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Pain and Regional Anesthesia

Clonidine Prolongation of Lidocaine Analgesia after Sciatic Nerve Block in Rats Is Mediated via the Hyperpolarization-activated Cation Current, Not by α-Adrenoreceptors

Kroin, Jeffrey S. Ph.D.*; Buvanendran, Asokumar M.D.†; Beck, Daniel R. M.S.‡; Topic, Julie E. B.S.§; Watts, Daniel E. B.S.§; Tuman, Kenneth J. M.D.∥

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Background: Although clonidine is commonly combined with local anesthetics to extend duration of peripheral nerve block, the mechanism by which clonidine potentiates local anesthetic action in vivo is unclear.
Methods: Male Sprague-Dawley rats received percutaneous injections of 1% lidocaine with/without clonidine or epinephrine into the sciatic notch and duration of sensory blockade was quantified by inhibition of pinprick foot withdrawal. The antagonists prazosin or yohimbine were injected before lidocaine with clonidine or epinephrine to determine the role of α-adrenergic receptors. The role of the hyperpolarization-activated cation current (Ih) was evaluated by injecting the current blocker ZD 7288 as well as the current enhancers forskolin and 8-Br-cAMP before lidocaine alone or with 15 μg/ml clonidine.
Results: Mean duration of sensory block for lidocaine alone was 69 ± 2 min. Sensory block duration increased monotonically with increasing doses of added clonidine or epinephrine. Preinjection of prazosin but not yohimbine prevented the increase in block duration seen with epinephrine. Neither α-adrenergic antagonist attenuated the extended duration of block with clonidine. ZD 7288 extended sensory blockade equivalent to the prolongation observed with clonidine. There was no additive effect when ZD 7288 and clonidine were combined, and a decreased duration of nerve block when either forskolin or 8-Br-cAMP preceded injection of lidocaine with clonidine.
Conclusions: The findings indicate that prolongation of duration of in vivo lidocaine nerve blockade by clonidine is not mediated by an α-adrenergic mechanism but likely involves the Ih current.
PERIPHERAL nerve blocks are being increasingly used to provide postoperative analgesia because of reduced concern regarding the risks of anticoagulation compared with other forms of regional analgesia.1 Clonidine is commonly injected with local anesthetics to extend the duration of peripheral nerve blocks,2–4 although the optimal dose of clonidine and the mechanism of this effect are not definitely known.4,5
Clonidine is an α-adrenoreceptor agonist with selectivity for α2-adrenoreceptors.6 Therefore, it is possible that α-adrenoreceptors (e.g., via local vasoconstriction) have a role in clonidine enhancement of peripheral nerve blockade.3 In a clinical study involving local anesthetic blockade of the terminal branch of the superficial peroneal nerve, the local tissue lidocaine concentration was increased over time when 10 μg clonidine was added to 1% lidocaine compared with lidocaine alone.7 This observation suggests that a pharmacokinetic mechanism, with some similarity to the effect of adding epinephrine, may be important in clonidine prolongation of lidocaine nerve blockade. However, clonidine enhancement of nerve block cannot be explained entirely by a pharmacokinetic mechanism because the tissue concentration of lidocaine at the time when sensation returned tended to be lower with the lidocaine plus clonidine combination in that study.7 Clonidine alone has local anesthetic properties. In desheathed rabbit vagus nerve, clonidine at doses of 500 μm or greater decreased the amplitude of the compound action potential.8 Similar results have been shown in desheathed rat sciatic nerve in which 450 μm clonidine decreased the C-fiber compound action potential.9 In comparison, when used clinically as an additive to lidocaine, clonidine extends block duration at much lower concentrations (10 μg/ml, 34 μm). Therefore, the clonidine concentration producing the reduction in compound action potential amplitude observed in these in vitro studies is much too high to explain the efficacy of clonidine in the clinical setting.
