Bupivacaine, levobupivacaine and ropivacaine: are they clinically different?

Best Practice & Research Clinical Anaesthesiology Vol. 19, No. 2, pp. 247–268, 2005 doi:10.1016/j.bpa.2004.12.003 available online at http://www.sciencedirect.com

6 Bupivacaine, levobupivacaine and ropivacaine: are they clinically different? Andrea Casati*

MD

Staff Anesthesiology

Marta Putzu

MD

Anesthesia Fellow Department of Anaesthesiology, University of Parma, Italy

Two new, long-acting local anaesthetics have been developed after the evidence of bupivacaine-related severe toxicity: levobupivacaine and ropivacaine. Both these agents are pure left-isomers and, based on their three-dimensional structure, they have less toxic potential both on the central nervous system and on the heart. Several clinical studies have evaluated their toxicology and clinical profiles: theoretically and experimentally, some differences can be seen, but the reflections of these characteristics into clinical practice have not been evident. Evaluating randomised, controlled trials that have compared these three local anaesthetics, this chapter supports the evidence that both levobupivacaine and ropivacaine have a clinical profile similar to that of racemic bupivacaine, and that the minimal differences observed between the three agents are mainly related to the slightly different anaesthetic potency, with racemic bupivacaineOlevobupivacaineOropivacaine. However, the reduced toxic potential of the two pure left-isomers supports their use in those clinical situations in which the risk of systemic toxicity related to either overdosing or unwanted intravascular injection is high, such as during epidural or peripheral nerve blocks. Key words: bupivacaine; epidural nerve block; levobupivacaine; local anaesthetics; peripheral nerve block; regional anaesthesia techniques; ropivacaine; spinal nerve block; toxicity.

Bupivacaine has been the most widely used long-acting local anaesthetic for several decades. However, after the report of six cases of almost simultaneous seizure and cardiac arrest, with prolonged resuscitation and a disproportionally high number of deaths following unintended intravascular injection of bupivacaine1, it became evident

* Corresponding author. Address: Department of Anaesthesiology, Azienda Ospedaliera di Parma, Via Gramsci 14-33100 Parma, Italy. Tel.: C39 0521 702 159; Fax: C39 0521 702 733. E-mail address: [email protected] (A. Casati). 1521-6896/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.

248 A. Casati and M. Putzu

that bupivacaine differs from other local anaesthetics in that it has a narrower margin between the dose or plasma concentrations required to produce seizures and those resulting in cardiovascular collapse.2,3 For this reason, there has been a search for alternative drugs with the desirable blocking properties of bupivacaine but with a greater margin of safety. The development of new long-acting amides has taken advantage of the fact that most amide local anaesthetics are chiral molecules. When a molecule has a chiral centre it is possible to obtain two different three-dimensional structures (stereoisomers) that remain different with respect to each other in the way that a right hand will not fit properly into a left-handed glove. Enantiomers (a pair of stereoisomers) have an identical chemical constitution and atomic connections but a different spatial orientation of their constituent atoms. Because they are optically active, stereoisomers can be differentiated by their effect on the rotation of the plan of polarized light into dextrorotatory [clockwise rotation (RC)] or levorotatory [counterclockwise rotation (SK)] stereoisomers. Most organic molecules are chiral ones, and this is usually determined by the presence of a carbon atom bonded to four different molecules. Although the physicochemical properties of such molecules are identical, significant differences exist in their interaction with biological receptors, the conformation of which favours interactions with one form over interactions with the other. This is important for amide local anaesthetics because it has been demonstrated that the levorotatory isomer has less potential for systemic toxicity than the dextrorotatory one.4 Accordingly, two new, long-acting local anaesthetics have been developed and introduced into clinical practice: levobupivacaine and ropivacaine. Both these agents are prepared as the single levorotatory isomer rather than as a racemic mixture of levo- and dextro- forms of the drug. Several clinical studies have been reported evaluating the toxicology and clinical profiles of these three long-acting local anaesthetics. Theoretically and experimentally some differences can be seen, but the reflections of these characteristics into clinical practice have not been evident. This chapter aims to evaluate these theoretical differences and to discuss the most important clinical studies that compared these local anaesthetics.

PHARMACOLOGY AND TOXICOLOGY Bupivacaine is an amino-amide local anaesthetic belonging to the family of the n-alkylsubstituted pipecholyl xylidines, which were first synthetized by Ekenstam in 19575; the alkylic substitute is formed by a four-carbon-atom chain (butylic). Mepivacaine (with a methylic chain) and ropivacaine (with a propylic chain) belong to the same family (Figure 1). These three molecules all have a carbon atom that is bound to four different molecules, thus representing a chiral centre. Whereas bupivacaine and mepivacaine are marketed as racemic solutions, consisting of a mixture of equimolar amounts of both dextro- and levorotatory enantiomers, levobupivacaine and ropivacaine consist of the pure S(K) isomer. If we consider the chemical and physical properties of these three agents it is clear that they have very similar characteristics (Table 1). The only difference is that ropivacaine is much less lipophilic than the two other molecules, due to the substitution of the pipecoloxylidine with a 3-carbon side-chain instead of a 4-carbon side-chain. As for all local anaesthetics, the mechanism of action of the three drugs under consideration is based on their ability to reversibly inhibit voltage-gated sodium channels

Bupivacaine, levobupivacaine and ropivacaine: are they clinically different? 249 CH3

CH3 N H

C CH2 O

N

Mepivacaine

CH3 C 3H 7 N N

Propivacaine C4H9 N

Bupivacaine Chiral center: one carbon atom bound to four different molecules

Figure 1. Structure of the n-alkyl-substituted pipecolyl xylidines mepivacaine, ropivacaine and bupivacaine.

in nervous fibres. This inhibition occurs in a manner that is both time dependent and voltage dependent and results in an increased threshold for activating the action potential, reducing the propagation of the electric impulse along the nerve fibres with complete block of their function.6 However, interaction occurs with other ion channels in excitable tissues, such as the central nervous system (CNS) and myocardium. CNS toxicity The CNS is usually more sensitive to local anaesthetic toxicity than the cardiovascular system and CNS intoxication is usually evident before signs of cardiovascular toxicity. Intoxication is first characterized by signs of CNS activation due to the preferential block of inhibitory central pathways, with shivering, muscle twitching, and tremors, which are followed by tonic–clonic seizure activity. With increasing the plasma levels of the local anaesthetic, both inhibitory and excitatory pathways are blocked, leading to generalized CNS depression with hypoventilation and respiratory arrest. The convulsive threshold dose is one of the objective measures of CNS toxicity. However, it must be remembered that such toxicity studies can be performed only in animals, and that species to species variability and differences between human and animal models can affect extrapolation to the human context of the results of these studies.7 Table 2 shows the convulsive local anaesthetic doses for bupivacaine, levobupivacaine and ropivacaine in different animal models. Interestingly, the propensity for seizure activity after local anaesthetic intoxication with the two levo- isomers Table 1. Chemical and physical properties of the three considered long-acting local anaesthetics. Bupivacaine Molecular weight pKa Liposolubility Partition coefficient Protein binding (%)

288 8.1 30 28 95

Ropivacaine 274 8.1 2.8 9 94

Levobupivacaine 288 8.1 30 28 95

250 A. Casati and M. Putzu

Table 2. Convulsive doses of racemic bupivacaine, levobupivacaine and ropivacaine in various animal species and dosing regimens (modified from Groban7). Animal model Rat Dog Sheep Sheep

Sheep

Dosing regimen Intravenous infusion Intravenous infusion Intravenous infusion Plasma concentration Intravenous bolus Plasma concentration Total dose Intravenous bolus

Bupivacaine 2.8 mg/kg 9.3 mg/kg 0.014 mmol/kg 2.49 mg/ml 1.6 mg/kg 10 mg/ml 69 mg 69–85 mg

Levobupivacaine 12.8 mg/kg 0.018 mmol/kg 5.59 mg/ml

Ropivacaine 4.5 mg/kg 13.2 mg/kg 0.21 mmol/kg 4.7 mg/ml 3.5 mg/kg 17 mg/ml 155 mg

