Anesth Analg 2008; 107:96-101
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e318176be73
ANESTHETIC PHARMACOLOGY
Dexmedetomidine Enhances the Local Anesthetic Action of Lidocaine via an  -2A Adrenoceptor
Tatsushi Yoshitomi, DDS*,
Atsushi Kohjitani, DDS, PhD ,
Shigeru Maeda, DDS, PhD*,
Hitoshi Higuchi, DDS, PhD*,
Masahiko Shimada, DDS, PhD , and
Takuya Miyawaki, DDS, PhD*
From the *Department of Dental Anesthesiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan; Department of Dental Anesthesiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan; and Orofacial Pain Management, Department of Oral Restitution Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Address correspondence and reprint requests to Takuya Miyawaki, DDS, PhD, Department of Dental Anesthesiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8525, Japan. Address e-mail to miyawaki{at}md.okayama-u.ac.jp.
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Abstract
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BACKGROUND: Clonidine, an  -2 adrenoceptor agonist, is a common adjunct in both central and peripheral blocks. Dexmedetomidine, a more selective -2 adrenoceptor agonist, is also known to enhance central neural blockades. Its peripheral effect, however, has not been fully elucidated. Thus, we evaluated the effect of dexmedetomidine and other -2 adrenoceptor agonists on the local anesthetic action of lidocaine at the periphery and explored the mechanism involved.
METHODS: -2 Adrenoceptor agonists, including dexmedetomidine, clonidine, and oxymetazoline, combined with lidocaine were intracutaneously injected into the back of male guinea pigs. The test of six pinpricks was applied every 5 min until 60 min after the injection. The number of times which the prick failed to elicit a response during the 60-min period was added and the sum served as an anesthetic score indicating the degree of local anesthesia. Differences from the control value within the group were analyzed using an analysis of variance followed by a post hoc Dunnett’s test. Furthermore, we evaluated the antagonism of the effect of dexmedetomidine by yohimbine, an -2A, 2B, and 2C adrenoceptor antagonist, or prazosin, an -1, -2B, and 2C adrenoceptor antagonist, analyzed using a two-way analysis of variance.
RESULTS: All -2 adrenoceptor agonists enhanced the degree of local anesthesia of lidocaine in a dose-dependent manner. Furthermore, yohimbine inhibited the effect of dexmedetomidine, whereas prazosin did not.
CONCLUSION: We demonstrated that -2 adrenoceptor agonists enhanced the local anesthetic action of lidocaine, and suggest that dexmedetomidine acts via -2A adrenoceptors.
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Introduction
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Increasing attention has been focused on the clinical application of -2 adrenoceptor agonists for anesthetic management in anticipation of sympatholytic, sedative, analgesic, and anesthetic-sparing effects.1–3 Furthermore, various methods of administration, such as epidural, intrathecal, and peripheral injections, have been tried alone or in combination with another drug to prolong and intensify the anesthesia.4–13
An -2 adrenoceptor agonist, clonidine, combined with a local anesthetic, has been found to extend the duration of the peripheral nerve block. The action of clonidine was suggested to be due to local vasoconstriction and/or direct inhibition of impulse conduction in peripheral nerves.4–11 However, the mechanism of action has not been fully elucidated. Clonidine is not particularly specific for -2 adrenoceptors and acts via -1 adrenoceptors at comparatively high concentrations.14 Clonidine has the ability to induce vasoconstriction.15 Thus, it is unclear whether it acts via -2 adrenoceptors. On the other hand, another -2 adrenoceptor agonist, dexmedetomidine, acts more specifically against -2 adrenoceptors and has more than eight times the affinity for -2 adrenoceptors of clonidine.14 Dexmedetomidine has also been reported to enhance central and peripheral neural blockades by local anesthetics11–13; however, the peripheral effect has not been fully clarified. Thus, the purpose of the present study was to evaluate the local effect of -2 adrenoceptor agonists on the anesthetic action of a local anesthetic at the periphery, using mainly dexmedetomidine.
-2 Adrenoceptors were subdivided into four subtypes: -2A, -2B, -2C, and -2D. The -2A, -2B, and -2C adrenoceptors have been well identified pharmacologically. They are differentially distributed in central and peripheral cells and tissues, and have different physiological functions and pharmacological activities.16–18 Thus, we used oxymetazoline hydrochloride (oxymetazoline), a specific agonist for -2A adrenoceptor,16 yohimbine hydrochloride (yohimbine), an -2A, -2B, and -2C adrenoceptor antagonist,16 and prazosin hydrochloride (prazosin), an -1, -2B, and -2C adrenoceptor antagonist16,17 to explore the mechanism of the peripheral effect of -2 adrenoceptor agonists on the anesthetic action of a local anesthetic.
