Developments in local anaesthetic drugs

J. B. Whiteside and J. A. W. Wildsmith

University Department of Anaesthesia, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK*Corresponding author


    Abstract
 Top
 Abstract
 Introduction
 Chirality and local anaesthetics
 Ropivacaine
 Levobupivacaine
 Other developments
 Declaration of interest
 References
 
Br J Anaesth 2001; 87: 27–35

Keywords: anaesthetics, local


    Introduction
 Top
 Abstract
 Introduction
 Chirality and local anaesthetics
 Ropivacaine
 Levobupivacaine
 Other developments
 Declaration of interest
 References
 
Most of the recent developments in local anaesthetics have been a direct consequence of the recognition, 20 yr ago, of the acute, life-threatening cardiotoxicity of bupivacaine.5 All local anaesthetics produce a dose dependent delay in the transmission of impulses through the cardiac conduction system by their action on the cardiac sodium and potassium channels. However, overt cardiotoxicity usually only becomes apparent as the last feature of a reasonably predictable sequence of changes.33 One of the specific features of bupivacaine is that clinical evidence of accumulation of the drug in plasma may be diminished until a fairly late stage because of its high affinity for plasma protein binding sites. The ‘free’ concentration of drug in plasma remains low until all the protein binding sites are fully occupied after which it increases rapidly, and toxicity can occur without patients exhibiting signs of CNS toxicity before cardiovascular collapse.49 110 In addition to, and probably more important than, this pharmacokinetic component to its toxicity, bupivacaine has been shown to have selective cardiac effects related to the slow rate at which it dissociates from the sodium channel.29 An important aspect of this toxicity is that it involves a significant degree of stereo-specificity, with the ‘S’ isomer showing significantly less cardio-depressant effect than the ‘R’.99

These findings generated two parallel areas of research, one clinical and the other laboratory; the outcome of both has affected clinical practice. The clinical programme was aimed at avoidance of the rapid accidental intravascular injection of a large dose of bupivacaine, the common factor in all serious reactions. Much study of ‘test’ doses has shown that no such test is completely reliable at identifying accidental intravascular placement. Thus, it is still essential that the main dose of local anaesthetic is injected incrementally (4–5 ml at a time) with sufficient pause between each bolus to allow identification of any systemic consequences. The laboratory research programme was aimed at identifying a local anaesthetic with a similar clinical profile, but with less cardiotoxicity than bupivacaine. Given that a more cautious approach to clinical use seems to have prevented any further deaths, it may be argued that the expense of a new agent is unnecessary. However, it is an agent with a relatively low therapeutic index, and as little as 50 mg has caused primary ventricular fibrillation on accidental i.v. administration in a susceptible patient. Less risk of toxicity may be justification alone for new drugs when very large doses are required as in brachial plexus block. However, perhaps a new drug should offer additional advantages when used in other ways if the expense is to be justified.

The search for alternatives to bupivacaine has concentrated on amide-linked agents, which in current practice have largely superseded the ester type drugs. Investigation of the possible aetiological mechanisms of local anaesthetic induced cardiotoxicity, along with advances in stereoselective synthesis, have demonstrated the potential clinical advantages of agents comprised of a single enantiomer.1 97 99 Of the commonly used, older amide drugs, only lidocaine is not ‘chiral’; for example, it exists as a single structural entity at molecular level. Prilocaine, mepivacaine, and bupivacaine all have an ‘asymmetric’ carbon atom which means that traditional manufacturing methods result in the production of equal amounts of ‘S’ and ‘R’ isomers, something which is reflected in the clinically available preparations. Ropivacaine and levobupivacaine are two relatively new amide local anaesthetic agents that have been produced in order to address the issue of bupivacaine cardiotoxicity. Each is produced as a pure ‘S’ isomer. Levobupivacaine is the ‘S’ isomer of bupivacaine. Ropivacaine is the propyl analogue of, bupivacaine having a butyl group in the same position.

Current developments are not exclusively restricted to variations on the traditional amide drug theme as a response to rare toxic reactions. Other work is looking to identify agents that interrupt nerve transmission in a more specific way with the aim of maximizing analgesia and minimizing other manifestations of nerve block. Much of this research is concentrating on the modulation of synaptic transmission at spinal cord level and is beyond the scope of this review. However, manipulation of the effects of the physico-chemical properties of local anaesthetic drugs can influence the degree of differential nerve block,20 103 and the lower lipid solubility of ropivacaine results in less motor block than bupivacaine. Studies of an agent with very significantly lower lipid solubility than these (butyl amino-benzoate68 91 92) may yet provide the practising anaesthetist with a ‘local analgesic’ not only with a specific action, but one with a duration measured in weeks. The prolongation of effect is due more to the formulation, a suspension, than to the drug itself. An alternative ‘slow release’ strategy is the incorporation of standard drugs into liposomes,16 38 53 71 but this review will concentrate on drugs. Problems with the liposome method have been reported.39