103–127 mg

(levobupivacaine and ropivacaine) appears to be 1.5–2.5 times less than with racemic bupivacaine.7 Comparative CNS toxicity between the two left isomers are in part species dependent, with no differences between levobupivacaine and ropivacaine in the anaesthetized ventilated rat, and slightly greater convulsant dose with ropivacaine than levobupivacaine in the conscious sheep.7 The route and rate of administration, the rapidity with which a certain plasma concentration is achieved, and whether the animal is awake or anaesthetized all affect the absolute doses of local anaesthetic inducing the toxic effect. This often makes it difficult to compare and extrapolate the results of animal studies to human patients. Again, such studies cannot be performed in humans for ethical reasons. That being said, a few clinical studies have evaluated the dose of local anaesthetic, given by intravenous infusion, tolerated by human volunteers before the occurrence of the initial signs of CNS toxicity (dizziness, ear disorder and deafness, tinnitus, speech disorders, circumoral paresthesia, and taste perversion). When comparing the CNS and cardiovascular effects of levobupivacaine and ropivacaine given intravenously to healthy male volunteers in a double-blind, cross-over study, Stewart et al8 reported no significant differences between the two drugs in terms of mean time to first onset of CNS symptoms and mean total volume of study drug administered at the onset of the first CNS symptom, suggesting that the two left isomers produce similar CNS effects when infused intravenously at equal concentrations, milligram doses, and infusion rates. Indeed, in similar human volunteer studies both ropivacaine and levobupivacaine have been shown to result in less CNS toxicity than racemic bupivacaine, with doses of levobupivacaine and ropivacaine that are 10–25% larger than doses of bupivacaine before signs of CNS toxicity occur.9–11 Accordingly, it can be concluded that, based on animal and volunteers studies, both levobupivacaine and ropivacaine are consistently associated with a reduced potential for CNS toxicity than bupivacaine, having higher convulsive thresholds in animal models, fewer CNS symptoms after intravenous administration in human volunteers, and fewer excitatory changes in the EEG than bupivacaine. Cardiovascular toxicity The cardiovascular toxic effects of local anaesthetics also follow a two-stage pathway: an initial activation of the sympathetic nervous system during the CNS excitatory phase leads to tachycardia and hypertension that can mask direct myocardial depression

Bupivacaine, levobupivacaine and ropivacaine: are they clinically different? 251

induced by the local anaesthetic. This stage is followed by arrhythmias and profound contractile dysfunction that overcome sympathetic activation with increasing plasma concentrations. This can result in cardiovascular collapse, which in the case of bupivacaine-induced toxicity can be difficult or impossible to recover.7 All three long-acting local anaesthetics show a dose-dependent prolongation of cardiac conduction, with an increase in the PR interval and QRS duration on the electrocardiogram. These effects are related to the persistence of block of sodium channels into diastole and predispose the heart to re-entrant arrhythmias.12 As the dissociation constant for bupivacaine is nearly 10 times longer than that of lidocaine, bupivacaine-induced block can accumulate, resulting in greater cardiac depressant effect.12,13 However, local anaesthetics also influence the conductivity of potassium channels, prolonging the QTc interval and enhancing the block of the inactivated state of the sodium channel.14 The stereoselective interaction between local anaesthetic and potassium channels has been investigated with patch-clamp techniques. The dissociation constant reported for the R(C) and L(K) enantiomers of bupivacaine demonstrated that the dextrorotatory isomer is seven-fold more potent in blocking the potassium channel than the levorotatory isomer.15 The same group also demonstrated that the potency and degree of stereoselective binding of the R(C) enantiomer to the potassium channel is mainly dependent on the length of the alkyl substituent at position 1, being more marked for the butylic chain than for propylic and methylic chains.16,17 However, despite electrophysiological evidence of stereoselective binding to sodium and potassium channels, Groban et al18 reported that the plasma concentrations resulting in a 35% reduction in dP/dtmax and ejection fraction were 4.0 and 3.0 mg/ml for ropivacaine, 2.4 and 1.3 mg/ml for levobupivacaine, and 2.3 and 2.1 mg/ml for racemic bupivacaine. Similar results have been reported in conscious sheep19 and isolated heart preparations20, and might be related to the lack of enantiomer-selective inhibition of calcium channels21 or to the different effects of the three long-acting anaesthetics on mitochontrial energy metabolism.22,23 Inhibition of cardiac contractility is also proportional to the lipid solubility and nerve-blocking potency of the local anaesthetics, suggesting a rank order (from lowest to highest) of the cardiotoxic potency of the three local anaesthetics with ropivacaine!L(K) bupivacaine!racemic bupivacaine!R(C) bupivacaine.24 Another important issue when considering local-anaesthetic-induced cardiac toxicity is the ease of resuscitation after toxicity occurs. Groban et al25 evaluated cardiac resuscitation after incremental overdosage with lidocaine, bupivacaine, levobupivacaine and ropivacaine in anaesthetized dogs. They reported clinically relevant differences in the inability to resuscitate the intoxicated dogs between the racemic bupivacaine- and levobupivacaine-treated animals (50 and 30%, respectively) and the ropivacaine- and lidocaine-treated ones (10 and 0%, respectively). In rats, no differences in the numbers of successfully resuscitated animals were reported between ropivacaine, levobupivacaine and bupivacaine (92, 92 and 83%, respectively), even though the cumulative dose producing cardiac arrest was greater for ropivacaine (108G27 mg/kg) than for levobupivacaine (57G8 mg/kg) and racemic bupivacaine (39G9 mg/kg).26 However, significantly less adrenaline (epinephrine) was required to treat ropivacaine-induced cardiac arrest than for levobupivacaine- or bupivacaine-treated rats.26 As for CNS toxicity, the toxic effects of local anaesthetic are much more difficult to evaluate in the human than in animals. When comparing the cardiovascular effects of levobupivacaine and ropivacaine infused intravenously in healthy volunteers, no differences in mean percentage changes from baseline to the end of infusion were

252 A. Casati and M. Putzu

reported for stroke index, cardiac index, and acceleration index, or for PR interval, QRS duration, QT interval and heart rate8; depression of conductivity and contractility appeared at lower dosage and plasma concentration when infusing racemic bupivacaine than ropivacaine9,10 or levobupivacaine.11 Nonetheless, several case reports on unwanted intravascular injection of either levobupivacaine or ropivacaine during different regional anaesthesia techniques have reported complete recovery without severe cardiovascular effects; in all cases the first signs of toxicity were at the CNS.27–32 Relative potency To interpret correctly information provided by toxicological investigation, the relative potency of the different drugs should be clearly determined. This is not easy, especially in the clinical setting, where the doses of local anaesthetic used are usually at the top of the dose–response curve to afford the highest possible efficacy of the considered regional anaesthesia technique. However, the rank order of the potency of inhibition of sodium channel conductance under voltage clamp is generally the same as the rank order of the drugs in producing clinical local anaesthesia, which is also the same order as the potency in producing cardiac toxicity.7 The potency of local anaesthetics is thus correlated to the lipid solubility of the drug, which is also correlated with its toxicity. When considering the ability to inhibit tetrodoxin-resistant sodium channels, Brau et al33 reported that ropivacaine was nearly 50% less potent than levobupivacaine or racemic bupivacaine; whereas Kanai et al34 compared the anaesthetic effects of S(K)bupivacaine, R(C)bupivacaine and ropivacaine on action potential amplitude and maximal rate of rise of action potential in crayfish giant axon, and reported that S(K)bupivacaine has a more potent phasic blocking effect than ropivacaine. Sinnott et al35 compared three concentrations of either ropivacaine or levobupivacaine (0.0625, 0.125 and 0.25%) for sciatic nerve block in the rat and demonstrated that, at lower concentrations, levobupivacaine produces a greater motor impairment and a longer duration of proprioceptive impairment relative to ropivacaine. There were no differences between the two local anaesthetics at midconcentration. At the higher concentration of 0.25%, levobupivacaine produced an approximately 30% longer duration of complete block in each modality than ropivacaine, suggesting that levobupivacaine is marginally more potent than ropivacaine for sciatic nerve block in the rat. The evaluation of relative potencies of local anaesthetic by determining the whole dose–response curve is not feasible in humans. Alley et al36 evaluated three intrathecal doses of levobupivacaine and bupivacaine (4, 6 and 8 mg) in healthy volunteers and found no differences in clinical profile of sensory and motor blocks or in recovery from spinal anaesthesia. The same group also compared the same doses of ropivacaine and bupivacaine in a similar study on volunteers37 and reported that ropivacaine is half as potent as bupivacaine; using a 1–1.5 dose ratio between bupivacaine and ropivacaine produced a similar spinal block. Another way of overcome the problem of potency comparison between these three long-acting local anaesthetic in a clinical setting is to determine the minimum effective local anaesthetic concentration (MLAC) required to produced adequate pain control in 50% of subjects using an up-and-down sequential allocation technique. This method provides accurate estimation of the ED50 for a certain response, and although it does not provide information on the whole dose–response curve, it also allows extrapolation

Bupivacaine, levobupivacaine and ropivacaine: are they clinically different? 253

of the ED95 using a logistic regression analysis after a probit transformation. This model has been applied for epidural analgesia during labour and initial reports demonstrated that, although no differences were observed between the MLAC of levobupivacaine (0.083%) and bupivacaine (0.081%)38, two different research groups estimated values nearly 40–50% higher for ropivacaine.39,40 However, to make matters more confused, two recent prospective, randomised, blinded studies directly comparing the relative analgesic potencies of levobupivacaine and ropivacaine for epidural labour analgesia found either no difference (0.087% for levobupivacaine versus 0.089% for ropivacaine)41 or a slight but not statistically significant difference (0.077% for levobupivacaine versus 0.092% for ropivacaine)42 in the MLAC of the two drugs. Furthermore, in a study comparing the relative motor block potencies of bupivacaine and levobupivacaine during labour, Lacassie and Columb43 reported that the minimum local anaesthetic concentration producing motor block after epidural injection was 0.27% for bupivacaine and 0.31% for levobupivacaine, with a bupivacaine/levobupivacaine potency ratio of 0.87 (95% confidence intervals 0.77–0.98). However, contrasting results have been reported in other clinical settings. In fact, based on the reported difference in the analgesic potency between ropivacaine and bupivacaine according to the MLAC studies during epidural analgesia for pain during labour39,40, Casati et al44 evaluated the minimum volume of local anaesthetic required to produce effective femoral nerve block in 50% of patients using an up-and-down sequential allocation technique. Their results did not confirm the MLAC findings because the volume of 0.5% ropivacaine required to produce effective block of the femoral nerve in 50% of patients was similar to that required when using 0.5% bupivacaine. Although the true equipotency ratio among these three long-acting local anaesthetics remains a subject of further investigation, results coming from different studies seem to suggest a rank order of potency of ropivacaine!levobupivacaine!bupivacaine.