The exact mechanism by which clonidine potentiates local anesthetic peripheral nerve block has not been precisely elucidated.7,10 Clonidine alters hyperpolarizing afterpotentials of nonmyelinated nerve fibers in vitro.11,12 In desheathed rabbit vagus nerve 50 μm clonidine strongly enhanced both posttetanic and low-frequency hyperpolarization in C fibers.10 The 50% effective concentration for these effects was 8.7–9.6 μm (approximately 2 μg/ml) and therefore well within the range of clonidine’s clinical effectiveness. Interestingly, the same degree of hyperpolarization was achieved with 10 μm of ZD 7288, a specific blocker of the hyperpolarization-activated cation current (Ih).13 In addition, the combination of ZD 7288 plus clonidine did not further enhance the hyperpolarization observed with either agent individually. These results suggest that clonidine enhances activity-dependent hyperpolarizations by inhibiting Ih.10 A previous study had demonstrated that ZD 7288 blocks Ih channels in desheathed rat vagus nerves, leading to enhanced posttetanic hyperpolarization and slowing of conduction in C fibers.14 However, all of these studies are in vitro, and it is not known whether the same results with clonidine or ZD 7288 can be produced in the intact animal.
The aim of the current study is to interrogate the mechanism by which clonidine enhances lidocaine nerve block in an in vivo animal model, defining the clonidine dose–response curve and testing the relative role of α-adrenergic receptors or the hyperpolarization-activated cation current in clonidine prolongation of lidocaine-induced nerve block in intact animals. As a comparison, the epinephrine dose–response curve and the effect of α-adrenergic antagonists was also investigated in the same model.
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Materials and Methods

Sciatic Nerve Block Technique
After Institutional Animal Care and Use Committee approval, experiments were performed on 168 male Sprague-Dawley rats (350–400 g; Sasco, Wilmington, MA). Sciatic nerve block was performed using methods similar to Thalhammer et al.15 Animals were briefly anesthetized with 1.2% isoflurane in oxygen and placed in lateral recumbency. A 16 mm long 25-gauge hypodermic needle, with a prefilled 1 ml tuberculin syringe attached, was inserted percutaneously into the sciatic notch between the greater trochanter and the ischial tuberosity, pointing toward the ischium. Stimulating pulses (0.3 v, 2 ms, 2 Hz, negative polarity) were delivered via a clip lead attached to the top of the needle, and the syringe/needle was advanced until a vigorous ipsilateral hindleg kick was observed. Then, 0.5 ml test drug solution was injected over 5 s and the needle was removed after an additional 5 s.
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Criteria For Nerve Block
Before drug injection, animals were placed on a metal grid and sensory response was evaluated by observation of foot withdrawal when a pin was applied to the plantar midline surface of the ipsilateral hind paw (tibial nerve distribution). Any foot withdrawal, whether sciatic or femoral nerve mediated, was considered a response. Motor response was evaluated by observation of the toe-spreading reflex (sciatic nerve motor fibers), a vestibular reflex induced by lifting the rat and generating a response with the toes extended and spread. For both tests, responses were rated as present or absent.
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Drug Injection Protocols
For the single injection studies, baseline sensory (pin) and motor (toe spread) responses were recorded and 0.5 ml drug was injected into the sciatic notch. Animals were then reevaluated at 10-min intervals for the absence or presence of sensory and motor responses. Because the animals are anesthetized for injection, the initial 10-min evaluation cannot be a precise indicator of the actual onset time, and so the duration of nerve block is calculated as the latency from the end of the injection to the return of response. Drug solutions consisted of 1% lidocaine (commercial preservative-free solution intended for nerve block; Xylocaine-MPF, AstraZeneca, Wilmington, DE) with or without added clonidine hydrochloride or epinephrine hydrochloride at concentrations of 0–25 μg/ml. In control experiments, clonidine or epinephrine alone at 25 μg/ml was injected into the sciatic notch. Animals were also monitored for overt sedation at 30 min postinjection by testing ability to ambulate on a rotating rod (10 rpm, 180 s). Clonidine or epinephrine were also injected intraperitoneally in 0.5 ml volume, 5 min before the sciatic notch injection of lidocaine in some experiments, to determine if clonidine or epinephrine were acting at a distal site (in addition to the sciatic nerve site) reached by systemic absorption. The selective α1-adrenergic antagonist prazosin (1 or 2 mg/kg) or the selective α2-adrenergic antagonist yohimbine (1, 2, or 4 mg/kg) were injected intraperitoneally 5 min before the sciatic notch injection of lidocaine plus 2.5 μg/ml clonidine to ascertain if receptors outside of the sciatic nerve bed contribute to clonidine modulation of lidocaine nerve block. The drug solutions were prepared by one of the investigators (J.S.K.), and the personnel (D.R.B., J.E.T., D.E.W.) performing the drug injections, behavioral assessments, data recording, and group statistics were blinded to the drug identities.
