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Anesth Analg 2000;90:400
© 2000 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MANAGEMENT

Antinociception by Epidural and Systemic {alpha}2-Adrenoceptor Agonists and Their Binding Affinity in Rat Spinal Cord and Brain

Toshio Asano, MD, Shuji Dohi, MD, Shuichiro Ohta, MD, Hiroyuki Shimonaka, MD, and Hiroki Iida, MD

Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, Gifu City, Gifu, Japan

Address correspondence and reprint requests to Shuji Dohi, MD, Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, 40 Tsukasamachi, Gifu City, Gifu 500-8705, Japan. Address e-mail to shu-dohi{at}cc.gifu-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
This study was designed primarily to relate the antinociceptive and hemodynamic effects of clinically available {alpha}2-adrenoceptor agonists to their binding affinity for {alpha}2-adrenoceptors in the spinal cord and brain. In rats with chronic indwelling epidural catheters, the percentage maximal possible effect on tail-flick latency was measured after epidural or IM dexmedetomidine (DXM), clonidine (CL), or tizanidine (TZ) administration. To examine their binding affinities, isolated spinal cord and brain membranes with an {alpha}2 agonist were incubated with 3H-UK14304, a selective {alpha}2 agonist, and the radioactivity in the reaction mixtures was measured by liquid scintillation spectrometry. Epidural DXM (0.5–10 µg), CL (10–500 µg), and TZ (5–500 µg) all produced dose-dependent antinociceptive effects; the rank order of potencies was DXM > CL > TZ, the same as for their systemic administration. The antinociceptive effects were blocked by epidural yohimbine. The receptor binding affinities expressed as the concentration that inhibits 50% for spinal cord and brain, respectively, were 0.25 and 1.3 nM (DXM), 10.8 and 12.5 nM (CL), and 48.2 and 96.8 nM (TZ). The changes in arterial blood pressure and heart rate evoked by antinociceptive doses did not correlate with the rank order of antinociceptive potencies. The relative antinociceptive potencies of epidural {alpha}2 agonists may depend on their binding affinities to {alpha}2-adrenoceptors in the spinal cord, but their cardiovascular effects may result from actions both inside and outside the central nervous system.

Implications: Spinal antinociception caused by the epidural administration of {alpha}2 agonists is well correlated with their binding affinity to spinal {alpha}2-adrenoceptors.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Over the last two decades, there has been a considerable accumulation of experimental and clinical data relating to the pharmacology of {alpha}2-adrenoceptor agonists ({alpha}2 agonists), and their clinical use in anesthesia has increased. Among their many clinically significant properties, including sedative, anxiolytic, analgesic, and hemodynamic stabilizing effects (1,2), the antinociceptive actions of spinally or systemically administered {alpha}2 agonists are significant and varied. Indeed, the {alpha}2 agonists dexmedetomidine (DXM), clonidine (CL), and tizanidine (TZ), which are clinically available, seem to have a diversity of actions; thus, one drug may have a potent hypnotic action when given systemically, while another has a potent analgesic action when given spinally. Several clinical observations have suggested that oral CL has effects similar to those seen during its spinal administration (a potentiation of the neuronal block induced by spinal anesthesia) (3,4). Systemic (oral) administration of TZ produces sedative and hypnotic effects (5), and prolongs tetracaine spinal anesthesia (6).

However, whether there are differences in efficacy between systemically and epidurally administered {alpha}2 agonists is not known. Further, although {alpha}2 agonists are thought to produce antinociceptive effects via activation of spinal and supraspinal {alpha}2-adrenoceptors, no studies have examined the correlation between their analgesic potency and their relative binding affinity to {alpha}2-adrenoceptors in brain and spinal cord using the same experimental model. In addition, no study has yet compared the binding affinity of a given {alpha}2-adrenoceptor between the spinal cord and brain. Because it is possible that the different effects seen with different {alpha}2 agonists could be caused by differences in binding affinity between spinal and supraspinal neuronal structures, we undertook the present study in rats primarily to examine the analgesic action of three {alpha}2 agonists when they were given by systemic or epidural injection and to try to relate their analgesic effect to their binding affinity to {alpha}2-adrenoceptors in the spinal cord and brain.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
All experimental procedures in the present study were approved by our animal research committee.