CLINICAL APPLICATIONS To begin with, we wish to express a few words of caution regarding the interpretation of findings of levobupivacaine in comparison with the same concentration of bupivacaine and ropivacaine. The fact is that in most clinical studies, the levobupivacaine hydrochloride concentration is about 13% greater than that mentioned, i.e. the concentrations of a 0.5% solution should actually be 0.563%. The reason for this is that the concentration of levobupivacaine (Chirocainew) is denoted on the drug label as the concentration of the base of the molecule and not as the concentration of the hydrochloride of the molecule, as is the case with all other amide-linked local anaesthetics, including racemic bupivacaine and ropivacaine.45 Epidural anaesthesia/analgesia Ropivacaine was introduced in clinical practice earlier than levobupivacaine and more studies have been published comparing it with racemic bupivacaine. There are thus a number of studies showing that, when used at clinically relevant concentrations (0.5–0.75%), epidural ropivacaine produces a profile of nerve block that is substantially similar to that produced by equivalent concentrations and doses of racemic bupivacaine.46–51

254 A. Casati and M. Putzu

Much less is known about levobupivacaine. When evaluating the use of levobupivacaine for epidural anaesthesia for both lower limb and abdominal surgery, the first studies reported in the literature showed that clinical profile of levobupivacaine 0.5 and 0.75% is similar to that produced by the same concentrations of racemic bupivacaine.52,53 Comparison of the 0.75% levobupivacaine and the 0.5% concentration resulted in a dose-dependent prolongation of duration of sensory and motor blocks with no differences in the quality of nerve blockade. Faccenda et al54 also compared the epidural injection of up to 25 ml of 0.5% levobupivacaine or racemic bupivacaine for elective caesarean section. The only difference observed was that the duration of motor block provided by levobupivacaine lasted longer but was less deep than that produced by racemic bupivacaine. Taking into account the supposed relative potency between ropivacaine and levobupivacaine based on MLAC studies during labour analgesia, Peduto et al55 compared the epidural injection of 15 ml of either 0.5% levobupivacaine or 0.75% ropivacaine in 75 patients undergoing lower limb procedure. They concluded that these two agents, at the studied concentrations, produce an epidural block with the same clinical profile. In another study directly comparing epidural injection of 15 ml of 0.5% levobupivacaine, 0.5% ropivacaine or 0.5% bupivacaine in patients undergoing total hip replacement, Casati et al56 reported no differences in the onset time, maximum level of sensory block and time to regression of sensory block to T12. However, patients receiving 0.5% ropivacaine more frequently had an inadequate motor blockade during surgery than those receiving the other two drugs. In the same study, the authors also evaluated the quality of postoperative analgesia provided with a patient-controlled epidural infusion of 0.125% bupivacaine, 0.125% levobupivacaine or 0.2% ropivacaine. They reported adequate pain relief and similar sparing of motor function during the first postoperative period. Bertini et al57 compared epidural analgesia with the same concentration of ropivacaine and bupivacaine (0.2%) after total hip replacement. They reported that, despite similar analgesic effects, epidural infusion of ropivacaine provided less motor blockade and higher patient satisfaction than equal doses of bupivacaine. Pouzeratte et al58 reported that thoracic epidural analgesia with 0.125% bupivacaine was more effective than with 0.125% ropivacaine when these two local anaesthetics were used in a mixture with 0.5 mg/ml sufentanil; whereas 0.2% ropivacaine alone was less effective than 0.125% ropivacaine combined with sufentanil. However, contrasting results have been reported in different studies, most of which reported that ropivacaine and bupivacaine have a similar clinical profile and result in comparable analgesia when used at low concentrations.59–61 Contrasting results have been also reported when comparing bupivacaine and ropivacaine for analgesia during labour.62–65 Meta-analysis studies demonstrated that both ropivacaine and bupivacaine provide excellent labour analgesia. However, the presence, or not, of any difference in motor block at clinically relevant doses remains unresolved.66 When considering the effects of different concentrations of levobupivacaine (0.0625, 0.125 and 0.25) for lumbar epidural analgesia after orthopaedic surgery, Murdoch et al67 showed a dose-dependent effect on quality of postoperative analgesia, and a sparing effect on morphine consumption with increasing concentrations of levobupivacaine. However, using the highest concentration resulted in a more marked motor blockade, suggesting that if minimum impairment of motor function is required for early rehabilitation, the concentration should be kept as low as possible. However, when

Bupivacaine, levobupivacaine and ropivacaine: are they clinically different? 255

the same hourly dose is given through a thoracic epidural catheter (15 mg/h), Darnedde et al68,69 reported that large-concentration/small-volume (3 ml/h of 0.5% levobupivacaine) provided an equal quality of postoperative analgesia as the small-concentration/ large-volume (10 ml/h of 0.15% levobupivacaine) infusion, and induced less motor blockade and fewer hemodynamic repercussions. Launo et al70 compared 0.125% levobupivacaine and 0.2% ropivacaine with added fentanyl 2 mg/ml for thoracic epidural analgesia after aortic surgery. They reported no differences in quality of analgesia and degree of motor block. Senard et al71 compared the efficacy, dose requirements, side effects and motor block observed during epidural infusion of 0.1% levobupivacaine or 0.1% ropivacaine in combination with 0.1 mg/h morphine after major abdominal surgery. They showed no differences in quality of pain relief and hourly consumption of the local anaesthetic mixture. However, on the second postoperative day, 19 patients in the ropivacaine group (76%) versus 12 in the levobupivacaine group (48%) were able to ambulate (P!0.05). Similar results have been reported by Purdie et al72, who compared ropivacaine and levobupivacaine at the same concentration for analgesia during labour and reported that 0.1% ropivacaine with 0.0002% fentanyl, and 0.1% levobupivacaine with 0.0002% fentanyl are clinically indistinguishable for labour analgesia, appearing pharmacologically equipotent when using a patient-controlled epidural analgesia. Other authors evaluated the usefulness of combining different additives with levobupivacaine, e.g. adrenaline, clonidine and opioids for epidural anaesthesia and analgesia. They showed that no advantages can be observed with the addition of adrenaline (epinephrine) at 2.5 or 5 mg/ml concentrations73, and that the addition of opioids improved the quality of pain relief without affecting the degree of motor blockade.74 Similar results have also reported with the use of ropivacaine for thoracic epidural analgesia after major abdominal surgery.75 Clonidine has been found to improve the postoperative analgesia of 0.125% levobupivacaine but to slow the resolution of motor blockade76 (Table 3). Spinal anaesthesia Racemic bupivacaine is undoubtedly one of the most widely used agents for spinal anaesthesia. Moreover, spinal anaesthesia does not require large doses of local anaesthetic, and the risk for systemic toxicity associated with the use of spinal bupivacaine is not an issue. Several studies published in recent years have reported on the use of these two new long-acting agents for intrathecal use. The two dose-finding volunteer studies discussed above36,37 are of particular interest because they clearly showed that whereas levobupivacaine and racemic bupivacaine have a similar clinical profile and potency ratio, intrathecal ropivacaine was half as potent as bupivacaine. McNamee et al77 reported that intrathecal administration of 17.5 mg plain ropivacaine 0.5% or plain bupivacaine 0.5% was well tolerated, and an adequate block for total hip arthroplasty was achieved in all patients. However, a more rapid postoperative recovery of sensory and motor function was seen with ropivacaine than bupivacaine (Table 4). Comparing 8, 10, 12 and 14 mg ropivacaine with 8 mg bupivacaine for ambulatory surgery, Gautier et al78 reported that ropivacaine 10 mg induced a shorter-lasting block than bupivacaine 8 mg, but was also associated with a poorer quality of intraoperative anaesthesia. However, when increasing the dose of ropivacaine to

Reference

Dose/concentration

No. of patients

Kopacz et al53

20 ml levobupivacaine 0.75% 20 ml bupivacaine 0.75% 15 ml ropivacaine 0.75% 15 ml levobupivacaine 0.5% 15 ml bupivacaine 0.5% 15 ml ropivacaine 0.5% 15 ml levobupivacaine 0.5%