The clinical use of the new drugs mentioned above will be the prime focus of this review, but the obvious importance of chirality to the pharmacology of ropivacaine and levobupivacaine means that some explanation is appropriate. Butyl amino-benzoate represents an extreme example of the differential nerve blocking effect of local anaesthetics, as well as an indication of how slow release preparations may be used to prolong their action. Finally, there will be some consideration of articaine. This is not a new drug and, unlike the others mentioned above, it has a relatively short duration, but there has been some renewed interest in it. This interest may be increased by the recent withdrawal of a large number of prilocaine preparations because articaine has similar properties.17


    Chirality and local anaesthetics
 Top
 Abstract
 Introduction
 Chirality and local anaesthetics
 Ropivacaine
 Levobupivacaine
 Other developments
 Declaration of interest
 References
 
Chirality is a word derived from the Greek chiros meaning ‘handed’. Chemically, a chiral compound is one that contains at least one tetraco-ordinate carbon (or sulphur) atom to which four different atoms or chemical groups are attached. If a molecule contains one such ‘asymmetric’ carbon atom, two distinct spatial arrangements are possible, each a mirror image of the other. These ‘stereo-isomers’ are molecules with identical atomic composition and chemical properties, but the different spatial arrangement of their atoms means that they do not match when superimposed one upon the other. A pair of such stereo-isomers are called enantiomers, and each rotates plane-polarized light in equal magnitude, but in opposite directions. When a compound contains equimolar amounts of the two enantiomers it is referred to as a ‘racemate’ or ‘racemic’ mixture. Enantiomers have identical physico-chemical properties, so they will have the same pKa and lipid solubility figures.95 However, they differ, both qualitatively and quantitatively, in regard to pharmacokinetic and pharmacodynamic properties, because of stereoselective interactions (i.e., those as a result of differences in three-dimensional structure) at molecular sites of drug action.

Each stereo-isomer of any pair may be described in a number of ways, but the current standard is the ‘Sequence Rule Notation’.25 This is based on attaching an order of priority to substituent groups (or atoms) attached to the central chiral atom, having identified the ‘smallest’ of the four first. The molecule is ‘positioned’ with this smallest group directed away from the ‘viewer’ and note taken of the sizes of the other three. If the sequence from smallest to largest is ‘clockwise’, it is defined as a ‘R’ isomer from the Latin rectus (right), whereas if the sequence is ‘anticlockwise’ the isomer is defined as ‘S’ from the Latin sinister (left). These are known as absolute descriptors and may be most simply illustrated by reference to the isomers of lactic acid (Fig. 1).



View larger version (12K):
[in this window]
[in a new window]
 
Fig 1 Structural chemistry of the isomers of lactic acid. The top representation shows the standard two-dimensional representation. In the other two, the smallest group (-H) attached to the central carbon atom is ‘directed’ away from the viewer. If the sequence of the other three (smallest to largest) is ‘clockwise’ as viewed, it is an R isomer, and an S isomer if the sequence is reversed.

 
However, the best-known method of referring to the chirality of a molecule relates to the effect it has on the rotation of plane polarized light, either clockwise (+) or anticlockwise (–)—the relative descriptors. Unfortunately, there is no consistency between the absolute and relative descriptors. Within an homologous series of compounds the S/R notation may change as the length of a particular side chain increases so the full description of a chiral compound may be given by a combination of both descriptors (e.g. S(–) bupivacaine).

Differences in both the pharmacokinetic and pharmacodynamic properties of the different isomers of various local anaesthetic drugs have been recognized for many years. Prilocaine was probably the first agent to be studied extensively,2 but the costs of production were then prohibitive for clinical availability and the differences between the isomers were of relatively little clinical impact. The local anaesthetic and toxic effects of the enantiomers of bupivacaine were first described in 1972 by Aberg and colleagues,1 who showed that the S(–) enantiomer is less toxic than the R(+) form. Subsequent studies confirmed the lower neurotoxicity and cardiotoxicity of the S(–) enantiomer in animal models.60 72 99 Human studies have also shown that larger doses of S(–) bupivacaine than racemic bupivacaine are required before the onset of neurological symptoms.12

Ropivacaine is the ‘S’ isomer of the propyl analogue of mepivacaine and bupivacaine. The parent compound of ropivacaine was, like the other two, first synthesized in the 1950s,4 but they were selected for further development as short and long-acting agents, respectively. It was only when concerns about the cardiotoxicity of bupivacaine became apparent that ropivacaine was evaluated fully. The S(–) enantiomer was selected initially because it has a longer duration of action than the R(+),3 but later animal studies showed that ropivacaine dissociates from sodium channels more rapidly, produces less accumulation of sodium channel block and is less cardiotoxic than racemic bupivacaine.7 78 85 Infusion studies in human volunteers have confirmed that larger doses are required to produce early features of neurotoxicity and cardiotoxicity than racemic bupivacaine.65 88 The commercial preparation has an enantiomeric purity of 99.5%.44