Adult male Sprague-Dawley rats, weighing 350–450 g, were anesthetized with pentobarbital (50 mg/kg, intraperitoneally). Each animal was prepared for the implantation of a permanent, indwelling epidural catheter. Briefly, after a midline incision and a laminectomy at T12, a polyethelene-10, 15-cm long catheter with an approximate volume of 15 µL (Natsume Co Ltd, Tokyo, Japan) was inserted into the epidural space under direct visual control, then advanced 2 cm toward the tail so that the tip was at approximately the L1-2 spinal level. The catheter was cemented to the bone, and its end was plugged with a stainless steel insert. The free end of the catheter was exteriorized through a second skin incision in the midline over the upper cervical area by tunneling it under the skin. The cervical portion of the catheter was fixed to the fascia of the neck muscles with nylon suture. After surgery, all animals were housed individually in a temperature- and light-controlled environment with free access to food and water. The patency of the catheter was checked periodically. Each animal received one or three of the drugs tested, with an interval of 2–4 days between administrations of the drugs tested. Any animals exhibiting signs of a neurological or motor deficit were eliminated from the study. Fifty-five rats were instrumented during the course of this investigation. Eight rats were excluded for neurological deficit. After the completion of drug testing, bromphenol blue was injected to aid postmortem verification of catheter positioning in each animal.

Animals were allowed 7 days to recover from surgery, and 2% lidocaine (150 µL) was injected through the epidural catheter to confirm correct positioning. The rats were habituated daily to the laboratory environment and to the analgesia-testing apparatus. An evaluation of the antinociceptive effect of each of the three {alpha}2 agonists, administered epidurally or IM, was performed by using the tail-flick test. The doses used were DXM (0.5, 1, 5, and 10 µg epidurally and 5 and 50 µg IM), CL (10, 25, 50, 100, 125, 250, and 500 µg epidurally and 10, 100, and 1000 µg IM), and TZ (5, 10, 50, 100, 250, and 500 µg epidurally and 100 and 1000 µg IM). A combination of yohimbine, an {alpha}2-adrenoceptor antagonist, and a given {alpha}2 agonist was administered epidurally to challenge the effect of the agonist. The numbers of rats used to test each drug or combination was six for each dose. A custom-made tail-flick apparatus was used to assess the ther- mal nociceptive response. It consisted of a variable-intensity 50-W quartz projector bulb, focused approximately 2 cm from the upper surface of the tail, and a photodetector-automatic timer. The latency to respond after the onset of the radiant heat stimulus was monitored, the first visible twitch or flick being taken as the response. Light intensity was adjusted to yield a 3- to 4-s mean baseline latency, and the automatic cutoff was set at 10 s to avoid damage to the tail. The compounds to be tested were dissolved in sterile saline and injected in a volume of 50 µL for epidural or 200 µL for IM administration. After each injection, the catheter was flushed with sterile saline (20 µL), with the flush completed within 5 min. Postdrug latency measurements were performed between 10 and 30 min after the injection. The difference between the baseline and postdrug latencies constituted the analgesic response at a given time point. These values were normalized further to give values of percentage maximal possible effect (%MPE) using the following formula:


where TF is the postdrug tail-flick latency (in s), BL is the baseline latency (in s), and 10 s is the cutoff time. Thus, a %MPE value of 100 meant that the postdrug tail-flick latency had increased to 10 s. The ED50 value was taken as the half-maximal effective dose calculated from the dose-response curve for each animal.

For the first 30 min after the drug administration, systolic arterial blood pressure (AP) and heart rate (HR) were determined in conscious, warmed, restrained rats by a tail-cuff method, by using a programmed sphygmomanometer (MK-1000, Muromachi Kikai Co., Tokyo, Japan). The values given are the percentage changes (%Change in AP or HR) from baseline values, calculated by using the following formula: Go


The rats used for AP and HR measurements did not take part in the testing of tail-flick latencies.