28 28 30 35 15 15 15

6 ml/h ropivacaine 0.2%CPCEA 6 ml/h bupivacaine 0.2%CPCEA 0.1% ropivacaine C0.1 mg/h morphine 0.1% bupivacaine C0.1 mg/h morphine Ropivacaine 0.1%Cfentanyl 2 m/mlCPCEA Levobupivacaine 0.1%Cfentanyl 2 m/mlCPCEA

25

Peduto et al55 Casati et al56

Bertini et al57

Senard et al71

Purdie et al72

a

P!0.05 versus bupivacaine and levobupivacaine; P!0.05 versus ropivacaine; c P!0.05 versus ropivacaine. b

Type of surgery

Anaesthesia Abdominal 13.6G5.6 minutes 14.0G9.9 minutes Lower limb 25G22 minutes 29G24 minutes Hip surgery 25G19 minutes 30G24 minutes 31G16 minutes Analgesia Hip surgery

26 25

Abdominal

25 30 30

Onset time

Labour

Duration of the block

Percentage of motor block

550G87 minutes 505G71 minutes 201G48 minutes 185G77 minutes 213G53 233G34 214G61

100 60a 80

Consumption of local anaesthetic

0

175G12 ml

27b

178G12 ml

6/25

347G199 mg

13/25c

344G178 mg

BromageK1: 30

115G54 ml

BromageK1: 32

95G45 ml

256 A. Casati and M. Putzu

Table 3. Onset times and duration of epidural anaesthesia/analgesia of the three considered long-acting local anaesthetics.

Table 4. Spinal anaesthesia characteristics with the three long-acting agents.

Reference

Danelli et al81

Breebaart et al84

Glaser et al85 Casati et al87

a

c

Type of surgery Hip surgery

Max. sensory level

Duration of block

Complete motor block

2 (2–5) minutes 2 (2–9) minutes 14G6 minutes

T8

3.0 (1.5–4.6) hour 3.5 (2.7–5.2) hours 181G4.4 minutes

100% 100% 73%

15G8 minutes 18G5 minutes 18G6 minutes 12G5 minutes

T9 T8 T8 T4

130G27 minute 1) 152G44 minutes 176G42 minutes 211G48 minutes

26% 1) 77% 96%a 100%

8G2 minutes

T4

254G76 minutesb

100%

145G30 minutes

96%

Time to void 245G65 minutes

100% 89% 100% 100% 100%

285G65 minutesc 284G57 minutesc

T8 T8 T6

167G49 minutesc 173G47 minutesc 237G88 minutes 284G80 minutes 190G51 minutesd

T8 T5

210G63 minutesd 166G42 minutes

100% 100%

Onset time

3.5 ml plain ropivacaine 0.5% 3.5 ml plain bupivacaine 0.5% 8 mg bupivacaine 0.5%

32 34 30

8 mg ropivacaine 0.5% 10 mg ropivacaine 0.5% 12 mg ropivacaine 0.5% 20 mg ropivacaine C0.1 mg morphine 15 mg bupivacaine C0.1 mg morphine 60 mg lidocaine

30 30 30 30

20

Outpatient knee arthroscopy

15 mg ropivacaine 10 mg levobupivacaine 3.5 ml plain levobupivacaine 0.5% 3.5 ml plain ropivacaine 0.5% 8 mg hyperbaric bupivacaine 0.5%

20 20 40 40 20

8 mg hyperbaric levobupivacaine 0.5% 12 mg hyperbaric ropivacaine 0.5%

20 20

7G4 minutes 8G6 minutes Hip surgery 11G6 minutes 13G8 minutes Inguinal hernia 10G4 minutes repair 10G5 minutes 10G6 minutes

P!0.05 versus bupivacaine; P!0.05 versus ropivacaine; P!0.05 versus lidocaine; d P!0.05 versus ropivacaine. b

No. of patients

Outpatient knee arthroscopy

Caesarean section

30

6G4 minutes

Time to walk/void

Time to walk 192G48 minutes 107G25 minutesa 135G31 minutes 162G37 minutes

Time to void 298G68 minutes 255G58 minutes 302G48 minutes

Bupivacaine, levobupivacaine and ropivacaine: are they clinically different? 257

McNamee et al77 Gautier et al78

Dose/ concentration

258 A. Casati and M. Putzu

12 mg, these authors reported characteristics of sensory and motor blocks similar to those produced with 8 mg bupivacaine, indirectly confirming a bupivacaine to ropivacaine equipotency ratio of 1–1.5. Comparing 15 mg of either 0.5% ropivacaine or 0.5% bupivacaine in 8% glucose, Whiteside et al79 reported that ropivacaine provided reliable spinal anaesthesia of shorter duration and with less hypotension than bupivacaine. Similar findings have been also reported when comparing ropivacaine to racemic bupivacaine, alone or in combination with small doses of morphine, in women undergoing elective caesarean section. Also in this clinical setting, ropivacaine was reported to provide a similar quality of intraoperative block but earlier recovery of sensory and motor functions.80,81 The faster recovery profile of ropivacaine is reasonably related to its lower potency as compared to bupivacaine, but has the interesting potential for allowing a faster recovery from spinal anaesthesia when early patient discharge is required, such as for outpatient procedures.82 This characteristic of the spinal block produced by ropivacaine is even more marked when small doses of local anaesthetic are used, and the use of doses of as low as 4 mg ropivacaine with the addition of 120 mg fentanyl for anorectal surgery in an ambulatory setting has been associated with a complete regression of spinal block after less than 2 hours, with patients discharged home nearly 3 hours after spinal injection.83 Breebaart et al84 compared 10 mg levobupivacaine and 15 mg ropivacaine for outpatient knee arthroscopy, and reported L2 regression of sensory block after 173 and 167 minutes, with home discharge after 311 and 305 minutes, respectively. Clinical use of levobupivacaine results in clinical profile of spinal block undistinguishable from that of racemic bupivacaine. Glaser et al85 reported that 3.5 ml of 0.5% levobupivacaine provides exactly the same profile of spinal block as that obtained with the same volume of 0.5% racemic bupivacaine in patients receiving orthopaedic surgery. Gautier et al86 evaluated intrathecal injection of 8 mg 0.5% levobupivacaine, 8 mg 0.5% racemic bupivacaine and 12 mg 0.5% ropivacaine for caesarean section, and reported higher success rates as well as deeper and longer spinal block with bupivacaine than with the other two long-acting local anaesthetics. Casati et al87 compared unilateral spinal block produced with 8 mg hyperbaric bupivacaine 0.5%, 8 mg hyperbaric levobupivacaine 0.5% and 12 mg hyperbaric ropivacaine 0.5% in patients undergoing inguinal hernia repair. They reported that hyperbaric levobupivacaine and ropivacaine produce a spinal block with a similar clinical profile and restriction at the operated side as that produced with equipotent doses of hyperbaric bupivacaine, and could be used effectively also in an outpatient setting to provide spinal anaesthesia for inguinal hernia repair. Peripheral nerve blocks Animal studies on nerve conduction block produced by bupivacaine, levobupivacaine and ropivacaine for infraorbital or sciatic nerve block in the rat demonstrated that the duration of sensory block induced by equimolar doses of these three agents was similar.88 Ropivacaine has been compared with other local anaesthetics in different peripheral nerve blocks. Most of the studies seem to agree that, when used at similar concentrations and doses, ropivacaine produces a clinical profile of nerve block that is similar to that obtained with racemic bupivacaine, whereas the use of 0.75% or even 1%