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METHODS
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Agents
Lidocaine (lidocaine hydrochloride) was purchased from Sigma (St. Louis, MO). Dexmedetomidine (PrecedexR), an agonist specific for -2 adrenoceptors, was purchased from Maruishi Pharmaceutical (Osaka, Japan). Clonidine, oxymetazoline, yohimbine, and prazosin were purchased from Sigma (St. Louis, MO). All drugs were dissolved and diluted with saline. The pH of 0.5% lidocaine, dexmedetomidine, clonidine, oxymetazoline, yohimbine, and prazosin solutions at a concentration of 10–6 M was 5.17, 5.60, 5.59, 5.62, 5.70, and 5.60, respectively.
Animals
The protocol of the present study was approved by the Okayama University Animal Care and Use Committee. We studied male Hartley guinea pigs (weighing 300–350 g, Japan SLC, Hamamatsu, Japan), which had been housed at a room temperature of 24°C with a 12-h light dark cycle and given free access to food and water.
Evaluation of the Degree of Local Anesthesia
The degree of local anesthesia was evaluated using the method described by Bulbring and Wajda.19 Hair on the backs of guinea pigs was clipped and the animals then rested for at least 10 min. Five different test solutions at a dose of 0.1 mL were intracutaneously injected at five respective areas on the back of the same guinea pig at intervals of 1 min, randomly and blindly. Each injection caused formation of an increased circular area of skin, a wheal, that was marked with ink immediately after the injection (Fig. 1). After the animal’s normal reaction to a prick applied outside the wheal was observed, six pricks were applied inside each wheal, using a fixed-weight needle, which is a specific pinprick sensory threshold apparatus (weight: 6 g, needle gauge: No. 23, Yuhu Seiki, Tokyo, Japan). The test of six pinpricks was applied at intervals of about 3–5 s every 5 min until 60 min after the injection. The number of times that the prick failed to elicit a response during the 60-min period was added and the sum (maximum value: 72) served as an anesthetic score indicating the degree of local anesthesia.
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Figure 1. The back of a guinea pig injected with five different test solutions intracutaneously, causing five respective wheals.
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Administration of Drugs
To clarify that our method is appropriate for evaluating the degree of local anesthesia, we performed a preliminary experiment. Lidocaine solutions were intracutaneously injected in each of the six guinea pigs at concentrations of 0.25%, 0.5%, 1.0%, and 2.0%. After the preliminary experiment, the drugs were administered to six guinea pigs for each experiment as described in Table 1. The series of five test solutions at different concentrations was injected and caused the five respective wheals on the back of each guinea pig. Six guinea pigs were tested in the same way in each experiment. Experiments 3 and 4 used the same guinea pigs as used in Experiment 1 after a 1-wk interval to compare among the results in these experiments. We confirmed that there were no differences in the degree of local anesthesia among the first, second, and third tests performed at intervals of 1 week in the same guinea pigs. Similarly, Experiment 6 used the same guinea pigs as used in Experiment 5. Thus, we used 24 guinea pigs for all experiments, including the preliminary experiment and Experiments 1–5.
The investigator who performed the pinpricking and observed the reaction was blinded to the drugs and concentrations throughout each series of experiments by attaching an unidentified mark to each test solution. Furthermore, both the order and area injected were randomly changed for each guinea pig so as to prevent any bias.
Statistical Analysis
Differences from the control value within a group were analyzed using a one-way analysis of variance followed by a post hoc Dunnett’s test. A two-way analysis of variance was used for between-group comparisons. P value <0.05 was considered significant. All data are shown as the mean ± sd.
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RESULTS
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The Degree of Local Anesthesia of Lidocaine (Preliminary Experiment)
Fig. 2 shows the time course of the mean number of pricks, which did not evoke a reaction after the injection of lidocaine at each concentration in six guinea pigs. The anesthetic scores, the sum of numbers of pricks during the 60-min period, increased at 0.25%–2.0% of lidocaine in a dose-dependent manner (Fig. 3).
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Figure 2. Time course of the number of pricks which did not evoke a reaction after the intracutaneous injection of lidocaine at concentrations of 0.25%, 0.5%, 1.0%, and 2.0%. Data are shown as the mean values for six guinea pigs.
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Figure 3. The anesthetic score increased dose-dependently when lidocaine was injected intracutaneously at concentrations of 0.25%, 0.5%, 1.0%, and 2.0%. Data are shown as the mean ± sd (n = 6).
