Effects of levobupivacaine, bupivacaine, and ropivacaine on tail-flick response and motor function in rats following epidural or intrathecal administration

Regional Anesthesia and Pain Medicine 24(5): 444-452, 1999

Effects of L e v o b u p i v a c a i n e , B u p i v a c a i n e , and R o p i v a c a i n e on Tail-Flick R e s p o n s e and M o t o r F u n c t i o n in Rats F o l l o w i n g Epidural or Intrathecal A d m i n i s t r a t i o n Yuko Kanai, M.D., Shingo Tateyama, M.D., Tadashi Nakamura, M.D., Toshiharu Kasaba, M.D., Ph.D., and Mayumi Takasaki, M.D., Ph.D.

Background and Objectives.Commerdally available bupivacaine is a racemic mixture of S ( - )and R(+)-enantiomers. Although the S(-)-enantiomers levobupivacaine and ropivacaine are less toxic to the cardiovascular and central nervous systems than bupivacaine, their relative efficacy has not been determined. This study directly compares the dose response of levobupivacaine, ropivaca_ine, and bupivacaine following epidural and intrathecal administration in the rat. Methods. The time course of change in tail-flick latency and qualitative motor function was studied in rats following epidural or intrathecal administration of 0.25-0.75 % levobupivacaine, ropivacaine, or bupivacaine in blinded, randomized fashion. Results. Levobupivacaine and bupivacaine produced comparable and significantly enduring antinodceptive effects compared with ropivacaine at all test concentrations following both epidural and intrathecal administrations. Duration of motor block at lower local anesthetic concentrations (epidurally and intrathecally) was comparable with levobupivacaine and ropivacaine but significantly shorter than with bupivacaine. Epidural 0.75% levobupivacaine and bupivacaine showed more enduring motor block than ropivacaine. Conclusions. Levobupivacaine, given epidurally or intrathecally, produces longer lasting antinociceptive action than ropivacaine at equivalent concentrations and similar motor blocking effect at lower concentrations in both epidural and intrathecal administrations. Levobupivacaineinduced prolongation of the tail-flick latency is comparable to that of bupivacaine, as is motor blocking effect at higher concentrations. The possibility of significant differential block with levobupivacaine compared with bupivacaine warrants further study. Reg Anesth Pain Med 1999: 24: 444-452. K e y w o r d s : local anesthetics, levobupivacaine, ropivacaine, epidural, intrathecal, enantiomer

C o m m e r c i a l l y available b u p i v a c a i n e is a r a c e m i c m i x t u r e of S ( - ) - a n d R ( + ) - e n a n t i o m e r s . S ( - ) e n a n t i o m e r , l e v o b u p i v a c a i n e , has a l o w e r p o t e n t i a l for p r o d u c i n g toxicity in t h e central n e r v o u s s y s t e m a n d cardiovascular s y s t e m t h a n does R ( + ) - b u p i v a caine in a n i m a l s (1,2) a n d h u m a n s (3). The greater toxicity of R ( + ) - b u p i v a c a i n e m a y be partly attribu t e d to t h e greater b i n d i n g of R ( + ) - e n a n t i o m e r , particularly to s o d i u m c h a n n e l s of n e u r a l or cardiac tissue (4,5). L e v o b u p i v a c a i n e is a n S ( - ) - e n a n t i o m e r n o w u n d e r g o i n g clinical trials. Previous stud-

From the Department of Anesthesiology, Miyazald Medical College, Miyazaki, Japan. Accepted for publication May 2 I, 1999. Supported in part by Grant-in-Aid 10671427 for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan, and supported in part by Maruishi Pharmaceutical Co., Ltd., Osaka, Japan. Reprint requests: Yuko Kanai, M.D., Department of Anesthesiology, MiyazakiMedical College, I¢iyotake,Miyazaki 889-1692, Japan. Copyright © 1999 by the American Society of Regional Anesthesia. 1098-733919912405-001355.00t0