To obtain whole brains and spinal cords, adult male Sprague-Dawley rats (200–250 g) were killed by decapitation without anesthesia (5 rats and 20 rats, respectively). The brain or spinal cord was rapidly removed, processed on ice, and homogenized in a 20 times volume of 0.32 M sucrose using a Biotron (Kimura Co, Tokyo, Japan). The homogenate was centrifuged (1000 g) for 10 min at 4°C. The supernatant was recentrifuged (20,000 g) for 20 min at 4°C; then, the pellet was washed twice with 50 mM Tris-HCl buffer (pH 7.4) by centrifugation (20,000 g) for 20 min at 4°C. The final pellet (crude synaptosomal fraction, P-2) was resuspended in Tris buffer and stored at -80°C until use.

A modification of {alpha}2 receptor binding assays of Loftus et al. (7) was used. The binding experiments were performed at 25°C for 40 min in duplicate by incubating the crude synaptosomal fraction with 2 nM of 3H-UK14304, a selective {alpha}2 agonist, in the presence or absence of various concentrations of tested agonists. Then, the reaction mixture was filtered rapidly through G-10 glass filters (Inotech, Dottikon, Switzerland) under reduced pressure (400 mbar) using a Cell Harvester System (Inotech) to trap the labeled membrane fragments, followed by a 3 x 3-mL washing with ice-cold Tris buffer. The residues on the filter were solubilized in a 4-mL liquid scintillation cocktail, and the radioactivity was measured by means of a liquid scintillation counter (Beckmann-LS9000, Fullerton, CA). The specific binding of 3H-UK14304 to {alpha}2-adrenoceptors was calculated from the difference between the counts obtained in the presence and absence of 2 mM clonidine. Then, the apparent dissociation constant (Kd) and the maximal binding capacity (Bmax) values were calculated from the saturation curves by using a concentration range of 0.1 to 5 nM of 3H-UK14304. Competition experiments of {alpha}2 agonists were performed with fixed concentration of 3H-UK14304. Ki values were calculated from competition data with Ki = IC50/(1 + L/Kd), in which IC50 was the concentration of unlabelled ligand that caused 50% inhibition of binding of 3H-UK14304, L was the concentration of radioligand, and Kd was the equilibrium dissociation of 3H-UK14304. Protein content was determined with the BCA® assay (Pierce, Rockford, IL) by using bovine serum albumin as protein standard. IC50 values were calculated from log regression-fitting of the dose-response data plotted. Data of saturation and displacement experiments were analyzed by using the nonlinear curve-fitting program LIGAND (8).

The mean values for ED50 or IC50 and Ki were evaluated for significant differences among the three {alpha}2 agonist groups using a one-way analysis of variance followed by post hoc testing by using the Scheffé method. The mean ED50 values for each {alpha}2 agonist were evaluated for significant differences between epidural and IM injection by using an unpaired t-test. The mean IC50 and Ki values for each {alpha}2 agonist were evaluated for significant differences between spinal cord and brain membranes by using an unpaired t-test. %Changes in HR and AP in each {alpha}2 agonist group were evaluated for significance by using analysis of variance followed by post hoc testing using the Scheffé method. P < 0.05 was considered to be significant.

Dexmedetomidine hydrochloride was provided by Abbott Laboratories, Abbott Park, IL; clonidine hydrochloride and yohimbine hydrochloride (MW 390.9) were obtained from Sigma Chemical Co, St. Louis, MO; tizanidine hydrochloride was provided by Sandoz Pharmaceuticals Ltd (Novartis Pharma K.K. at present), Tokyo, Japan; morphine hydrochloride (MW 321.8) was provided by Takeda Chemical Industries Ltd, Osaka, Japan; and 3H-UK14304 (76.5 Ci/mmol) was obtained from New England Nuclear, Boston, MA.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Antinociceptive Effects
In preliminary experiments, epidurally or IM injected morphine induced antinociceptive effects in a dose-dependent manner (Figure 1A), the ED50 values being 13.4 ± 2.1 and 285 ± 23.3 µg/rat, respectively (mean ± SEM, n = 6).