    Ropivacaine
 Top
 Abstract
 Introduction
 Chirality and local anaesthetics
 Ropivacaine
 Levobupivacaine
 Other developments
 Declaration of interest
 References
 
Ropivacaine (N-n-propyl 2',6'-pipecoloxylidide) is an amino-amide local anaesthetic, some important basic aspects of which have been described already. It was first registered for clinical use in 1996 and a full review of its clinical pharmacology was published at that time.73 As well as having less cardiotoxicity, there is evidence that any such effect occurring after inadvertent intravascular injection may be more easily reversed than is the case with bupivacaine.9 45 83

The physico-chemical properties of ropivacaine (Table 1) suggest that its rate of onset (related to pKa) should be similar to that of bupivacaine, and that its absolute potency (lipid solubility) and duration of effect (protein binding) should be slightly less.


View this table:
[in this window]
[in a new window]
 
Table 1 Physico-chemical properties and plasma protein binding characteristics of local anaesthetic agents.95 104 PKa=dissociation constant
 
In addition, the lower lipid solubility of ropivacaine would predict that it is likely to produce a greater differential block of sensory and motor function than bupivacaine. Laboratory studies have confirmed these predictions,10 86 103 but selection of the longer acting S(–) isomer should compensate for the possible shorter duration. Thus, ropivacaine has other potential advantages besides that of reduced cardiotoxicity.

Further evaluation in both animal and volunteer human studies confirmed that ropivacaine is an effective local anaesthetic and showed that, unlike bupivacaine, it has a slight vasoconstrictor effect at lower concentrations.28 36 66 Epinephrine was found to have little effect on the local action or the resultant systemic concentrations of ropivacaine in human studies.28 56 81

Clinical efficacy
Ropivacaine has been compared with bupivacaine in many clinical trials involving most forms of regional anaesthesia. Most studies have shown that the onset, potency and duration are very similar to those of bupivacaine. However, some studies, particularly those utilizing the concept of Minimum Local Analgesic Concentration (MLAC) in epidural analgesia, have questioned whether the difference in cardiotoxicity seen between the two agents is in fact a result of an absolute difference in potency.27 84 The suggestion is that the therapeutic ratio of the two may be the same. Such concerns must be viewed against the important basic principle that the local, and subsequent systemic, dynamics of a particular local anaesthetic will depend on the site of injection.8 Thus, each clinical application must be considered in turn.

Wound infiltration
Ropivacaine has been used successfully for post-operative analgesia in patients undergoing inguinal herniorrhaphy80 and open cholecystectomy.61 Equal doses (100 mg) of ropivacaine and bupivacaine have been shown to provide similar analgesia after inguinal hernia surgery.41 The intrinsic vasoconstrictive properties of ropivacaine may help explain the findings of one study which demonstrated cutaneous anaesthesia two to three times longer than that produced by bupivacaine.28 Some authors have questioned the safety of this because of the possibility of inducing microcirculatory insufficiency or compromising end-arterial blood supply.94 There has been one report of local ischaemia after the use of 0.75% ropivacaine for penile block, but no long-term sequelae were observed.21 Therefore, ropivacaine may be unsuitable for infiltration in tissues without collateral blood supply.

Major nerve block
A large number of studies on the use of ropivacaine for brachial plexus anaesthesia, utilizing a variety of techniques, have been published.43 57 The majority of studies suggest that the clinical outcome is similar to that of equivalent doses of bupivacaine,58 59 96 with the 0.25% concentration of both drugs being associated with an unacceptable incidence of inadequate block of either sensory or motor nerves. Some, more recent studies have shown a significantly faster onset in both upper and lower limb blocks with ropivacaine than with an equal dose of bupivacaine.15 43 Bertini and colleagues also demonstrated a better quality of block with ropivacaine as indicated by intra-operative opioid requirements and patient satisfaction scores.15

Although there is some variation between the reports in the literature, an overview suggests that there may be no more than slight differences in onset, but no difference between ropivacaine and bupivacaine in completeness or duration of block. Both drugs produce effective long-acting local anaesthesia.

Spinal anaesthesia
Ropivacaine has been used relatively infrequently for spinal anaesthesia. Its very early evaluation included two studies of the intrathecal injection of glucose-free solutions performed primarily for safety reasons to confirm that accidental intrathecal injection during epidural block would be without adverse sequelae.98 100 Sensory block of variable extent and intermediate duration was produced. Currently, ropivacaine is not licensed for intrathecal use, but two more recent, clinical studies have compared ropivacaine unfavourably with bupivacaine.51 77

Gautier and colleagues51 used glucose-free preparations, but in larger volumes of less concentrated solutions than are normally used in clinical practice. The onset and extent of sensory block were similar, but both the duration of that sensory block and the degree of motor block produced were less with ropivacaine. These findings, particularly the shorter duration of action, led the authors to claim that ropivacaine is less potent than bupivacaine and that it offers no significant advantage. However, it is noteworthy that the patients who received ropivacaine passed urine and mobilized more rapidly than those who received bupivacaine.