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ies with the drug indicate it has lower frequency of toxicity (1-3), but a comparable potency to bupivacaine in humans when administered epidurally (6,7). Ropivacaine is a pure S ( -)-enantiomer that is structurally similar to bupivacaine but less toxic to the cardiovascular and central nervous systems (8,9). Present studies of anesthetic efficacy have compared the effects of either levobupivacaine or ropivacaine with those of bupivacaine. With epidural administration, the sensory and motor blocking effects of levobupivacaine in humans are not different from those of bupivacaine (6), whereas ropivacaine's effects are less predictable, varying from equipotent to less potent than those of bupivacaine (10-13). When administered intrathecally, bupivacaine produces effective surgical anesthesia, and ropivacaine also appears to have good analgesic properties in the 0.5% and 0.75% solutions with reliable motor block when given at 0.75 % (14). To our knowledge, the epidural and intrathecal blocking effects of levobupivacaine and ropivacaine have not been directly compared. Only one study thus far reports their relative effects on peripheral nerve block in the rat (15). In a part of a prectinica] evaluation of levobupivacaine, the present study was performed to directly compare the effects of levobupivacaine, relative to the effects of ropivacaine and bupivacaine on duration of sensory and motor block by assessing tail-flick latency (TFL) and motor function following epidural or intrathecal administration in the rat.

Methods Local Anesthetic Test Solutions Local anesthetic test solutions were prepared before injection as 0.25, 0.5, and 0.75% solutions by dissolving S(-)-bupivacaine hydrochlofide (levobupivacaine), racemic bupivacaine hydrochloride, or ropivacaine hydrochloride (Chiroscience Ltd, Cambridge, UK) in distilled water (pH, 5.1-5.5).

Animals After receiving approval from the Animal Research and Use Committee of Miyazaki Medical College, we studied male Sprague-Dawley rats weighing 250-390 g. Rats were individually housed in a temperature- and humidity-controlled environment with a 12-hour light-dark cycle and were permitted free access to food and water until 1 hour before study began. In the epidural group, animals were anesthetized by intraperitoneal injection of pentobarbital sodium

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(50 mg/kg) (Nembutal sodium). Catheters were then introduced into the epidural space using the following technique. The skin of the back was shaved and treated with 10% povidone iodine. To flex the lower thoracic and lumbar vertebrae, a foam rubber wedge was placed beneath the abdomen. A skin incision was made on the midline of the spinous process of the T12 and L2 vertebrae. After piercing the ligament between the T13 and L1 vertebrae, a PE-10 catheter was gently introduced and advanced 20 m m caudally into the epidural space. A drop of surgical glue (~-cyanoacrylate, Zerotime, Cemedine, Tokyo) was applied over the site of catheter entry. The remaining portion of the catheter was tunneled subcutaneously, and the distal tip exposed through a slit in the skin of the neck. Benzylpenicillin potassium (0.3 U) and 0. i mg pentazocine were injected intramuscularly, and the skin was dosed. Rats were allowed to recover for 4 days before experiments began. Each animal was evaluated during recovery from catheterization to ensure normal gait and motor, and sensory responses. Rats exhibiting any neurologic deficit, infection, or other complication were excluded from study. Placement of the catheter in the epidural space was confirmed at the end of experiments by injection of methylene blue dye and by dissection after intraperitoneal injection of pentobarbital sodium. Data obtained from rats in whom dye failed to stain the lumbar epidural space and from rats with visible injury to the spinal cord were excluded from analysis. Each rat was studied only once at a single epidural dose. In preparation for intrathecal administration, the skin of the back was shaved at least 2 days before experiments began. On the day of study, after obtaining baseline values for TFL and motor function, anesthesia was induced by inhalation of low concentration of sevofiurane (Sevofrane, Maruishi, Osaka), allowing awakening within 2-3 minutes (16). Following induction of inhalation anesthesia, the lumbar surface was treated with 10% povidone iodine, and local anesthetics were injected into the intrathecal space at the L4-L5 interspace with a positive indication of the tail movement. This movement of the tail is "electrical shock-like" and observed only when the needle is inserted into intrathecal space. Movement of a limb during a needle insertion excluded the animal from study, based on the observation in preliminary study that the tip of the needle had shifted laterally. During injection, a 30-gauge needle connected to a 50-pL syringe (Hamilton, Nevada) was applied in a slightly caudal direction with the bevel angled cephalad, while the rat lay in elevated lumbar position (17). Immediately after injection until awakening from anesthe-