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  		Figure 1. Log dose-response curves for the antinociceptive effects of epidurally (epid) or IM administered morphine (A), dexmedetomidine (DXM), clonidine (CL), and tizanidine (TZ) (B). The percentage of the maximal possible effect (%MPE) was calculated from the latency in the tail-flick test obtained in the first 30 min after the administration of the drug. The antinociceptive effect versus time course with each drug at typical doses for 30 min were presented in C and D. Each point represents the mean ± SEM for 3–7 rats.

 
DXM, CL, and TZ administered into the epidural space induced a dose-dependent increase in tail-flick latency (Figure 1B). The increased latencies with each agonist were constant for 30 min after its administration. Epidural saline induced slight hyperalgesia (%MPE = -11.6 ± 8.5, n = 6) in our experimental model. (Figure 1, C and D). Epidurally administered yohimbine did not itself significantly affect tail-flick latency at a dose of 250 µg (%MPE = -7.7 ± 2.8, n = 6), but its pretreatment significantly reduced the measured increase in %MPE induced by epidural {alpha}2 agonists (Figure 2). Likewise, on systemic administration, DXM, CL, and TZ each induced a dose-dependent increase in tail-flick latency (Figure 1B). For both epidural and systemic administration, the rank order of the antinociceptive potencies (compared by using the mean ED50 values) was DXM > CL > TZ (Table 1). DXM, CL, and TZ each exhibited a significantly greater antinociceptive potency on epidural than on systemic administration as assessed using the ED50 values.



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  		Figure 2. Blockade of the antinociceptive effects of epidural dexmedetomidine (5 µg), clonidine (100 µg), and tizanidine (100 µg) by epidural yohimbine (250 µg). Columns present the maximal possible effect (%MPE) (mean values ± SEM) for the following groups of rats: {alpha}2 agonist alone (n = 6), yohimbine + {alpha}2 agonist (n = 6), and yohimbine alone (n = 6).

 

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  		Table 1. ED50 Values (µg/rat) for Antinociceptive Effect and IC50 Values (nmol/l) for Binding Affinity of {alpha}2 Agonists
 
{alpha}2-Adrenoceptor Binding
In 50 mM Tris-HCl buffer at 25°C, specific binding of 3H-UK14304 (2 nM) reached equilibrium within 30 min and was maintained for at least 60 min. Nonspecific binding was <30% of total 3H-UK14304 binding. Saturation experiment data revealed, in both brain and spinal cord membranes, a single binding site with a Kd value of 1.63 ± 0.14 nM and 1.13 ± 0.17 nM, and Bmax value of 97.3 ± 9.3 fmol/mg protein and 79.1 ± 6.4 fmol/mg protein, respectively.

DXM, CL, and TZ each induced a concentration-dependent increase in the %inhibition of 3H-UK14304 stereospecific binding (Figure 3). The rank order of their binding affinities for {alpha}2-adrenoceptors (compared by using the mean IC50 and Ki values) was DXM > CL > TZ (Table 1) for both brain and spinal cord membranes. The binding affinity of CL in the spinal cord was not significantly different from that in the brain. In contrast, the binding of DXM and TZ was significantly greater in the spinal cord than in the brain (Table 1).



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  		Figure 3. Log dose-response curves for the effects of dexmedetomidine (DXM), clonidine (CL), and tizanidine (TZ) on displacement of 3H-UK14304-binding in brain (open symbols) or spinal cord (closed symbols) membranes in rats. Each symbol indicates the percentage inhibition of binding plotted against the log concentration (M: mol/L) of the appropriate {alpha}2 agonist. Mean values ± SEM from three independent experiments, each performed in duplicate.

 
At doses large enough to produce near-maximal antinociceptive effects, epidural DXM (10 µg), CL (100 µg), and TZ (100 µg) significantly decreased HR (Figure 4). Conversely, at larger doses of epidural DXM and CL, there were trends toward relative increases in AP. Epidural TZ tended to decrease AP at either dose, but the effects didn’t significantly differ from those in the saline group. On IM administration, DXM (10 and 100 µg), CL (100 and 1000 µg), and TZ (100 and 1000 µg), each significantly decreased HR at both doses tested. On IM administration at the larger of those two doses (which produced maximal antinociceptive effects), DXM, CL, and TZ each significantly increased AP.