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Effect of Dexmedetomidine on the Degree of Local Anesthesia of Lidocaine (Experiments 1 and 2)
Dexmedetomidine combined with 0.5% lidocaine increased both the duration and the degree of the local anesthetic effect of lidocaine in a dose-dependent manner, and sustained the effect for more than 1 h at a concentration of 10–6 M (Fig. 4). The scores were significantly higher at 10–7 and 10–6 M of dexmedetomidine than without dexmedetomidine (control), but did not increase at 10–9 to 10–6 M when only dexmedetomidine was intracutaneously injected (Fig. 5).
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Figure 4. Time course of the number of pricks which did not evoke a reaction after the intracutaneous injection of dexmedetomidine (DEX) combined with 0.5% lidocaine at concentrations of 0 (control) and 10–9 to 10–6 M. Data are shown as the mean values for six guinea pigs.
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Figure 5. Effect of dexmedetomidine (DEX) on the local anesthetic potency of lidocaine. DEX alone up to a concentration of 10–6 M had no anesthetic potency (closed square) but increased the anesthetic scores of 0.5% lidocaine injected intracutaneously (open circle). *P < 0.05 vs the value for 0.5% lidocaine without DEX (control). Data are shown as the mean ± sd (n = 6).
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Antagonism of the Effect of Dexmedetomidine by Specific Antagonists (Experiments 3 and 4)
To evaluate the antagonism of the effect of dexmedetomidine by specific antagonists, yohimbine or prazosin at a concentration of 10–6 M was added to a mixed solution of 0.5% lidocaine and dexmedetomidine at concentrations of 10–9, 10–8, 10–7, and 10–6 M. Yohimbine significantly inhibited the increase in the anesthetic scores of the mixed solution of 0.5% lidocaine and dexmedetomidine at concentrations of 10–7 and 10–6 M; however, prazosin did not alter the anesthetic scores of the mixed solution at any concentration (Fig. 6).
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Figure 6. The antagonism of dexmedetomidine (DEX)’s effect on the local anesthetic potency of lidocaine by -2 adrenoceptor antagonists. Yohimbine at a concentration of 10–6 M inhibited DEX’s effect (closed circle), whereas prazosin at a concentration of 10–6 M did not alter it (closed triangle). #P < 0.05 vs the value for 0.5% lidocaine combined with DEX (open circle). Data are shown as the mean ± sd (n = 6).
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Effects of Other -2 Adrenoceptor Agonists on the Local Anesthetic Action of Lidocaine (Experiments 5 and 6)
Clonidine at concentrations of 10–9, 10–8, 10–7, and 10–6 M increased the anesthetic scores in a dose-dependent manner, similar to dexmedetomidine. The scores were significantly higher at 10–8, 10–7, and 10–6 M of clonidine than without clonidine (control). Furthermore, oxymetazoline at 10–9, 10–8, 10–7, and 10–6 M also increased the anesthetic score in a dose-dependent manner, similar to dexmedetomidine and clonidine. The scores were significantly higher at 10–7 and 10–6 M of oxymetazoline than without oxymetazoline (control) (Fig. 7).
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Figure 7. Effects of clonidine and oxymetazoline on the local anesthetic potency of lidocaine. Both clonidine (closed circle) and oxymetazoline (open square) dose-dependently increased the anesthetic scores of lidocaine. *P < 0.05 vs the value for 0.5% lidocaine without clonidine or oxymetazoline (control). Data are shown as the mean ± sd (n = 6).
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DISCUSSION
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Our results showed that dexmedetomidine enhanced the local anesthetic action of lidocaine. Dexmedetomidine is highly specific to -2 adrenoceptors, yielding an -2/-1 ratio of 1620.14 Yohimbine, an -2 adrenoceptor antagonist, at a concentration of 10–6 M, inhibited the effect of dexmedetomidine at concentrations of 10–7 and 10–6 M, whereas prazosin, an -1 adrenoceptor antagonist, at 10–6 M, did not. Furthermore, both clonidine and oxymetazoline had a similar effect to dexmedetomidine. These findings indicated that an -2 adrenoceptor agonist combined with lidocaine enhances local anesthetic action via -2 adrenoceptors, not via -1 adrenoceptors. -2 Adrenoceptors are widely distributed in the central nervous system (CNS) and peripheral tissues, including sympathetic nerve endings, neurons, vascular smooth muscles, and platelets16,17; however, the peripheral receptors themselves have not been considered to have an analgesic effect at the periphery. In our study, dexmedetomidine, even at a concentration of 10–6 M and without lidocaine, did not have any anesthetic effect. Thus, -2 adrenoceptor agonists are considered to enhance the local anesthetic action of lidocaine.