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sia, the rat was placed in prone, horizontal position. Rats were studied twice in the intrathecal study, with at least 7 days b e t w e e n experiments.

Experimental Protocol After obtaining baseline values for TFL and m o t o r function (see m e a s u r e m e n t techniques), the test solutions were administered epidurally in blinded, randomized fashion at doses of 0.25, 0.5, or 0.75%. All test solutions were injected epidurally at a v o l u m e of 100 laL administered manually over 2 minutes, followed by a 20-gL flush of n o r m a l saline. Animals were observed continuously during and after epidural injection. Intrathecal injection of test solutions at a concentration of 0.5 or 0.75% was p e r f o r m e d manually in blinded, randomized fashion at 30 I~L over approximately 5 seconds. Preservation of the animal's ability to m o v e its tail following injection was confirmed by observing mobility in response to hold up. This confirmation was done after recovering the cutaneous truncal muscle reflex. To distinguish the paralytic effect from TFL, a behavioral response to the noxious stimulus (e.g., leg or head m o v e m e n t s , escape behavior) was observed (18). Tail-flick latency was t h e n assessed every 5 minutes for 60 or 75 minutes. Motor function was observed continuously.

Measurement of Tail-flick Latency and Motor Function Tail-flick latency and m o t o r function were assessed by an investigator blinded to the local anesthetic solution received. A heat stimulus was directed at a portion of the tail approximately 5 cm from the tip. The time b e t w e e n stimulus onset and withdrawal of the tail was defined as the response latency. The tail-flick testing device (type 7360, Ugo Basile, Comerio-Varese, Italy) was calibrated to give an average baseline latency of approximately 5 seconds. To prevent tissue damage, the heat stimulus was concluded if no response occurred by 12 seconds (cut-Off latency). Tail-flick testing began after confirmation of the animal's ability to m o v e its tail following local anesthetic injection. Motor block was defined as the animal's inability to mobilize its hind limbs to traverse a smooth floor and was assessed by continuous observation. The onset of m o t o r block was defined as the time from completing epidural or intrathecal injection of local anesthetic to the time at which the animal no longer had sufficient muscle p o w e r to activate its hind limbs to cross the floor. The duration of block was therefore m e a s u r e d by the time from the end of injection to recovery of the animal's ability to achieve m o v e m e n t . We chose to use the time from

end of epidural or intrathecal injection as the initial m a r k e r of onset to provide a consistent data point. Consequently, onset of m o t o r block was rapid and similar to all three agents (within 1-2 minutes) following epidural injection, whereas onset following intrathecal injection could not be precisely d e t e r m i n e d because the effect of sevofiurane rem a i n e d for 2-3 minutes.

Data Analysis Statistical analysis of the data was conducted in blinded fashion. To assess the effect of local anesthetic on sensory function, TFL was converted to percent m a x i m u m possible effect (MPE), calculated as %MPE = {(TFL--baseline)/(cut-off baseline)} × 100%. The area u n d e r the time-effect curve (AUC) was calculated by integrating the %MPE m e a s u r e d at 5- or 10-minute intervals using the trapezoidal integration method. To evaluate the duration of suppression of TFL, the time from the end of local anesthetic injection to the time of %MPE 50% (%MPE50T) was calculated from the time-effect curve and compared. Values for the %MPE, AUC, %MPE50T, and the duration of m o t o r disturbance with each local anesthetic solution are expressed as the m e a n +_ SEM. The differences a m o n g local anesthetics in %MPE, AUC, %MPE50T, and the duration of m o t o r block were compared using oneway analysis of variance, followed by the Bonierroni (Dunn) test. P < .05 was considered significant.

