767, 1991