The effect of a local anesthetic depends on the pH of the solution. However, there was little difference in pH among the solutions used in the present study: the pH ranged from 5.17 to 5.70. We investigated the difference in the effect of 0.5% lidocaine solutions between pH 5.0 and pH 6.0, adjusted by adding hydrochloride or sodium hydroxide, and obtained no difference between them (data not shown). Thus, the influence of the pH of solutions could be excluded in the present study.
-2 Adrenoceptor agonists have analgesic effects on the CNS.17,20 In the present study, the total dose of each -2 adrenoceptor agonist was the same in all guinea pigs in each experiment because all animals equally received all test solutions in each experiment. Furthermore, the total dose of each -2 adrenoceptor agonist injected into a guinea pig was <0.11 µg/kg, which is too low to induce a central analgesic effect because the ED50 value of dexmedetomidine for increasing the mechanical threshold in rats was reported to be 144 µg/kg intraperitoneally.20 Thus, it is considered that the effect on the CNS did not influence the results in the present study.
Dexmedetomidine binds -2A, -2B, and -2C adrenoceptors with high affinity.16,17 In the present study, oxymetazoline, a selective agonist for -2A adrenoceptors, enhanced lidocaine’s action whereas prazosin, an antagonist of both -2B and -2C adrenoceptors, did not alter lidocaine local anesthetic effect. These results demonstrated that dexmedetomidine enhances the local anesthetic action of lidocaine via an -2A adrenoceptor. -2 Adrenoceptor agonists induce analgesia, sedation, inhibition of epileptic seizures, hypothermia, and neuroprotection via an -2A adrenoceptor.21 To our knowledge, there have been no reports suggesting that -2A adrenoceptors are directly involved in peripheral local anesthetic action.
The results of the present study indicated that -2 adrenoceptor agonists dose dependently enhanced the local anesthetic action of lidocaine and prolonged its duration. Two possible mechanisms for this action have been proposed: one is vasoconstriction around the site of injection, resulting in a delay of the absorption of the local anesthetic and a prolonging of the local anesthetic effect.5 It is possible that the -2 adrenoceptor agonists interfered with the absorption of lidocaine injected via vasoconstriction. -2 Adrenoceptors are also involved in the control of arterial blood pressure, and nonselective -2 adrenoceptor agonists usually evoke a biphasic arterial blood pressure response: a short hypertensive phase and subsequent hypotension. The two phases are considered to be mediated by two different -2 adrenoceptor subtypes: the -2B adrenoceptor is responsible for the initial hypertensive phase, whereas hypotension is mediated by the -2A adrenoceptor.18 However, vasoconstriction mediated by direct activation of vascular -2 adrenoceptors was demonstrated to be attributable to the -2A subtype in mice.22 Furthermore, Masuki et al.23 suggested that dexmedetomidine induces vasoconstriction via -2 adrenoceptors in the human forearm. On the other hand, many investigators have supported another mechanism for the action of clonidine rather than vasoconstriction: a direct effect on peripheral nerve activity.5–11 Clonidine has been demonstrated to inhibit peripheral nerve action directly.24,25 Thus, the effect of -2 adrenoceptor agonists might have been induced by a direct action toward peripheral blood vessels and/or peripheral nerves; however it will be necessary to explore the pharmacological mechanism for the actions in detail.
Our results demonstrated that dexmedetomidine as well as clonidine enhanced the local anesthetic action of lidocaine via peripheral -2A adrenoceptors. Dexmedetomidine has some advantageous pharmacological characteristics compared with other clinically available sedative drugs.26 The hemodynamic stability achieved with dexmedetomidine is related to the fact that it is more selective for -2 adrenoceptors than clonidine. It was suggested that the baroceptor reflex and heart rate response to a pressor are well preserved with the use of dexmedetomidine.27 The findings in the present study suggest that dexmedetomidine has potential as a new safety adjunct to local anesthetics especially for patients with cardiovascular disease, compared with other vasoconstrictors such as epinephrine. Furthermore, dexmedetomidine may also be useful in peripheral nerve blocks in patients with chronic pain because of its differential mechanism. The use of dexmedetomidine is expected for developing the reliability and efficacy of regional anesthesia.
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Footnotes
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Accepted for publication March 17, 2008.
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Abstract
Introduction