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  		Figure 4. Percentage changes from the baseline in systolic arterial blood pressure (AP) and heart rate (HR) in the first 30 min after epidural or IM administration of dexmedetomidine (DXM), clonidine (CL), or tizanidine (TZ). Dose 0 indicates control, which was given a 50 µL of normal saline solution. Data are presented as mean ± SEM; n = 5 for each group. Significantly different (P < 0.05) from: * saline group (0); {dagger} the small dose of the same {alpha}2 agonist.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our results indicate that, whether given systemically or epidurally, the {alpha}2 agonists DXM, CL, and TZ each produce a dose-related antinociceptive effect in chronically catheterized rats. The effects were approximately 5 times greater on epidural than on systemic administration, and the former was completely blocked by epidural yohimbine. In our model, epidural saline and yohimbine produce slight hyperalgesia and TZ’s potency was the smallest in the three {alpha}2 agonists. The rank order of antinociceptive potencies (based on changes in %MPE) for the three {alpha}2 agonists, regardless of whether they were given epidurally or systemically, was DXM > CL > TZ. This rank order for their antinociceptive effect was the same as that for their binding affinity to {alpha}2-adrenoceptors in the spinal cord, but not the same as that for the changes in AP and HR evoked by doses producing near-maximal antinociception. The binding affinity of DXM and TZ for {alpha}2-adrenoceptors was significantly greater in spinal cord membranes than in the brain, but the binding affinity of CL did not differ between spinal cord and brain. Potentially, these findings could help establish a background for the assessment of the spinal antinociception induced by {alpha}2 agonists directly injected in close proximity to neuronal structures.

Several studies have indicated that on intrathecal administration in rats, the {alpha}2 agonists DXM (9,10), CL (9,10,11), and TZ (11,12) [and others such as ST-91 (9,10)] produce an antinociceptive effect that can be inhibited or attenuated by {alpha}2-adrenoceptor antagonists such as yohimbine. In addition, many clinical studies have indicated that epidural {alpha}2 agonists such as CL, given alone or in combination with local anesthetics (13) or opioids (14), may have an analgesic effect or potentiate another drug’s analgesic effect (1). The epidural route is probably more applicable to clinical practice than the intrathecal one, and the present study is the first to provide comparative data on the antinociceptive effect, probably via activation of spinal {alpha}2-adrenoceptors, produced epidurally by the three {alpha}2 agonists clinically available at present. The spinal antinociception induced by {alpha}2 agonists is mediated by an inhibition of synaptic transmission within the dorsal horn of the rat’s spinal cord (15), principally (a) via a direct suppression of the activity of dorsal horn neurons (16), (b) via an activation of the descending noradrenergic inhibitory system (17), and (c) via an activation of spinal cholinergic neurons (18).

{alpha}2-Adrenoceptors are found at many sites in the spinal cord, including the dorsal horn and ventral horn (ventral > dorsal) (19) and in the cerebral cortex in humans (20), and three subtypes have been cloned, {alpha}2A, {alpha}2B, and {alpha}2C (21). In rats, the {alpha}2A-adrenoceptor subtype is involved in {alpha}2 agonist-induced antinociceptive (10,22) and hypnotic action (23) of {alpha}2 agonists. Using ligand binding, Lawhead et al. (24) and Smith et al. (19) found that {alpha}2-adrenoceptors are in their largest concentration in the sacral > lumbar = thoracic regions of the human spinal cord, and that, in any given region of the spinal cord, the {alpha}2A-adrenoceptor subtype accounts for at least 80%–90% of the {alpha}2-adrenoceptor population.

Until now, there has been neither a comparative study of the antinociceptive effects produced by systemic as opposed to spinal administration of {alpha}2 agonists nor a comparative study of their binding affinity for {alpha}2 adrenergic receptors in brain as opposed to spinal cord. Their rank order of potencies against nociceptive responses and the behaviors probably reflect differences in their agonist-receptor binding or selectivity (25) or in their heterogenicity (26) and may perhaps reflect differences in binding affinity between spinal cord and brain. Using systemic and intrathecal administration of {alpha}2 agonists, Yaksh et al. (27,28) concluded that {alpha}2 agonists modulate nociception through an action within the spinal cord, whereas supraspinal sites mediate their sedative effect. In the supraspinal region, their action on the locus ceruleus is considered to result in an increased activation of {alpha}2-adrenoceptors in the spinal cord (29). Although we used whole brain and whole spinal cord for our ligand binding study, leading to certain inherent limitations, the data may provide a framework for a more detailed evaluation of the clinical differences among {alpha}2 agonists.