McDonald and colleagues77 compared hyperbaric preparations of the two drugs in volunteers not undergoing surgery. The concentrations of their solutions were also less than are normally used clinically, as were the total doses injected. The two drugs produced sensory blocks of similar onset and extent, but there was less motor block, which regressed faster, with ropivacaine. Again, on the basis of the shorter duration of action and despite equivalence in the onset and extent of sensory block, the conclusion was that ropivacaine is less potent than bupivacaine. This study also noted a higher incidence of backache after ropivacaine and concluded that the incidence of side effects was higher, even though the difference was not statistically significant.

However, more recent work has shown that glucose containing solutions of ropivacaine in concentrations and doses more appropriate to spinal anaesthesia produce a clinical block profile that is very appropriate to much of the surgery for which this application of regional anaesthesia is currently used.102 No direct comparison of ropivacaine and bupivacaine in formulations more suited to clinical use is yet available, but ropivacaine does seem worthy of more definitive study for spinal anaesthesia. There is also some need for questioning the interpretation of a difference in duration as an indicator of a difference in potency.105

Epidural anaesthesia and analgesia
The historical background, the potential for less cardiotoxicity, and the early evidence suggesting that the motor block produced by ropivacaine is less intense and of shorter duration than with bupivacaine, have all led to extensive evaluation of its role in epidural block.1819 47 63 107108 111112 These are ideal qualities for an agent for epidural use, where accidental i.v. injection of large doses of local anaesthetic is a potential hazard and where preservation of lower limb motor function is often desirable.

Early, ‘open’ studies of ropivacaine showed that it could be used to provide long-acting, good quality anaesthesia for surgery when administered by the lumbar route.31 101 The lower lipid solubility of ropivacaine, and the in vitro and in vivo demonstration of slightly lower potency than bupivacaine,46 86 led some investigators to compare ropivacaine with somewhat lower concentrations of bupivacaine.62 107108 They demonstrated similar onset and extent of both motor and sensory block, and similar duration of motor block, but slightly longer duration of analgesia with the more concentrated solutions of ropivacaine. However, when direct comparison of equal concentrations have been made, in both the obstetric and non-obstetric population, no significant differences in onset, speed or duration of sensory block were found, but the motor block was less intense and of shorter duration.18 54 79

This work was for ‘anaesthetic’ use in a wide range of clinical settings, but most of the studies of ropivacaine as an ‘analgesic’ have been performed in the obstetric population. Maternal safety, good patient mobility during labour and minimal need for obstetric intervention are key outcomes in this field of practice and the lower cardiotoxic potential and the greater degree of sensory and motor block separation have led some to suggest that ropivacaine offers significant advantages over bupivacaine.74

Many studies have compared the two during labour, all of them demonstrating similar degrees of pain relief with equal doses of the agents.14 40 50 7576 82 A meta-analysis of such studies showed that ropivacaine was associated with significantly more spontaneous vaginal deliveries, fewer instrumental deliveries and better neonatal outcome scores than bupivacaine.109 Both agents have also been shown to be equally effective when combined in low doses with opioids.26 52 89

However, more recent studies have questioned the relative potencies of ropivacaine and bupivacaine.27 84 Using an ‘up–down’ sequential allocation method to compare the minimum local analgesic concentration (MLAC) of these agents it has been suggested that ropivacaine may be 40% less potent than bupivacaine. This method, first described by Columb and Lyons in 1995,30 aims to determine the ‘ED50’, or more correctly the effective concentration of each agent for 50% of patients, using a fixed volume of local anaesthetic. The results have been used to support an argument that any advantages that ropivacaine may have over bupivacaine in terms of reduced motor block and risk of cardiotoxicity must be balanced against the apparent reduction in potency. The implication is that more drug will be required and any potential advantage lost.

Against this conclusion, a number of authorities have questioned the basic validity of the MLAC method for determining local anaesthetic potency.37 93 First, the clinical relevance of the figure obtained has been questioned, because only 50% of patients studied receive obtain pain relief. Second, while the results are expressed as a concentration, it is inherent in the method that the dose of drug injected changes as well as the concentration. Third, analyses based on the results of the MLAC method make assumptions about the shape of the remainder of the ‘dose’ response curve even though only one point on it has been obtained. Without formal studies to define the dose response curves for both ropivacaine and bupivacaine it is impossible to speculate on the shape of the curves based on a single data point. Thus, the findings of the two MLAC studies comparing ropivacaine and bupivacaine must be questioned because they contradict directly the results of other clinical studies in which pain relief has been provided for all the patients. These, as has already been noted, have shown equal degrees of pain relief with equal concentrations of the two agents, but with significant other advantages for ropivacaine.