Results Epidural Anesthesia Following surgical preparation in the epidural group, two rats were excluded from study because they had developed a limp. Data from a n o t h e r 5 rats were excluded from analysis w h e n the catheterization technique failed or resulted in injury to the spinal cord. All remaining animals (n = 81) recovered fully w i t h o u t complication from catheterization or epidural injection of local anesthetic. No animals sustained visible injury or bleeding in the spinal cord at the end of experiments in either epidural or intrathecal groups. The %MPE calculated from TFL is s h o w n in Fig. 1. All three local anesthetics epidurally administered prolonged TFL. At all test concentrations, the %MPE decreased significantly sooner with ropivacaine t h a n with levobupivacaine or bupivacaine. The time to recovery of m o t o r block was shorter t h a n the time to recovery from sensory block in all three local anesthetics (Figs. 1, 2). The AUC and

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levobupivacaine (Fig. 4). The time to recovery of m o t o r block was shorter t h a n the time to recovery from sensory block (Figs. 4, 5). The time to recovery of m o v e m e n t of the tail was shorter at all test concentrations t h a n the time to recovery from sensory block [e.g., the average time to m o v e the tail freely after intrathecal administration of 0.75% levobupivacaine, bupivacaine, and ropivacaine was 28 + 4, 27 + 4, and 26 - 2 minutes (mean -+ SEM), respectively, compared with 55 + 1, 53 -+ 2, and 44 _+ 3 minutes for the duration of %MPE = 100%]. The AUC and %MPE50T were significantly greater with levobupivacaine and bupivacaine t h a n with ropivacaine (Fig. 6). The duration of m o t o r block was significantly longer at 0.5% bupivacaine t h a n ropivacaine or levobupivacaine (Fig. 6). At 0.75%, duration of m o t o r block did not differ significantly (30 _+ 3 minutes for bupivacaine, 26 + 2 minutes for levobupivacaine, and 22 -+ 1 minutes for ropivacaine).

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half-life after i.v. or epidural injection than bupivacaine (20). The similarity in the duration of motor block with levobupivacaine and ropivacaine at the lower intrathecal and epidural test concentrations suggests that, like ropivacaine ( 10,21 ), low concentrations of levobupivacaine may produce weak motor block. However, the duration of block differed by the route of administration at the highest concentration (i.e., ropivacaine-induced block was equal to that of levobupivacaine intrathecally, but shorter epidurally). With this exception, the effect of the route of administration on suppression of tail-flick response or motor function by these two agents per se did not appear to be great. Whether administered epidurally or intrathecally, levobupivacaine-induced antinociceptive effect was equivalent to that of bupivacaine and significantly greater than that of ropivacaine.

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0.5 0.75 Concentration (%) Fig. 6. Relationship for concentration (%) versus the area under the curve, the duration of %MPE --> 50% (%MPE50T), and duration of motor block after intrathecal administration of levobupivacaine, bupivacaine, or ropivacaine; n = l l or 12 for each group. Intrathecal levobupivacaine at 0.5 % produced enduring suppression of TFL like bupivacaine and shorter duration of motor block like ropivacaine. Data are presented as mean -SEM. *Significant difference compared with the same dose of ropivacaine, tSignificant difference compared with the same dose of levobupivacaine. (©) Levobupivacaine, (0) bupivacaine, (A) ropivacaine. (Fig. 6)]. These differences between levobupivacaine and bupivacaine for motor block suggest stereoselectivity.