Bupivacaine, levobupivacaine and ropivacaine: are they clinically different? 259

ropivacaine significantly shortens the onset time and prolongs the duration of ropivacaine’s nerve block.89–93 Evaluating low concentrations of ropivacaine for continuous peripheral nerve block, Borgeat et al94 reported that, when used at 0.2% concentration to produce patientcontrolled interscalene analgesia after major shoulder surgery, ropivacaine provides a much better preservation of motor function than a supposed equipotent concentration of bupivacaine (0.15%), even if no differences in pain relief and anaesthetic consumption were observed. This potential for a better preservation of motor function is very important to facilitate early rehabilitation after orthopaedic surgery. Much less is known on clinical use of levobupivacaine for peripheral nerve blocks. Cox et al95 compared 0.4 ml/kg of two concentrations of levobupivacaine (0.25 and 0.5%) with 0.5% bupivacaine for supraclavicular brachial plexus block, and reported similar onset times and duration of nerve block with the three drugs, although there was a tendency for levobupivacaine 0.25% to have a slower onset, shorter duration of action and lower overall success rate than levobupivacaine 0.5% and bupivacaine 0.5%. Crews et al96 compared the clinical characteristics of 0.5% levobupivacaine for axillary block in patients with normal renal function versus patients with end-stage renal disease. They demonstrated the clinical efficacy and equivalence of the pharmacoknetic characteristics in the two groups of patients. Interestingly, although very large doses of levobupivacaine (50–60 ml of the 0.5% concentration) were injected in studied patients, maximum plasma concentration ranged between 1.2 and 1.6 mg/ml, with time to peak concentration of 48–55 minutes. Similar findings have been also reported by Liisanantti et al97 who compared the use of high-dose bupivacaine, levobupivacaine or ropivacaine for axillary brachial plexus block and observed that ropivacaine produced slightly better intensity of sensory and motor blocks than the same dose of levobupivacaine. However, general success rate of surgical block and duration of both nerve block and postoperative analgesia was similar in the three groups. When comparing 30 ml of 0.5% levobupivacaine or 0.5% ropivacaine injected through an interscalene catheter, followed by a patient-controlled interscalene analgesia with 0.125% levobupivacaine or 0.2% ropivacaine, respectively, Casati et al98 reported no differences in onset time and quality of intraoperative anaesthesia, efficacy of postoperative analgesia, and recovery of motor function between the two drugs. However, total consumption of local anaesthetic infused during the first 24 hour was less in patients receiving levobupivacaine than in those receiving ropivacaine. This was associated with a deeper motor blockade with levobupivacaine when starting postoperative infusion in patients receiving levobupivacaine, and could be explained by a different recovery profile from the initial bolus, potentially related to a differential in potency between the two drugs. However, it must be noted that in this study the authors did not objectively assess the recovery of motor function, and further investigations with more objective measures of motor block recovery are advocated to better evaluate the sensory/motor differentiation of levobupivacaine and ropivacaine. Urbanek et al99 compared two concentrations of levobupivacaine (0.25 and 0.5%) with 0.5% bupivacaine for a three-in-one block. They reported similar clinical profiles in terms of onset time but complete surgical block was achieved less frequently with 0.25% levobupivacaine, with significantly shorter duration of postoperative analgesia than the other two groups. Three different studies have compared the use of levobupivacaine for sciatic nerve block for foot surgery with bupivacaine and ropivacaine at 0.5 and 0.75% concentrations.100–102 An identical clinical profile has been reported with the three

260 A. Casati and M. Putzu

agents at the 0.5% concentration. However, using 0.75% levobupivacaine for sciatic nerve block reduced the onset time compared to 0.5% levobupivacaine and provided a longer duration of postoperative analgesia than the same volume of 0.75% ropivacaine, also reducing total consumption of rescue tramadol during the first 24 hours after surgery.102 Levobupivacaine 0.75% has been also compared with bupivacaine 0.75% for peribulbar anaesthesia103, and no differences in clinical profile of nerve block have been observed. Continuous sciatic nerve block with 0.2% ropivacaine has been also compared with that produced by both an equivalent (0.2%) and equipotent (0.125%) concentration of levobupivacaine in patients receiving hallux valgus repair. Both 0.125 and 0.2% concentrations of levobupivacaine provide good postoperative analgesia when continuous lateral popliteal sciatic nerve block is used, with pain relief similar to that produced by 0.2% ropivacaine. Interestingly, although no differences in recovery of motor function were observed between 0.125% levobupivacaine and 0.2% ropivacaine, the infusion of 0.2% levobupivacaine resulted in more marked motor blockade without significant reduction in the volume of the local anaesthetic solution administered during the first two postoperative days. This seems to suggest that the 0.125% concentration of levobupivacaine can be considered a good compromise between adequate pain relief and no motor block, providing a sensory/motor differentiation similar to that provided by 0.2% ropivacaine.104 Further studies should be advocated to compare the sensory/ motor differentiation of levobupivacaine and racemic bupivacaine. Table 5 CONCLUSIONS Several points must be considered when choosing between different drugs with a similar clinical profile, including the efficacy, safety profile and the costs of the drug. These three, potent, long-acting agents have been studied and directly compared in several animal and clinical studies, including almost all regional anaesthesia techniques. As usual in the literature, contrasting results have been often reported, although reviewing the published literature strongly supports the idea that, even if minimal differences can be observed from one study to the other, both levobupivacaine and ropivacaine provide nerve-blocking characteristics similar to those of racemic bupivacaine in almost all regional anaesthesia techniques. The ‘equipotency issue’ between the three agents has gained a great deal of attention in the last few years and several studies evaluating the dose–response profile of ropivacaine, levobupivacaine and bupivacaine for epidural and spinal anaesthesia suggest an order of decreasing potency: racemic bupivacaineOlevobupivacaineOropivacaine. However, it is important to remember that in clinical anaesthesia we need a 100% success rate, and that the efficacy rather than the potency of a local anaesthetic must be considered. When high concentrations of the three drugs are used to produce a surgical block, there is a tendency towards a longer duration of racemic bupivacaine and levobupivacaine as compared to ropivacaine. However, although statistically significant, the observed differences do not seem to be clinically relevant in terms of success rate of surgical anaesthesia and both the two new agents provide a similarly effective and adequate surgical block when used at 0.5–0.75% concentrations, with no differences as compared to the same concentrations of racemic bupivacaine. The differential in local anaesthetic potency between the three agents becomes more evident when low concentrations are used to manage postoperative pain relief. In this clinical setting, irrespective of whether central or peripheral nerve blocks are being used, the 0.2% concentration of ropivacaine seems to be equipotent and as effective as

Table 5. Peripheral nerve block characteristics with the three long-acting agents.

Reference

Casati et al92 Borgeat et al94

Cox et al95

Liisanantti et al97 Casati et al98

Casati et al101

No. of patients

30 ml ropivacaine 0.75% 30 ml bupivacaine 0.5% 30 ml ropivacaine 0.75% 30 ml bupivacaine 0.5% 30 ml ropivacaine 0.5% 30 ml ropivacaine 0.75% 30 ml bupivacaine 0.5% 20 ml ropivacaine 0.5% 20 ml bupivacaine 0.5% 40 ml ropivacaine 0.6%

49 49 15 15 30 30 30 15 15 30

40 ml bupivacaine 0.5%

30

0.4 ml/kg levobupivacaine 0.5%

25

0.4 ml/kg levobupivacaine 0.25% 0.4 ml/kg bupivacaine 0.5% 45 ml bupivacaine 0.5% 45 ml levobupivacaine 0.5% 45 ml ropivacaine 0.5% 30 ml levobupivacaine 0.5%

26 23 30 30 30 25

30 ml ropivacaine 0.5%

25

20 ml levobupivacaine 0.5% 20 ml ropivacaine 0.5%

25 25

Type of block

Onset time

Supraclavicular

Not significant

Sciatic/femoral

14G17 minutes 37G27 minutesa 16G4 minutesb 14G3 minutesb 22G8 minutes 22G8 minutes 28G15 minutes Postoperative

Axillary

Interscalene Interscalene

Success rate 35/49 30/49 100% 100% 100% 100% 100%

Infusion

Duration of the block 11.3–14.3 hours 10.3–17.1 hours 670G220 minutes 880G312 minutes 654G224 minutes 666G174 minutes 666G210 minutes 11.0G5 hours 10.9G4 hours Ropivacaine 0.2% Bupivacaine 0.15%

Supraclavicular

Axillary

Continuous interscalene

Sciatic

7G6 minutes

100%

892G250 minutes

6G5 minutes 8G8 minutes Not significant

20 (15–45) minutes

92% 91% 77%a 57%a 83% 92%

1039G317 minutes 896G284 minutes 17.8G7.0 hours 17.1G6.5 hours 15.3G5.0 hours Similar recovery of motor function

20 (10–40) minutes

96%

30 (5–60) minutes 15 (5–60) minutes

92% 96%

Postoperative analgesia

Reduced strength at 48 hours: 21% Reduced strength at 48 hours: 54%a

Levobupivacaine 0.125% (147 ml/ 24 hours) Ropivacaine 0.2% (162 ml/24 hoursc

16 (8–24) hours 16 (8–24) hours (continued on next page)

Bupivacaine, levobupivacaine and ropivacaine: are they clinically different? 261

Vaghadia et al89 Fanelli et al90 Bertini et al91

Dose/concentration

262 A. Casati and M. Putzu

Table 5 (continued)

Reference Urbanek et al99

a

No. of patients

Type of block

Onset time

20 ml bupivacaine 0.5%

20

3-in-1 block

27 (20–33) minutes

20 ml levobupivacaine 0.5%

20

24 (18–30) minutes

20 ml levobupivacaine 0.25%

20

30 (23–36) minutes

Dose/concentration

P!0.05 versus ropivacaine; P!0.05 versus bupivacaine; c P!0.05 versus levobupivacaine; d P!0.05 versus levobupivacaine 0.25%. b

Success rate

Duration of the block 17.5 (13.3–21.7) hoursd 16.6 (14.0–19.3) hoursd 11.7 (9.1–14.4) hours