    Levobupivacaine
 Top
 Abstract
 Introduction
 Chirality and local anaesthetics
 Ropivacaine
 Levobupivacaine
 Other developments
 Declaration of interest
 References
 
At the time that ropivacaine was being developed, it was not fully appreciated that the cardiotoxicity of bupivacaine exhibits a significant degree of enantioselectivity.1 69 However, once this was recognized, the S(–) enantiomer (levobupivacaine) was developed as an alternative long-acting local anaesthetic. Human volunteer studies have demonstrated that S(–) bupivacaine is better tolerated than racemic bupivacaine,12 although it produces a greater prolongation of the QRS complex than ropivacaine in conscious rats.42 The pharmacology of levobupivacaine has been reviewed extensively elsewhere.48

Levobupivacaine has only been introduced into clinical practice recently and, as a consequence, experience of its use is more limited than with ropivacaine. One important point that must be noted by clinicians using the commercial preparation is that there has been a change in the regulations governing the way in which drug salts are presented and labelled in Europe. As a new drug, levobupivacaine comes under the aegis of Directive 91/507 of the European Union Part 2, section A. Clause 3.3 of this directive states that formulations of a drug which exists as a hydrate or salt (both apply to most local anaesthetics) must be expressed in terms of the milligram concentration of the active moiety. Thus, a solution of levobupivacaine 0.5% contains 5 mg ml–1 of the base drug. However, both ropivacaine and racemic bupivacaine predate this directive so 0.5% solutions of these drugs contain 5 mg ml–1 of the hydrochloride salt. Thus, an ampoule of levobupivacaine contains 11% more molecules of local anaesthetic than an ampoule of racemic bupivacaine of the same concentration.70

Clinical efficacy
As with ropivacaine, most of the studies of levobupivacaine have used racemic bupivacaine as the comparator agent. Given that isomers have identical physico-chemical properties, it would be expected that the clinical performances of the two would be identical. As is the case with ropivacaine, the S(–) isomer of bupivacaine produces more vasoconstriction than the R(+) isomer.6 22 In theory, this might be detrimental in some vascular beds (e.g. by decreasing uterine blood flow), but no adverse effects on uterine blood flow were seen in animal models after the administration of levobupivacaine.87

Wound infiltration
Two studies have demonstrated similar effects on pain relief, supplementary analgesic requirements and patient satisfaction when 0.25% levobupivacaine and 0.25% bupivacaine were used for analgesia after inguinal hernia repair.13 64

Major nerve block
A double-blind comparison of equal doses of levobupivacaine and bupivacaine for supraclavicular brachial plexus block34 found almost no difference in clinical block profile. There was a slightly longer duration of sensory block with levobupivacaine, but the difference was not statistical significant.

Spinal anaesthesia
One open, non-comparative study of the clinical effects of a plain solution of levobupivacaine in spinal anaesthesia for lower limb surgery has been published.23 Variable spread of block, which was occasionally unsatisfactory for surgery, was found. As with bupivacaine, this can be attributed largely to the hypobaric nature of the solution at 37°C.

Epidural block
In the non-obstetric population, two studies have compared levobupivacaine with bupivacaine in epidural block. Comparable degrees of sensory and motor block were produced with 15 ml of 0.5% solution of either drug in patients undergoing lower limb surgery.35 There were no differences in the quality of surgical anaesthesia and similar findings were reported when the two drugs were compared for lower abdominal surgery.67

In the obstetric population, the two drugs have been compared in 0.5% solutions during epidural anaesthesia for Caesarian section.11 There were no differences in block characteristics, quality of anaesthesia or neonatal outcome. In addition, there have been two comparisons of their use for epidural analgesia during labour.24 32 The analgesia produced by the drugs was broadly similar, but significantly more patients in the levobupivacaine group required a second injection to achieve pain relief in one of the studies.24 However, this appears to have been related to the inclusion in that group of patients with a greater degree of cervical dilation and a higher proportion of those in whom labour had been induced in the levobupivacaine group.

Ropivacaine and levobupivacaine
An overview of the relatively small amount of published information on the clinical use of levobupivacaine seems to be that its clinical effects are, as might be expected, identical to those of bupivacaine. Thus, its only potential advantage is a potential safety one when large doses are required. There are, as yet, no definitive published comparisons with ropivacaine, and certainly no clinical ones, although it seems reasonable to conclude that ropivacaine differs from levobupivacaine in the same ways as bupivacaine. Some basic science work suggests that the risk of clinical toxicity is less with ropivacaine, but the key to safe practice must remain the avoidance of accidental intravascular injection. Time will tell whether either drug will displace bupivacaine as the standard long-acting local anaesthetic.