For adrenoreceptor antagonist studies, animals were first injected into the sciatic notch (0.5 ml) with prazosin hydrochloride (up to 40 μg/ml) or yohimbine hydrochloride (up to 100 μg/ml). The second sciatic notch injection of lidocaine with clonidine or epinephrine was administered 10 min later. In one additional experiment, the time between the first and second injections was increased to 60 min. All lidocaine alone animals for these experiments had a saline preinjection. In control experiments, prazosin 40 μg/ml or yohimbine 100 μg/ml alone was injected into the sciatic notch.
For Ih channel studies, the Ih blocker ZD 7288 (14, 56, 280, or 650 μg/ml) was first injected into the sciatic notch (0.5 ml), and 60 min later the second sciatic notch injection of lidocaine with or without clonidine was performed to determine the role of Ih channel blockade in extending the duration of nerve block. A 60-min delay was chosen between the first and second injections because even with desheathed nerve preparations at least 20 min of perfusion for ZD 7288 is required to effect Ih and the duration of action can be 2 or more hours.10,14 As the adenylyl cyclase activator forskolin and the cell-permeable cAMP analog 8-Br-cAMP have been shown to enhance Ih in nerve cells in vitro,16 forskolin (21 or 63 μg/ml) or 8-Br-cAMP (1.28 or 4.3 mg/ml) were injected into the sciatic notch and 10 min later the second sciatic notch injection of lidocaine with or without clonidine was performed to determine if Ih enhancement could decrease the duration of nerve block.
For all multiple injection experiments, duration of nerve block was timed to the end of the second injection. ZD 7288 was obtained from Tocris (Ballwin, MO) and all other drugs were from Sigma (St. Louis, MO). All drugs were directly dissolved in 0.9% sodium chloride injection, except forskolin, which was initially solubilized in dimethylsulfoxide, and then diluted in saline (final dimethylsulfoxide concentration 2%).
Animals received drug injections on either side at 5–7 day intervals, alternating between the left and right leg on different days. Multiple injections administered days apart were allowed because a previous study had demonstrated that a second lidocaine injection onto the sciatic nerve 24 h after the first injection produces an identical functional block.17 In addition, in a previous study in which 1% lidocaine was infused into a silicone rubber cuff surrounding the rat sciatic nerve three times a day for 3 days, we found no nerve fiber degeneration, no damage to underlying muscle, and no loss of motor function.18
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Statistical Analysis
In the dose–response studies, duration of nerve block at different added clonidine or epinephrine doses was compared by analysis of variance with post hoc comparison to the lidocaine alone group with Dunnett’s test. Student t test was used for comparison of nerve block duration after sciatic notch injection of added clonidine or epinephrine with duration after systemic injection of the same dose. In the receptor antagonist and Ih modulator experiments, the sensory block durations attributable to different drug combinations were compared by analysis of variance, followed by post hoc comparison with the Tukey-B test. All data in figures are shown as mean ± SEM. Statistical analysis was performed by one investigator (J.S.K.).
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Clonidine and Epinephrine Dose Response
Fig. 1
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Fig. 2
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The dose response curve for duration of nerve block with clonidine added to 1% lidocaine is shown in figure 1. In these experiments, the duration of sensory block for 1% lidocaine alone was 69 ± 2 min, and the duration of motor block was 72 ± 2 min. For comparative purposes, the dose–response curve for duration of nerve block with epinephrine added to 1% lidocaine is shown in figure 2. In these experiments, the duration of sensory (pinprick withdrawal) block for 1% lidocaine alone was 68 ± 3 min, and the duration of motor (toe-spreading reflex) block was 71 ± 2 min. With either drug the dose–response curve is monotonic, with the higher dose always producing a longer duration of blockade. None of the drug combinations affected the toe-spreading reflex in the contralateral limb. Because there was no difference between the duration of block using the pinprick test versus the toe-spreading reflex, for either lidocaine/clonidine (fig. 1) or lidocaine/epinephrine (fig. 2), only pinprick testing results are subsequently displayed for the α-adrenoreceptor and the Ih modulator studies.