Comparison of Levobupivacaine and Ropivacaine The significantly longer duration (as indicated by %MPE, AUC, and %MPE50T) with epidural and intrathecal levobupivacaine compared with ropivacaine may be a result of differences of physicochemical properties of these two agents. Ropivacaine has lower lipid solubility than bupivacaine and levobupivacaine (19) and a slightly shorter elimination

Our finding of similar potency of suppression of tail-flick response with epidural levobupivacaine and bupivacaine is consistent with the results of clinical trials demonstrating that epidural levobupivacaine and bupivacaine produce comparable sensory blocking effects (6,7,22). Our results with epidural motor block in rats have subtle differences from current data obtained in humans. Although the motor blocking effects with levobupivacaine and bupivacaine are not significantly different in humans (6,7,22), we found shorter duration of motor block with levobupivacaine at the lower test concentrations than with bupivacaine. The reduction in duration at the lower anesthetic concentrations may be a difference in the method of evaluation or may be species related. That is, the dose-response curve may shift between rats and humans. Additional clinical studies are necessary to understand the apparent variability in dose-effect response for m ot or block with levobupivacaine. The nearequivalent potency of antinociception with epidural levobupivacaine and bupivacaine likely is a result of the similarities in the pharmacologic structure and pharmacochemical properties of these two agents (23). A study of isomers of bupivacaine (24) in rabbits showed that the minimum anesthetic concentration of intrathecal levobupivacaine was lower than that for R(+)-bupivacaine. However, the methods of comparison and administered concentrations in this study were unclear, making it difficult to compare their findings with our own. Comparison with other effects of intrathecal levobupivacaine and bupivacaine on nociception also is limited because of

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differences in study design or incomplete information.

Comparison of Ropivacaine and Bupivacaine Our findings on the potency of epidural ropivacaine and racemi-bupivacaine are consistent with those of some previous studies in both animals (10,18) and humans (11,25) that report significantly greater epidural potency of racemi-bupivacaine. However, other studies conducted in humans ( 12,13,25) report no statistically significant difference between these two agents. Our results for epidural motor block confirm almost all earlier reports in animals (10,21) and humans (12,13) of significantly greater duration of block with racemibupivacaine than with ropivacaine. Only a few epidural studies (11,18,25) report a tendency toward shorter duration of motor block with ropivacaine that is not statistically significant. The differences between the results of certain studies and our own may be based on the use of different animal models, different number of the objects, and our cumulative method (AUC) of assessing both the potency and duration of epidural local anesthetic action. We used epidural catheterization and a single injection of local anesthetic test solution. Our results may therefore differ from those of clinical investigations applying continuous epidural infusion (e.g., for labor or postoperative analgesia). The diminished intensity and shorter duration of action of ropivacaine may be related to its lower lipid solubility relative to racemi-bupivacaine. A comparison with other investigations of the intrathecal effects of ropivacaine and racemibupivacaine is more difficult. We observed motor block of similar duration at 0.75 %, but significantly reduced duration with ropivacaine at 0.5%. Two separate studies comparing motor block following intrathecal injection of 0.75 % ropivacaine or racemibupivacaine in the dog (21 ) and injection of 0.1251.0% concentrations in mice (10) have reported a slightly shorter duration of motor block with ropivacaine that is not statistically significant. Our study confirms these findings. One explanation for our observing similar duration of motor block at the highest test concentration may be the potential of intrathecally administered ropivacaine for decreasing spinal cord blood flow in rats (26). This effect is stronger with ropivacaine than with bupivacaine (26), making it possible that a vasoconstrictive property of ropivacaine may have helped to "equalize" the effects ot the two agents at the higher dose. In a recent study of combined spinal and epidural anesthesia for labor (27), the effect of ropivacaine (2