    Other developments
 Top
 Abstract
 Introduction
 Chirality and local anaesthetics
 Ropivacaine
 Levobupivacaine
 Other developments
 Declaration of interest
 References
 
Butyl amino-benzoate
Butyl amino-benzoate (BAB) is an amino ester first discovered in 1923. Initially, it was thought unsuitable for anaesthetic use because of its extremely low pKa, low water solubility, poor dural permeability, and rapid hydrolysis. However, over 60 yr after it was first discovered, suspension preparations in polyethylene glycol and polysorbate-80 (Butamben) were manufactured which produced long-lasting analgesia when given epidurally to cancer patients as an alternative to alcohol or phenol neurolysis.68 91 More recently, BAB has also been used successfully in the treatment of both cancer and non-cancer pain.92

One attribute claimed for this preparation is an apparent selectivity of effect on A{delta}- and C-fibres, so that it produces minimal motor block with sparing of bladder and bowel function.68 92 Attempts to formulate other agents, such as lidocaine, in a similar suspension preparation were associated with more neuropathological changes and a much shorter duration of action.39 It seems likely that the low lipid solubility of BAB means that it is unable to diffuse through the myelin sheaths of other types of nerve fibre, with the long duration of effect being to the ‘slow release’ properties of the suspension. Further study of a drug with a very interesting clinical profile is warranted.

Articaine
Although not as old as BAB, this is also not a new agent. It has been used widely in dental practice in Canada and parts of Europe for many years, but is not being introduced into other countries. It is an anilide local anaesthetic agent, differing from the standard amide agents such as lidocaine by having a thiophene instead of a benzene ring within its structure.106 Initially, dental practitioners felt that it had a faster onset and wider spread than other agents, and this prompted further evaluation. However, double-blind comparisons with prilocaine and lidocaine in infiltration, IVRA and epidural blocks failed to demonstrate any significant differences.17 55 90 It is, therefore, unlikely that a place will be found for this agent within current anaesthetic practice although the recent reduction in availability of prilocaine might change this because it has similarly low potential for systemic toxicity.


    Declaration of interest
 Top
 Abstract
 Introduction
 Chirality and local anaesthetics
 Ropivacaine
 Levobupivacaine
 Other developments
 Declaration of interest
 References
 
Both authors have received financial support for research projects from AstraZeneca.


    References
 Top
 Abstract
 Introduction
 Chirality and local anaesthetics
 Ropivacaine
 Levobupivacaine
 Other developments
 Declaration of interest
 References
 
1 Aberg G. Toxicological and local anaesthetic effects of optically active isomers of two local anaesthetic compounds. Acta Pharmacol Toxicol 1972; 31: 444–50

2 Åckerman B, Persson H, Tegner C. Local anaesthetic properties of the optically active isomers of prilocaine (Citanest®) Acta Pharmacol Toxicol 1967; 25: 233–41[Medline]

3 Åckerman B, Hellberg I-B, Trossvik C. Primary evaluation of the local anaesthetic properties of the amino amide agent ropivacaine (LEA 103). Acta Anaesthesiol Scand 1988; 32: 571–8[ISI][Medline]

4 Af Ekenstam B, Egner B, Petersson G. Local anaesthetics: 1. N-alkyl pyrrolidine and N-alkyl piperidine carboxylic amides. Acta Chem Scand 1957; 11: 1183–1190[ISI]

5 Albright GA. Cardiac arrest following regional anaesthesia with etidocaine or bupivacaine. Anesthesiology 1979; 51: 285–7[ISI][Medline]

6 Aps C, Reynolds F. An intradermal study of the local anaesthetic and vascular effects of the isomers of bupivacaine. Br J Clin Pharmacol 1978; 6: 63–8[ISI][Medline]

7 Arlock P. Actions of three local anaesthetics: lidocaine, bupivacaine and ropivacaine on guinea pig papillary muscle sodium channels (Vmax). Pharmacol Toxocol 1988; 63: 96–104

8 Arthur GR, Wildsmith JAW, Tucker GT. Pharmacology of local anaesthetic drugs. In: Wildsmith JAW, Armitage EN, eds. Principles and Practice of Regional Anaesthesia. London: Churchill Livingstone, 1993; 29–45

9 Arthur GR, Covino BG. What’s new in local anesthetics? Anesth Clin North Am 1988; 6: 357–70

10 Bader AM, Datta S, Flanagan H, Covino BG. Comparison of bupivacaine and ropivacaine induced conduction blockade in the isolated rabbit vagus nerve. Anesth Analg 1989; 68: 724–7[Abstract]

11 Bader AM, Tsen LC, Camaan WR, Nephew E, Datta S. Clinical effects and maternal and fetal plasma concentrations of 0.5% epidural levobupivacaine versus bupivacaine for caesarean delivery. Anesthesiology 1999; 90: 1596–601[ISI][Medline]

12 Bardsley H, Gristwood R, Baker H, Watson N, Nimmo W. A comparison of the cardiovascular effects of levobupivacaine and rac-bupivacaine following intravenous administration to healthy volunteers. Br J Clin Pharm 1998; 46: 245–9[ISI]