Sciatic notch injection of clonidine or epinephrine alone at 25 μg/ml did not produce measurable sensory or motor blockade, nor did either produce overt sedation (rotating rod test). Systemic injection (intraperitoneal) of 25 μg/ml epinephrine before lidocaine injection did not extend the duration of sensory or motor block. However, systemic clonidine injection at the 25 μg/ml dose extended the duration of motor block by 14 min. At lower doses (15 μg/ml or less) there was no extended motor block with systemic clonidine preinjection. At the 25 μg/ml dose, systemic clonidine injection demonstrated a trend toward increased duration of sensory block (10 min increase, P = 0.067), and at lower doses (15 μg/ml or less) there was no increased duration of sensory block compared with lidocaine alone (intraperitoneal saline preinjection).
Systemic preinjection of prazosin, 1 mg/kg intraperitoneal, did not alter the duration of sensory block of lidocaine plus 2.5 μg/ml clonidine. Preinjection of prazosin, 2 mg/kg intraperitoneal, increased the duration of sensory block (114 ± 6 min with prazosin versus 92 ± 2 min with saline preinjection). Prazosin, 4 mg/kg intraperitoneal, was not tested because that dose decreased ambulation time on the rotating rod. Systemic preinjection of yohimbine, 1, 2, or 4 mg/kg intraperitoneal, did not alter the duration of sensory block of lidocaine plus 2.5 μg/ml clonidine. At 4 mg/kg yohimbine intraperitoneal, the block duration was 99 ± 6 min versus 101 ± 5 min with saline preinjection.
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Antagonist Studies
Fig. 3
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Epinephrine at 1.6 μg/ml increased the sensory block duration by approximately 50% of the maximum effect (seen at the 25 μg/ml dose). Using this intermediate 1.6 μg/ml dose, the α-adrenergic antagonists prazosin or yohimbine were given before the lidocaine/epinephrine combination. Prazosin at 10 μg/ml reduced the duration of sensory block of the lidocaine/epinephrine combination to that of lidocaine alone (fig. 3). Yohimbine at 40 μg/ml had no effect on the duration of the lidocaine/epinephrine induced sensory block.
Fig. 4
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Clonidine at 2.5 μg/ml increased the sensory block duration by approximately 50% of the maximum effect (seen at the 25 μg/ml dose). Using this intermediate 2.5 μg/ml dose, the α-adrenergic antagonists prazosin or yohimbine were given before the lidocaine/epinephrine combination. Neither prazosin at 40 μg/ml nor yohimbine up to 100 μg/ml altered the duration of the sensory block of the lidocaine/clonidine combination (fig. 4). The same result was obtained when the time between the first and second injections was increased to 60 min or with a 15 μg/ml dose of clonidine. Sciatic notch injection of prazosin or yohimbine alone at these same doses did not produce any sensory or motor blockade, nor did either produce overt sedation.
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Fig. 6
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When the Ih blocker ZD 7288 was injected into the sciatic notch at 650 μg/ml, the duration of lidocaine sensory block increased by 39 min (fig. 5). A similar increase in block (35 min) could be obtained with the addition of 15 μg/ml clonidine to lidocaine. Preinjection of ZD 7288 before that same lidocaine/clonidine combination did not produce any additional prolongation of sensory block duration compared with the lidocaine/clonidine combination alone. A lower dose of ZD 7288 (280 μg/ml) followed by lidocaine produced a smaller increase in lidocaine sensory block (20 min). The lowest doses of ZD 7288 (14 or 56 μg/ml) did not prolong lidocaine nerve block duration. Preinjection of forskolin at 63 μg/ml (150 μm) decreased the duration of lidocaine sensory nerve block by 19 min (fig. 6A). When forskolin at 63 μg/ml was given before the combination of lidocaine and 15 μg/ml clonidine, the duration of sensory nerve block was decreased by 54 min. A lower dose of forskolin (21 μg/ml) followed by lidocaine also reduced the duration of sensory block (13 min). Preinjection of 8-Br-cAMP at 4.3 mg/ml (10 mm) decreased the duration of lidocaine sensory block by 22 min (fig. 6B). When 8-Br-cAMP at 4.3 mg/ml was given before the combination of lidocaine and 15 μg/ml clonidine, the duration of sensory nerve block was decreased by 34 min. A lower dose of 8-Br-cAMP (1.28 mg/ml) followed by lidocaine did not reduce the duration of lidocaine sensory block, although that dose still decreased the duration of lidocaine/clonidine block by 34 min.