Postoperative analgesia

Bupivacaine, levobupivacaine and ropivacaine: are they clinically different? 263

0.125–0.15% levobupivacaine, whereas levobupivacaine is substantially identical to racemic bupivacaine used at the same concentrations. A potential advantage of ropivacaine over racemic bupivacaine is represented by its stronger differentiation between sensory and motor blocks. However, contrasting results have been reported in different clinical trials when low concentrations are used, such as for epidural analgesia in women in labour, and more extensive data should be obtained to confirm that this is related to a true characteristic of ropivacaine rather than to the differential in local anaesthetic potency. However, initial experiences with levobupivacaine used at supposed equipotent concentrations with respect to ropivacaine (according to a 1–1.5 potency ratio between the two drugs) for both peripheral and central nerve blocks seem to suggest that the same sensory/motor differentiation can be obtained with levobupivacaine and ropivacaine. Based on these findings, it can be concluded that the two, new, long-acting agents are very similar to bupivacaine, raising the question of whether the increased costs of the new agents can be justified based on the lack of clinical differences in their effectiveness. However, there is evidence in the literature to support the finding that both the two new pure left-isomers are less toxic than racemic bupivacaine. The reduced toxic potential of ropivacaine and levobupivacaine not only results in higher plasma concentrations and doses required before signs of systemic toxicity occur, but also in no cardiovascular toxicity or only minimal signs of cardiac effects after CNS toxicity occurs. Furthermore, the success rate of cardiopulmonary resuscitation observed after toxic doses are given to animals is much better than that obtained after bupivacaine intoxication. This means that the two new agents have a clear potential for reducing the severity of toxic effects induced either by overdosage or by unwanted intravascular injection. Accordingly, in those situations in which minimum doses of local anaesthetic are used with—substantially—no risks for systemic toxicity (e.g. spinal anaesthesia), bupivacaine remains strictly indicated, especially considering that no hyperbaric formulations are commercially available for levobupivacaine and ropivacaine. Moreover, although the addition of glucose could be performed directly by the anaesthesiologist to obtain hyperbaric solutions, mixing drugs to be injected into the cerebrospinal fluid could potentially reduce the safety of intrathecal injection and should not be used extensively. No clinically relevant advantages can be expected by the use of levobupivacaine or ropivacaine for spinal anaesthesia. However, in those clinical situations in which large volumes and infusion rates are required (e.g. epidural anaesthesia/analgesia or peripheral nerve blocks), and especially when performing lower limb blocks in which more than one nerve must be blocked to provide complete anaesthesia/analgesia of the operated limb, the use of the new left enantiomers should be advocated because of their reduced toxic potential. SUMMARY When new molecules are introduced, it is often difficult to understand whether their claimed advantages are really relevant to daily clinical practice. Ropivacaine and levobupivacaine have been developed and presented as alternative, long-acting local anaesthetics with the desirable blocking properties of racemic bupivacaine but a greater margin of safety due to their reduced toxic potential as compared to bupivacaine. From a clinical point of view, it seems clear that both these new molecules provide a long-lasting block, with a clinical profile very close to that provided by racemic bupivacaine, especially when high concentrations and doses are used to produce

264 A. Casati and M. Putzu

surgical anaesthesia. Ropivacaine has the theoretical advantage of a stronger differential in sensory/motor blocks than bupivacaine, especially when low concentrations are used postoperatively. However, it must be also considered that ropivacaine is less potent than bupivacaine and levobupivacaine because of its lower lipid solubility, and contrasting results have been reported in the literature about this supposed better differentiation in sensory/motor blockade. Nonetheless, these differences do not substantially affect the clinical efficacy of the three agents, and using proper concentrations of these three long-acting local anaesthetics results in similarly good preservation of motor function. Accordingly, the only relevant advantage of these new agents remains the reduced potential of toxicity as compared to bupivacaine, and their use should be advocated when large volumes and infusion rates are required to produce an effective nerve blockade, such as for epidural anaesthesia/analgesia and peripheral nerve blocks.

REFERENCES 1. Albright GA. Cardiac arrest following regional anesthesia with etidocaine and bupivacaine. Anesthesiology 1979; 51: 285–287. 2. Morishima HO, Pedersen H, Finster M et al. Bupivacaine toxicity in pregnant and nonpregnant ewes. Anesthesiology 1985; 63: 134–139. 3. Santos AC, Pedersen H, Harmon TW et al. Does pregnancy alter the systemic toxicity of local anesthetics? Anesthesiology 1989; 70: 991–995. 4. Aberg G. Toxicological and local anesthetic effects of optically active isomers of two local anesthetic compounds. Acta Pharmacol Toxicol Scand 1972; 31: 273–286. 5. Ekenstam BAF, Egner B & Petterson GN. N-alkyl pyrrolidine and N-alkyl piperidine carboxylic acid amines. Acta Chem Scand 1957; 11: 1183–1190. 6. Berde CB & Strichartz GR. Local anesthetics. In Miller RD (ed.)5th edn. Philadelphia, PA: ChurchillLivingstone, 2000, pp. 491–521. *7. Groban L. Central nervous system and cardiac effects from long-acting amide local anesthetic toxicity in the intact animal model. Reg Anesth Pain Med 2003; 28: 3–11. *8. Stewart J, Kellett N & Castro D. The central nervous system and cardiovascular effects of levobupivacaine and ropivacaine in healthy volunteers. Anesth Analg 2003; 97: 412–416. 9. Scott DB, Lee A, Fagan D et al. Acute toxicity of ropivacaine compared with that of bupivacaine. Anesth Analg 1989; 69: 563–569. 10. Knudsen K, Suurkula NB, Blomberg S et al. Central nervous system and cardiovascular effects of IV infusions of ropivacaine, bupivacaine, and placebo in volunteers. Br J Anaesth 1997; 78: 507–514. 11. Bardsley H, Gristwood R, Baker H et al. A comparison of the cardiovascular effects of levobupivaaine and rac-bupivacaine following intravenous administration to healthy volunteers. Br J Clin Pharmacol 1998; 46: 245–249. 12. Clarkson CW & Hondeghem LM. Mechanism for bupivacaine depression of cardiac conduction: fast block of sodium channels during the action potential with slow recovery from block during diastole. Anesthesiology 1985; 62: 396–405. 13. Arlock P. Actions of three local anesthetics: lidocaine, bupivacaine and ropivacaine on guinea pig papillary muscle sodium channels (Vmax). Pharmacol Toxicol 1988; 63: 96–104. 14. Avery P, Redon D, Schaenzer G et al. The influence of serum potassium on cerebral and cardiac toxicity of bupivacaine and lidocaine. Anesthesiology 1984; 61: 134–138. 15. Valenzuela C, Delpon E, Tamkun MM et al. Stereoselective block of a human cardiac potassium channel (Kv1.5) by bupivacaine enantiomers. Biophys J 1995; 69: 418–427. *16. Longobardo M, Delpon E, Caballero R et al. Structural determinants of potency and stereoselective block of hKv1.5 channels induced by local anesthetics. Mol Pharmacol 1998; 54: 162–169.