13 Bay-Nielsen M, Klarskov B, Bech K, Andersen J, Kehlet H. Levobupivacaine vs bupivacaine as infiltration anaesthesia in ingunal herniorrhaphy. Br J Anaesth 1999; 82: 280–2[Abstract/Free Full Text]

14 Benhamou D, Hamza J, Eledjam JJ, Dailland P, Palot M, Seebacher J, Milon D, Heeroma K. Continuous extradural infusion of ropivacaine 2 mg ml–1 for pain relief during labour. Br J Anaesth 1997; 78: 748–50[Abstract/Free Full Text]

15 Bertini L, Tagariello V, Mancini S, Ciaschi A, Posteraro CM, Di Benedetto P, Martini O. 0.75% and 0.5% ropivacaine for axillary brachial plexus block: A clinical comparison with 0.5% bupivacaine. Reg Anesth Pain Med 1999; 24: 514–8[ISI]

16 Boogaerts JG, Lafont ND, Declercq AG, Luo HC, Gravet ET, Bianchi JA, Legros FJ. Epidural administration of liposome-associated bupivacaine for the management of postsurgical pain: a first study. J Clin Anesth 1994; 6: 315–20[ISI][Medline]

17 Brinklov M. Clinical effects of carticaine, a new local anaesthetic. Acta Anaesthesiol Scand 1977; 21: 5–16[ISI][Medline]

18 Brockway MS, Bannister J, McClure JH, McKeown D, Wildsmith JAW. Comparison of extradural ropivacaine and bupivacaine. Br J Anaesth 1991; 66: 31–7[Abstract]

19 Brown DL, Carpenter RL, Thomson GE. Comparison of 0.5% ropivacaine and 0.5% bupivacaine for epidural anesthesia in patients undergoing lower-extremity surgery. Anesthesiology 1990; 72: 633–6[ISI][Medline]

20 Buchi J, Perlia X. Structure-activity relations and physiochemical properties of local anesthetics. In: International Encyclopaedia of Pharmacology and Therapeutics, Section 8, Vol. 1, Local Anesthetics. Oxford: Pergamon Press, 1971; 39–130

21 Burke D, Joypaul V, Thomson MF. Circumcision supplemented by dorsal penile nerve block with 0.75% ropivacaine: a complication. Reg Anesth Pain Med 2000; 25: 424–7[ISI]

22 Burke D, MacKenzie M, Newton D, Khan F, McLeod GA, Belch J, Bannister J. A comparison of the vasoactivity between levobupivacaine and bupivacaine (abstract). Br J Anaesth 1998; 81: 631–2P

23 Burke D, Kennedy S, Bannister J. Spinal anaesthesia with 0.5% S(–)-bupivacaine for elective lower limb surgery. Reg Anesth Pain Med 1999; 24: 519–23[ISI]

24 Burke D, Henderson DJ, Simpson AM, Faccenda KA, Morrison LMM, McGrady EM, McLeod GA, Bannister J. Comparison of 0.25% S(–)-bupivacaine with 0.25% RS-bupivacaine for epidural analgesia in labour. Br J Anaesth 1999; 83: 750–5[Abstract/Free Full Text]

25 Cahn RS, Ingold CK, Pelog V. The specification of asymmetric configuration in organic chemistry. Experentia 1956; 12: 81–124[ISI]

26 Campbell DC, Zwack RM, Crone LA, Yip RW. Ambulatory labor epidural analgesia: bupivacaine versus bupivacaine. Anesth Analg 2000; 90: 1384–9[Abstract/Free Full Text]

27 Capogna G, Celleno D, Fusco P, Lyons G, Columb M. Relative potencies of bupivacaine and ropivacaine for analgesia in labour. Br J Anaesth 1999; 82: 371–3[Abstract/Free Full Text]

28 Cederholm I, Åckerman B, Evers H. Local analgesic and vascular effects of intradermal ropivacaine and bupivacaine in various concentrations with and without adrenaline in man. Acta Anaesthesiol Scand 1994; 38: 322–7[ISI][Medline]

29 Clarkson CW, Hondeghem LM. Mechanism for bupivacaine depression of cardiovascular conduction: fast block of sodium channels during the action potential with slow recovery from block during diastole. Anesthesiology 1985; 62: 396–405[ISI][Medline]

30 Columb MO, Lyons G. Determination of the minimum local analgesic concentration of epidural bupivacaine and lidocaine in labor. Anesth Analg 1995; 81: 833–7[Abstract]

31 Concepcion M, Arthur GR, Steele SM, Bader AM, Covino BG. A new local anesthetic, ropivacaine. Its epidural effects in humans. Anesth Analg 1990; 70: 80–5[Abstract]