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Clonidine and Epinephrine Dose Response
In the animal model, the dose response curve for clonidine or epinephrine added to 1% lidocaine did not demonstrate any U-shaped characteristics in which higher doses would be less effective than lower doses in producing nerve block. Both dose–response curves represent monotonic functions. Our animal study does not provide an explanation for the reported finding that lower doses of clonidine added to lidocaine could be more effective in patients than higher doses of clonidine under certain conditions.4,5
Although epinephrine is slightly more potent than clonidine, no direct comparison is made between the two curves, as our study demonstrated that the two compounds act by different mechanisms. Notably, however, the epinephrine dose–response curve is similar to that measured in humans when 1% lidocaine was infiltrated subcutaneously with epinephrine in four doses from 0.3–20 μg/ml, and the half-maximum response (pinprick) was observed at a concentration of about 1.25 μg/ml.19
Sciatic nerve injections of 25 μg/ml clonidine alone did not produce sensory or motor block. This is consistent with in vitro experiments that demonstrate a local anesthetic effect of clonidine only at high doses (500 μm = 134 μg/ml)8,9 and an in vivo sciatic notch injection experiment showing that 1000 μm clonidine alone did not cause detectable nerve block using the hot plate test.20 One clinical study also showed that local application of clonidine alone (150 μg in 15 ml) onto the brachial plexus did not produce a local anesthetic effect.21 Although 25 μg/ml clonidine alone did not produce overt sedation, it may still have effects in the central nervous system related to systemic absorption. This is evidenced by the increased duration of motor block and the slight increase in sensory block with intraperitoneal clonidine combined with lidocaine, at the highest dose. The toe-spreading reflex is initiated by vestibular input, and higher doses of clonidine may have sedative effects in the brain.6,22 In patients, doses of 150 μg or greater in nerve block mixtures produce significant sedation.2,4 Therefore, the effects of large doses of clonidine on nerve block can be attributable to both local and central actions. Because systemic doses of clonidine 15 μg/ml or lower did not extend the duration of lidocaine nerve block, central nervous system inhibition does not appear to be an important factor over most of the useful clonidine dose range. This is supported by antagonist experiments showing that systemically administered α-adrenoreceptor antagonists did not reduce clonidine prolongation of lidocaine nerve block. The increase in lidocaine/clonidine sensory nerve block duration with 2 mg/kg prazosin preinjection may be attributable to mild sedation or motor impairment at that prazosin dose because other rodent studies have shown that prazosin, 2 mg/kg, decreases locomotion,23 and our 4 mg/kg dose caused impairment on the rotating rod. In the dose–response curves, there was no ambiguity with epinephrine at higher doses, as intraperitoneal epinephrine at 25 μg/ml did not extend the duration of lidocaine sensory or motor block.
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α-Adrenergic Receptors Do Not Contribute to Clonidine Prolongation of Nerve Blockade
It is widely believed that the effect of epinephrine on extending the duration of lidocaine nerve block is the result of vasoconstriction,24,25 and our study is in accord with that mechanism. The α1-adrenergic antagonist prazosin completely blocked the increased duration of analgesia and motor block obtained when epinephrine was added to lidocaine in the local injection mixture. Interestingly, the α2-adrenergic antagonist yohimbine was without measurable effect, although α2-adrenergic receptors are mediators of vasoconstriction in some blood vessels.26,27
Although clonidine could have local vasoconstrictive effects that might slow absorption of lidocaine, one clinical study did not show any prolongation of plasma lidocaine concentration when a clonidine/lidocaine admixture was used for brachial plexus block, whereas the epinephrine/lidocaine combination did produce this effect.2 However, in another study with blockade of the human dorsal cutaneous nerves, the tissue lidocaine concentration was increased when 10 μg/ml clonidine was added to 1% lidocaine compared to lidocaine alone, suggesting that the prolongation of nerve block was at least partially pharmacokinetically mediated.7 Nevertheless, we did not find any clonidine-induced prolongation of nerve block that could be attributed to α-adrenergic receptors. Although we did not examine the complete displacement of the dose–response curves with the α-adrenergic antagonists, the absence of any effect at an intermediate dose (2.5 μg/ml) or a high dose (15 μg/ml) makes it unlikely that our methodology was insufficiently sensitive to detect α-adrenergic interaction. It is possible that the deep sciatic nerve site in the animal study differs from the superficial tissue bed of human cutaneous nerves with respect to blood vessels subject to vasoconstriction24 or that there may be a species difference in α-adrenoreceptor distribution. Another consideration is that peripheral nerve block involves a balance between the amount of drug outside the peripheral nerve and that within the perineurial space,28 and this balance may also vary among different injection sites.