or 4 mg) was clinically indistinguishable from that of 2.5 mg bupivacaine when combined with sufentanil. We need simple comparative studies in humans. The differential block of sensory and motor fibers produced by local anesthetic agents is an important clinical consideration. Epidural bupivacaine is reported to have relative specificity for sensory fibers and to provide adequate sufficient analgesia with minimal motor block at 0.25 or 0.5% (28), but to prolong the duration of motor and sensory block at 0.75 % (29). Like bupivacaine, epidural ropivacaine has been shown to provide suitable analgesia for surgery with minimal motor block (12,13), and intrathecal ropivacaine to provide prolonged duration of motor and sensory block at 0.75% (i4). In our rat model, ropivacaine produced antinociceptive action with minimal motor block; however, a higher concentration delivered intrathecally significantly increased the duration of motor block. Levobupivacaine, too, provided antinociceptive action with minimal motor block at lower concentration, with a significant increase in duration of motor block at the highest epidural and intrathecal concentration. To date, the effects of only ropivacaine and bupivacaine on the compound action potentials of A- and C-fibers have been studied in isolated rabbit vagus nerves (30). They have shown that ropivacaine produced relatively less block of large motor fibers than does bupivacaine. Our study has several limitations. First, our resuits in rats may not be applicable to humans because of species-based differences in epidural and spinal anatomy and physiology. The injected epidural volume for our experiments was approximately 0.3 mL/kg, close to that used in humans. However, the intrathecally administered volume (approximately i00 pL/kg) was larger than conventional clinical volumes. We gave this large a dose to ensure paralysis adequate to permit evaluation of motor function. Second, motor paralysis might have interfered with the assessment of the tail-flick test. To avoid this possibility, we performed the tail-flick test only after confirming the rat's ability to move its tail freely, and we observed our animals for an escaping behavioral response to the heat stimulus (18) prior to the tail-flick response. Moreover, our results for the suppression of TFL by the three tested local anesthetics are within the range reported by most previous studies in both animals and humans (6, 7,10, I 1,18,22). We therefore believe our assessment of tail-flick test to be reliable. Third, we evaluated the duration of motor block qualitatively. However, each animal was tested individually, and

Epidural or Intrathecal New Local Anesthetics

the onset and duration of effect was fairly obvious. A l t h o u g h we could not quantify complete recovery of m o t o r function, we were able to d o c u m e n t a visible u n i f o r m intensity of muscle p o w e r to be used as our m e a s u r e of m o t o r function. In addition, despite the limitations inherent in qualitative assessment, we were able to demonstrate a significant difference b e t w e e n local anesthetics in the duration of m o t o r block. However, observed differences m a y only be evident not following initial injection but following recovery from m o t o r block. Fourth, the onset of block following intrathecal administration could not be assessed because this m e t h o d of direct access to intrathecal space needs inhalation anesthesia, while chronic intrathecal catheterization is able to assess the onset time of local anesthesia. Rats s h o w e d tail m o v e m e n t w h e n the needle was inserted into intrathecal space. The tail m o v e m e n t seems to be generated w h e n the needle touches cauda equina. However, at the end of the study, we observed no irreversible neurologic deficit or spinal injury, suggesting that our technique achieved direct intrathecal block w i t h o u t inducing complications or adverse effects. In summary, both epidurally and intrathecally administered levobupivacaine at lower concentrations shows shorter duration of m o t o r block like ropivacaine and enduring sensory block like bupivacaine. Thus, these findings suggest that there might be a greater degree of dissociation b e t w e e n the antinociceptive and m o t o r blocking effects of both epidural and intrathecal low-dose levobupivacaine t h a n bupivacaine. While enduring sensory block with minimal m o t o r block is advantageous in m a n y clinical settings, further study in additional animal models and in h u m a n s is necessary to evaluate the potential value of levobupivacaine for regional anesthesia.

Acknowledgment The authors t h a n k Chiroscience Ltd, Cambridge and Maruishi Pharmaceutical Co Ltd, Osaka for supply of local anesthetics and Ms. Winifred v o n E h r e n b u r g for her editorial assistance.

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