Bupivacaine, levobupivacaine and ropivacaine: are they clinically different? 265 17. Gonzalez T, Arias C, Caballero R et al. Effects of levobupivacaine, ropivacaine and bupivacaine on HERG channels: stereoselective bupivacaine block. Br J Pharmacol 2002; 137: 1269–1279. *18. Groban L, Deal DD, Vernon JC et al. Does local anesthetic stereoselectivity or structure predict myocardial depression in anesthetized canines? Reg Anesth Pain Med 2002; 27: 460–468. 19. Chang DH, Ladd LA, Copeland LA et al. Direct cardiac effects of intracoronary bupivacaine, levobupivacaine, and ropivacaine in sheep. Br J Pharmacol 2001; 132: 649–658. 20. Pitkanen M, Feldman HS, Arthur GR & Covino BG. Chronotropic and inotropipc effects of ropivacaine, bupivacaine, and lidocaine in the spontaneously beating and electrically paced isolated, perfused, rabbit heart. Reg Anesth Pain Med 1992; 17: 182–192. 21. Zapata-Sudo G, Trachez MM, Sudo RT et al. Is comparative cardiotoxicity of S(K) and R(C) bupivacaine related to enantiomer-selective inhibition of L-type Ca2C channels? Anesth Analg 2001; 92: 496–501. 22. Sztark F, Malgat M, Dabadie P & Mazat JP. Comparison of the effects of bupivacaine and ropivacaine on heart cell mitochontrial bioenergetics. Anesthesiology 1998; 88: 1340–1349. 23. Sztark F, Nouette-Gaulain K, Malgat M et al. Absence of sterospecific effects of bupivacaine isomers on heart mitochontrial bioenergetics. Anesthesiology 2000; 93: 456–462. *24. Heavner JE. Cardiac toxicity of local anesthetics in the intact isolated heart model: a review. Reg Anesth Pain Med 2002; 27: 545–555. 25. Groban L, Deal DD, Vernon JC et al. Cardiac resuscitation after incremental overdosage with lidocaine, bupivacaine, levobupivacaine, and ropivacaine in anesthetized dogs. Anesth Analg 2001; 92: 37–43. 26. Ohmura S, Kawada M, Ohta T et al. Systemic toxicity and resuscitation in bupivacaine-, levobupivacaine-, or ropivacaine-infused rats. Anesth Analg 2001; 93: 743–748. 27. Kopacz DJ & Allen HW. Accidental intravenous levobupivacaine. Anesth Analg 1999; 89: 1027–1029. 28. Abouleish EI, Elias M & Nelson C. Ropivacaine-induced seizure after extradural anaesthesia. Br J Anaesth 1998; 80: 843–844. 29. Petitjeans F, Mion G, Puidpupin M et al. Tachycardia and convulsions induced by accidental intravascular ropivacaine injection during sciatic block. Acta Anaesthesiol Scand 2002; 46: 616–617. 30. Breslin DS, Martin G, MacLeod DB et al. Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: a report of two cases. Reg Anesth Pain Med 2003; 28: 144–147. 31. Chazalon P, Tourtier JP, Villevielle T et al. Ropivacaine-induced cardiac arrest after peripheral nerve block: successful resuscitation. Anesthesiology 2003; 99: 1449–1451. 32. Pirotta D & Sprigge J. Convulsions following axillary brachial plexus blockade with levobupivacaine. Anaesthesia 2002; 57: 1187–1189. 33. Brau ME, Branitzki P, Olschewski A et al. Block of neuronal tetrodoxin-resistant NaC channels by stereoisomers of piperidine local anesthetics. Anesth Analg 2000; 91: 1499–1505. 34. Kanai Y, Katsuki H & Takasaki M. Comparison of the anesthetic potency and intracellular concentrations of S(K) and R(C) bupivacaine and ropivacaine in crayfish giant axon in vitro. Anesth Analg 2000; 90: 415–420. 35. Sinnott CJ & Stricharts GR. Levobupivacaine versus ropivacaine for sciatic nerve block in the rat. Reg Anesth Pain Med 2003; 28: 294–303. 36. Alley EA, Kopacz DJ, McDonald SB & Liu SS. Hyperbaric spinal levobupivacaine: a comparison to racemic bupivacaine in volunteers. Anesth Analg 2002; 94: 188–193. *37. McDonald SB, Liu SS, Kopacz DJ & Stephenson CA. Hyperbaric spinal ropivacaine: a comparison to bupivacaine in volunteers. Anesthesiology 1999; 90: 971–977. *38. Lyons G, Columb M, Wilson RC et al. Epidural pain relief in labour: potencies of levobupivacaine and racemic bupivacaine. Br J Anaesth 1998; 81: 899–901. 39. Polley LS, Columb MO, Naughton NN et al. Relative analgesic potencies of ropivacaine and bupivacaine for epidural analgesia in labor. Anesthesiology 1999; 90: 944–950. 40. Capogna G, Celleno D, Fusco P et al. Relative potencies of bupivacaine and ropivacaine for analgesia in labour. Br J Anaesth 1999; 82: 371–373. *41. Polley LS, Columb M, Naughton NN et al. Relative analgesic potencies of levobupivacaine and ropivacaine for epidural analgesia in labour. Anesthesiology 2003; 99: 1354–1358. 42. Benhamou D, Ghosh C & Mercier FJ. A randomised sequential allocation study to determine the minimum effective analgesic concentration of levobupivacaine and ropivacaine in patients receiving epidural analgesia for labor. Anesthesiology 2003; 99: 1383–1386.

266 A. Casati and M. Putzu 43. Lacassie HJ & Columb MO. The relative motor blocking potencies of bupivacaine and levobupivacaine in labor. Anesth Analg 2003; 97: 1509–1513. 44. Casati A, Fanelli G, Magistris L et al. Minimum local anesthetic volume blocking the femoral nerve in 50% of cases. A double-blinded comparison between 0.5% ropivacaine and 0.5% bupivacaine. Anesth Analg 2001; 92: 205–208. 45. Schug SA. Correction factor for comparisons between levobupivacaine and racemic bupivacaine. Reg Anesth Pain Med 2001; 26: 91. 46. Katz JA, Knarr D & Bridenbaugh PO. A double-blind comparison of 0.5% bupivacaine and 0.75% ropivacaine administered epidurally in humans. Reg Anesth 1990; 15: 250–252. 47. Kerkkamp HE, Gielen MJ & Edstrom HH. Comparison of 0.75% ropivacaine with epinephrine and 0.75% bupivacaine with epinephrine in lumbar epidural anesthesia. Reg Anesth 1990; 15: 204–207. 48. Wolff AP, Hasselstrom L, Kerkkamp HE & Gielen MJ. Extradural ropivacaine and bupivacaine in hip surgery. Br J Anaesth 1995; 74: 458–460. 49. McGlade DP, Kalpokas MV, Mooney PH et al. Comparison of 0.5% ropivacaine and 0.5% bupivacaine in lumbar epidural anaesthesia for lower limb orthopaedic surgery. Anaesth Intensive Care 1997; 25: 262–266. 50. Crosby E, Sandler A, Finucane B et al. Comparison of epidural anaesthesia with ropivacaine 0.5% and bupivacaine 0.5% for caesarean section. Can J Anaesth 1998; 45: 1066–1071. 51. Kampe S, Tausch B, Paul M et al. Epidural block with ropivacaine and bupivacaine for elective cesarean section: maternal cardiovascular parameters, comfort and neonatal well-being. Curr Med Res Opin 2004; 20: 7–12. 52. Cox CR, Faccenda KA, Gilhooly C et al. Extradural S(K)bupivacaine: comparison with racemic RS-bupivacaine. Br J Anaesth 1998; 80: 289–293. 53. Kopacz DJ, Allen HW & Thompson GE. A comparison of epidural levobupivacaine 0.75% with racemic bupivacaine for lower abdominal surgery. Anesth Analg 2000; 90: 642–648. 54. Faccenda KA, Simpson AM, Henderson DJ et al. A comparison of levobupivacaine 0.5% and racemic bupivacaine for extradural anesthesia for cesarean section. Reg Anesth Pain Med 2003; 28: 394–400. 55. Peduto VA, Baroncini S, Montanini S et al. A prospective, randomized, double-blind comparison of epidural levobupivacaine 0.5% with epidural ropivacaine 0.75% for lower limb procedures. Eur J Anaesthesiol 2003; 20: 979–983. 56. Casati A, Santorsola R, Aldegheri G et al. Intraoperative epidural anesthesia and postoperative analgesia with levobupivacaine for major orthopedic surgery: a double-blind, randomised comparison of racemic bupivacaine and ropivacaine. J Clin Anesth 2003; 15: 126–131. 57. Bertini L, Mancini S, Di Benedetto P et al. Postoperative analgesia by combined continuous infusion and patient-controlled epidural analgesia following hip replacement: ropivacaine versus bupivacaine. Acta Anaesthesiol Scand 2001; 45: 782–785. 58. Pouzeratte Y, Delay JM, Brunat G et al. Patient-controlled epidural analgesia after abdominal surgery: ropivacaine versus bupivacaine. Anesth Analg 2001; 93: 1587–1592. 59. Senard M, Joris JL, Ledoux D et al. A comparison of 0.1% and 0.2% ropivacaine and bupivacaine combined with morphine for postoperative patient-controlled epidural analgesia after major abdominal surgery. Anesth Analg 2002; 95: 444–449. 60. Macias A, Monedero P, Adame M et al. A randomised, double-blinded comparison of thoracic epidural ropivacaine, ropivacane/fentanyl, or bupivacaine/fentanyl for post-thoracotomy analgesia. Anesth Analg 2002; 95: 1344–1350. 61. Berti M, Fanelli G, Casati A et al. Patient supplemented epidural analgesia after major abdominal surgery with bupivacaine/fentanyl or ropivacaine/fentanyl. Can J Anaesth 2000; 47: 27–32. 62. Chua NP, Sia AT & Ocampo E. Parturient-controlled epidural analgesia during labour: bupivacaine versus ropivacaine. Anaesthesia 2001; 56: 1169–1173. 63. Dresner M, Freeman J, Calow C et al. Ropivacaine 0.2% versus bupivacaine 0.1% with fentanyl: a double blind comparison for analgesia during labour. Br J Anaesth 2000; 85: 826–829. 64. Owen MD, Thomas JA, Smith T et al. Ropivacaine 0.075% and bupivacaine 0.075% with fentanyl 2 mg/mL are equivalent for labor epidural analgesia. Anesth Analg 2002; 94: 179–183. 65. Clement HJ, Caruso L, Lopez F et al. Epidural analgesia with 0.15% ropivacaine plus sufentanil 0.5 microgram ml-1 versus 0.10% bupivacaine plus sufentanil 0.5 microgram ml-1: a double-blind comparison during labour. Br J Anaesth 2002; 88: 809–813.