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Role of the Hyperpolarization-activated Cationic Current
In vitro studies with desheathed peripheral nerve suggest that Ih currents, which are among the determinants of nerve after-potentials, may explain how clonidine potentiates local anesthetic action. The Ih blocker ZD 7288 produces slowing of conduction in rat C-fibers.14 When ZD 7288 at 10 μm (3 μg/ml) is applied to the isolated vagus nerve, activity-dependent hyperpolarization is enhanced, presumably by blocking the depolarizing effect of Ih.10 Clonidine 50 μm (13 μg/ml) produces a similar enhancement of activity-dependent hyperpolarization. However, combining the two drugs did not produce any additional hyperpolarization, implying that clonidine enhances this hyperpolarization by inhibiting Ih.10 We obtained the same combination of effects with the in vivo animal model. The only quantitative difference was that the concentration of ZD 7288 used in our study was 650 μg/ml. The likely reason for this difference is that ZD 7288 is a relatively hydrophilic compound,13 and therefore a much higher concentration is required to allow penetration through the perineurium and access to nerve fibers, unlike the in vitro experiments with desheathed nerve. The 15 μg/ml clonidine dose was used in this experiment, rather than a 25 μg/ml dose, as the systemic injection experiments showed that at the higher dose, part of the effect of clonidine may be attributable to central effects not directly related to the peripheral nerve activity. Compounds that stimulate adenylyl cyclase (forskolin) or are cAMP analogs (8-Br-cAMP) have been shown in vitro to enhance Ih in neurons16,29 or in dorsal root ganglion cells.30 It is not known if these compounds have the same effect in vitro on peripheral nerve. The decreased duration of nerve block seen in our experiments when either compound was injected before lidocaine/clonidine is consistent with the hypothesis that in vivo nerve blockade is modulated via Ih channel activity. Further confirmation of these results with electrophysiological studies would reinforce this hypothesis.
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The exact doses of clonidine used in the dose–response part of our rat study cannot be precisely compared with those used in clinical studies because the injection volume and site and amount of perfused tissue are different. However, the amount of added clonidine (2.5 μg/ml) required to produce a moderate enhancement of sensory nerve block duration is consistent with the sensitivity seen in clinical studies.2,4,5,31 One limitation of our study is that animals received more than one sciatic nerve injection (5–7 days apart), and so it is possible that there was some carryover effect of lidocaine or clonidine not anticipated by the authors. Also, as a result of the use of electrical stimulation for nerve location, the animals had to be briefly (<2 min) anesthetized during performance of the nerve block procedure. However, it has been shown that there is no difference in duration of sciatic nerve blockade performed under brief general anesthesia versus when awake, in animals injected with a local anesthetic (bupivacaine).32 Clonidine also binds to imidazoline receptors in the brainstem and has antagonist actions at the I1 receptor subtype.33 However, no I1 selective antagonists are available.34 When such compounds become available, it would be worthwhile to perform additional antagonist studies to examine if the I1 receptor can also mediate lidocaine/clonidine analgesia in a manner similar to the imidazoline receptor mediated antihypertensive effect.33
Our study is also in accord with clinical studies showing no advantage to using clonidine instead of epinephrine in lidocaine admixtures with respect to duration of nerve block.2,35 However, in patients with hypertension, cardiovascular disease, or hyperthyroidism,2 or where there is concern about local ischemia as a result of vasoconstriction, clonidine can be an effective alternative to epinephrine.
In conclusion, our results suggest that Ih channel blockade, and not α-adrenoreceptor activity, contributes to clonidine enhancement of in vivo lidocaine block of the sciatic nerve.
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