Although we found that the relative analgesic actions of the three {alpha}2 agonists seemed to be consistent with their receptor binding affinity in the spinal cord, the changes in AP and HR associated with their administration, although dose-related for each agonist, were not consistent with their receptor binding. Previous studies have indicated that a variety of hemodynamic effects occur after the epidural (28,30,31) or intrathecal administration (11,32) of {alpha}2 agonists. Unfortunately, there are no comparative data as to the vascular adrenoceptor binding of the three agonists. On pial vessels, the effects of DXM are similar to those of CL when both are given into the intrathecal space, when using the intracranial window technique (33,34). {alpha}2 agonists given systemically can affect vascular tone (and thus AP) through central and peripheral effects and may also have a cardiac effect (for example, via a suppression of sympathetic nervous system activity). It is thought that the decreases in AP and HR evoked by systemic administration of {alpha}2 agonists could be predominantly caused by a central effect via their binding to imidazoline receptors (35,36). Thus, in addition to their peripheral action, it is possible that epidural {alpha}2 agonists could also cause cardiovascular changes via central effects. The variety of cardiovascular responses to {alpha}2 agonists seen by different authors could well be the result of variation among the different agonists in terms of their preferential site(s) of action (both inside and outside the central nervous system).

The epidural route of administration for {alpha}2 agonists was chosen to provide a comparison with their systemic effects in this study because of its common use in clinical practice. Because of its pharmacokinetic and pharmacodynamic behavior, CL given epidurally passes into the spinal cord cerebrospinal fluid (31,37). No data, however, are available as to whether epidurally administered DXM and TZ can penetrate the spinal meninges as easily as CL. Bernards and Hill (38) found that there is a biphasic relationship between the log octanol:buffer distribution coefficient and the meningeal permeability coefficient. The optimal octanol:buffer distribution coefficient for maximal meningeal permeability is between 129 and 560. On the basis of their properties, DXM and CL would be close to or within the optimal range for meningeal penetration, but TZ would be outside the optimal range (Table 2). Thus, TZ might exhibit poor penetration of the spinal meninges. However, as was the case with DXM and CL, the antinociceptive effect of TZ was significantly greater on epidural than on systemic administration in the present study. The rank order for the antinociceptive effects of spinally administered {alpha}2 agonists seems to be DXM > CL > TZ [DXM > CL (9), and CL > TZ (12)]; this order agrees with our findings for epidural administration, for which the dose needed is 8–10 fold higher than for spinal administration. Thus, TZ is the least potent by spinal as well as by epidural administration, and so we cannot say at present to what extent the penetration of the spinal meninges by a given {alpha}2 agonist affects its spinal antinociceptive effect.


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  		Table 2. Molecular Weight and Hydrophobicity (Octanol:Water Partition Coefficient) of Three {alpha}2 Agonists: Dexmedetomidine, Clonidine, and Tizanidine
 
In summary, the present results suggest that epidural administration of {alpha}2 agonists is approximately 5 times more effective than systemic administration at producing an antinociceptive effect. Our present results are consistent with the idea that differences in antinociceptive action among the clinically available {alpha}2 agonists DXM, CL, and TZ could be caused principally by differences in their receptor binding affinity within the spinal cord. However, we cannot eliminate the possibility that the differences between spinal administration and the systemic or epidural administration of centrally acting drugs could be a result of, to some extent, differences in lipid solubility and meningeal penetration.


   Acknowledgments
 
This study was supported by Grant-in-Aid for Scientific Research Nos. 08457405 and 07771222 (Ministry of Education, Science and Culture, Japan).


   Footnotes
 
Presented in part at the annual meeting of Japan Society of Anesthesiology, April 19–21, 1995, Hamamatsu, and May 26–28, 1999, Sapporo, Japan.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication September 21, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press