Bupivacaine, levobupivacaine and ropivacaine: are they clinically different? 267 66. Halpern SH & Walsh V. Epidural ropivacaine versus bupivacaine for labor: a meta-analysis. Anesth Analg 2003; 96: 1473–1479. 67. Murdoch JA, Dickson UK, Wilson PA et al. The efficacy and safety of three concentrations of levobupivacaine administered as a continuous epidural infusion in patients undergoing orthopedic surgery. Anesth Analg 2002; 94: 438–444. 68. Dernedde M, Stadler M, Bardiau F & Boogaerts J. Comparison of different concentrations of levobupivacaine for post-operative epidural analgesia. Acta Anaesthesiol Scand 2003; 47: 884–890. *69. Dernedde M, Stadler M, Bardiau F & Boogaerts JG. Continuous epidural infusion of large concentration/small volume versus small concentration/large volume of levobupivacaine for postoperative analgesia. Anesth Analg 2003; 96: 796–801. 70. Launo C, Gastaldo P, Piccardo F et al. Perioperative thoracic epidural analgesia in aortic surgery: role of levobupivacaine. Minerva Anestesiol 2003; 69: 751–760. *71. Senard M, Kaba A, Jacquemin MJ et al. Epidural levobupivacaine 0.1% or ropivacaine 0.1% combined with morphine provides comparable analgesia after abdominal surgery. Anesth Analg 2004; 98: 389–394. 72. Purdie NL & McGrady EM. Comparison of patient-controlled epidural bolus administration of 0.1% ropivacaine and 0.1% levobupivacaine, both with 0.0002% fentanyl, for analgesia during labour. Anaesthesia 2004; 59: 133–137. 73. Kopacz DJ, Helman JD, Nussbaum CE et al. A comparison of epidural levobupivacaine 0.5% with or without epinephrine for lumbar spine surgery. Anesth Analg 2001; 93: 755–760. 74. Kopacz DJ, Sharrock NE & Allen HW. A comparison of levobupivacaine 0.125%, fentanyl 4 mg/mL, or their combination for patient-controlled epidural analgesia after major orthopedic surgery. Anesth Analg 1999; 89: 1497–1503. 75. Berti M, Casati A, Fanelli G et al. 0.2% ropivacaine with or without fentanyl for patient-controlled epidural analgesia after major abdominal surgery: a double-blind study. J Clin Anesth 2000; 12: 292–297. 76. Milligan KR, Convery PN, Weir P et al. The efficacy and safety of epidural infusions of levobupivacaine with and without clonidine for postoperative pain relief in patients undergoing total hip replacement. Anesth Analg 2000; 91: 393–397. 77. McNamee DA, McClelland AM, Scott S et al. Spinal anaesthesia: comparison of plain ropivacaine 5 mg ml-1 with bupivacaine 5 mg ml-1 for major orthopedic surgery. Br J Anaesth 2002; 89: 702–706. 78. Gautier P, de Kock M, Van Steenberge A et al. Intrathecal ropivacaine for ambulatory surgery. A comparison between intrathecal bupivacaine and intrathecal ropivacaine for knee arthroscopy. Anesthesiology 1999; 91: 1239–1245. 79. Whiteside JB, Burke & Wildsmith JA. Comparison of ropivacaine 0.5% (in glucose 5%) with bupivacaine 0.5% (in glucose 8%) for spinal anaesthesia for elective surgery. Br J Anaesth 2003; 90: 304–308. 80. Ogun CO, Kirgiz EN, Duman A et al. Comparison of intrathecal isobaric bupivacaine-morphine and ropivacaine-morphine for cesarean delivery. Br J Anaesth 2003; 90: 659–664. 81. Danelli G, Fanelli G, Berti M et al. Spinal ropivacaine or bupivacaine for cesarean delivery: a prospective, randomized, double-blind comparison. Reg Anesth Pain Med 2004; 29: 221–226. 82. Lopez-Soriano F, Lajarin B, Rivas F et al. Hyperbaric subarachnoid ropivacaine in ambulatory surgery: comparative study with hyperbaric bupivacaine. Rev Esp Anestesiol Reanim 2002; 49: 71–75. 83. Buckenmaier CC, Nielsen KC, Pietrobon R et al. Small-dose intrathecal lidocaine versus ropivacaine for anorectal surgery in an ambulatory setting. Anesth Analg 2002; 95: 1253–1257. 84. Breebaart MB, Vercauteren MP, Hoffmann VL & Adriaensen HA. Urinary bladder scanning after day-case arthroscopy under spinal anaesthesia: comparison between lidocaine, ropivacaine, and levobupivacaine. Br J Anaesth 2003; 90: 309–313. 85. Glaser C, Marhofer P, Zimpfer G et al. Levobupivacaine versus racemic bupivacaine for spinal anesthesia. Anesth Analg 2002; 94: 194–198. 86. Gautier P, de Kock M, Huberty L et al. Comparison of the effects of intrathecal ropivacaine, levobupivacaine, and bupivacaine for Caesarean section. Br J Anaesth 2003; 91: 684–689. 87. Casati A, Moizo E, Marchetti C, Vinciguerra F. A prospective, randomized, double-blind comparison of unilateral spinal anesthesia with hyperbaric bupivacaine, ropivacaine, or levobupivacaine for inguinal herniorraphy. Anesth Analg 99: in press. 88. Dyhre H, Lang M, Wallin R & Renck H. The duration of action of bupivacaine, levobupivacaine, ropivacaine in peripheral nerve block in the rat. Acta Anaesthesiol Scand 1997; 41: 1346–1352.

268 A. Casati and M. Putzu 89. Vaghadia H, Chan V, Ganapathy S et al. A multicentre trial of ropivacaine 7.5 mg!ml(K1) vs bupivacaine 5 mg!ml(K1) for supra clavicular brachial plexus anesthesia. Can J Anaesth 1999; 46: 946–951. 90. Fanelli G, Casati A, Beccaria P et al. A double-blind comparison of ropivacaine, bupivacaine and mepivacaine during sciatic and femoral nerve blockade. Anesth Analg 1998; 87: 597–600. 91. Bertini L, Tagariello V, Mancini S et al. 0.75% and 0.5% ropivacaine for axillary brachial plexus block: a clinical comparison with 0.5% bupivacaine. Reg Anesth Pain Med 1999; 24: 514–518. 92. Casati A, Fanelli G, Cappelleri GL et al. A clinical comparison of ropivacaine 0.75%, ropivacaine 1% or bupivacaine 0.5% for interscalene brachial plexus anaesthesia. Eur J Anaesth 1999; 16: 784–789. 93. Casati A, Fanelli G, Albertin A et al. Interscalene brachial plexus anesthesia with either 0.5% ropivacaine or 0.5% bupivacaine. Minerva Anestesiol 2000; 66: 39–44. 94. Borgeat A, Kalberer F, Jacob H et al. Patient-controlled interscalene analgesia with ropivacaine 0.2% versus bupivacaine 0.15% after major open shoulder surgery: the effects on hand and motor function. Anesth Analg 2001; 92: 218–223. 95. Cox CR, Checketts MR, MacKenzie N et al. Comparison of S(K)bupivacaine with racemic (RS)-bupivacaine in supraclavicular brachial plexus block. Br J Anaesth 1998; 80: 594–598. 96. Crews JC, Weller RS, Moss J & James RL. Levobupivacaine for axillary brachial plexus block: a pharmacokinetic and clinical comparison in patrients with normal renal function or renal disease. Anesth Analg 2002; 95: 219–223. 97. Liisanantti O, Luukkonen J & Rosenberg PH. High-dose bupivacaine, levobupivacaine and ropivacaine in axillary brachial plexus block. Acta Anaesthesiol Scand 2004; 48: 601–606. 98. Casati A, Borghi B, Fanelli G et al. Interscalene brachial plexus anestesia and analgesia for open shoulder surgery: a randomized, double-blinded comparison between levobupivacaine and ropivacaine. Anesth Analg 2003; 96: 253–259. 99. Urbanek B, Duma A, Kimberger O et al. Onset time, quality of blocade and duration of three-in-one blocks with levobupivacaine and bupivacaine. Anesth Analg 2003; 97: 88–92. 100. Casati A, Chelly JE, Cerchierini E et al. Clinical properties of levobupivacaine or racemic bupivacaine for sciatic nerve block. J Clin Anesth 2002; 14: 111–114. 101. Casati A, Borghi B, Fanelli G et al. A double-blind, randomized comparison of either 0.5% levobupivacaine or 0.5% ropivacaine for sciatic nerve block. Anesth Analg 2002; 94: 987–990. 102. Casati A, Vinciguerra F, Santorsola R, et al. A prospective, randomised, double-blind clinical comparison of 0.5% levobupivacaine, 0.75% levobupivacaine, or 0.75% ropivacaine for sciatic nerve block. Eur J Anaesthesiol 21: in press. 103. Birt DJ & Cummings GC. The efficacy and safety of 0.75% levobupivacaine vs 0.75% bupivacaine for peribulbar anaesthesia. Eye 2003; 17: 200–206. 104. Casati A, Vinciguerra F, Cappelleri G, et al. 0.2% or 0.125% levobupivacaine for continuous sciatic nerve block: a prospective, randomized, double-blind comparison with 0.2% ropivacaine. Anesth Analg 99: in press.