32 Convery PN, Milligan KR, Weir P. Comparison of 0.125% levobupivacaine and 0.125% bupivacaine epidural infusions for labour analgesia (abstract). Br J Anaesth 1999; 82(suppl. 1): 163

33 Covino BG, Wildsmith JAW. Clinical pharmacology of local anesthetic agents. In: Cousins MJ, Bridenbaugh PO, eds. Neural Blockade in Clinical Anesthesia and Management of Pain. Philadelphia: Lippincott-Raven, 1998; 97–128

34 Cox CR, Checketts MR, MacKenzie N, Scott NB, Bannister J. Comparison of S(–)-bupivacaine with racemic (RS)-bupivacaine in supraclavicular brachial plexus block. Br J Anaesth 1998; 80: 594–8[ISI][Medline]

35 Cox CR, Faccenda KA, Gilhooly C, Bannister J, Scott NB, Morrison LMM. Extradural S(–) bupivacaine: comparison with racemic RS-bupivacaine. Br J Anaesth 1998; 80: 289–93[Abstract/Free Full Text]

36 Dahl JB, Simonsen L, Mogensen T, Henriksen JH, Kehlet H. The effect of 0.5% ropivacaine on epidural blood flow. Acta Anaesthesiol Scand 1990; 34: 308–10[ISI][Medline]

37 D’Angelo R, James RL. Is ropivacaine less potent than bupivacaine ? Anesthesiology 2000; 92: 283–4[Medline]

38 Djordjevich L, Ivankovich AD, Chiguupati R, Woronowicz A, McCarthy R. Efficacy of liposome encapsulated bupivacaine. Anesthesiology 1986; 65: A185[ISI]

39 Duncan LA, Wildsmith JAW. Liposomal local anaesthetics [editorial]. Br J Anaesth 1995; 75: 260–1[Free Full Text]

40 Eddleston JM, Holland JJ, Griffin RP, Corbett A, Horsman EL, Reynolds F. A double-blind comparison of 0.25% ropivacaine and 0.25% bupivacaine for extradural analgesia in labour. Br J Anaesth 1996; 76: 66–71[Abstract/Free Full Text]

41 Erichsen CJ, Vibits H, Dahl JB, Kehlet H. Wound infiltration with ropivacaine and bupivacaine for pain after inguinal herniotomy. Acta Anaesthesiol Scand 1995; 39: 67–70[Medline]

42 Ericsson AC, Avesson M. Effects of ropivacaine, bupivacaine and S(–) bupivacaine on the ECG after rapid IV injections to conscious rats. Int Monitor Reg Anaesth 1996; 8: 51

43 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[Abstract]

44 Federsel H, Jaksch P, Sanberg R. An efficient synthesis of a new, chiral 2',6'-pipecoloxylidide local anaesthetic agent. Acta Chemica Scandanavica 1987; B41: 757–61

45 Feldman HS, Arthur GR, Pitkanen M, Hurley R, Doucette AM, Covino BG. Treatment of acute systemic toxicity after the rapid intravenous injection of ropivacaine and bupivacaine in the conscious dog. Anesth Analg 1991; 73: 373–84[Abstract]

46 Feldman HS, Covino B. Comparative motor blocking effects of bupivacaine and ropivacaine, a new amino amide local anesthetic, in the rat and dog. Anesth Analg 1988; 67: 1047–52[Abstract]

47 Finucane BT. Ropivacaine: epidural anesthesia for surgery. Am J Anesthesiol 1997; 24: 22–5

48 Foster RH, Markham A. Levobupivacaine: a review of its pharmacology and use as alocal anaesthetic. Drugs 2000; 59: 551–79[ISI][Medline]

49 Friedman GA, Rowlingson JC, DiFazio CA, Donegan MF. Evaluation of the analgesic effect and urinary excretion of sytemic bupivacaine in man. Anesth Analg 1982; 61: 23–7[Abstract]

50 Gatt S, Crooke S, Lockley S, Anderson A, Armstrong P, Alley L. A double-blind, randomized parallel investigation into the neurobehavioural status and outcome of infants born to mothers receiving epidural ropivacaine 0.25% and bupivacaine 0.25% for analgesia in labour. Anaesth Intensive Care 1996; 24: 108–9

51 Gautier PE, De Kock M, Van Steenberge A, et al. Intrathecal ropivacaine for ambulatory surgery: A comparison between intrathecal bupivacaine and ropivacaine for knee surgery. Anesthesiology 1999; 91: 1239–45[ISI][Medline]

52 Gautier P, De Kock M, van Steerbridge A, Miclot D, Fanard L, Hody JL. A double-blind comparison of 0.125% ropivacaine with sufentanil and 0.125% bupivacaine with sufentanil for epidural labor analgesia. Anesthesiology 1999; 90: 772–8[ISI][Medline]

53 Grant GJ, Vermuelen K, Langerman L, Zakowski M, Turndorf H. Prolonged analgesia with liposomal bupivacaine in a mouse model. Reg Anesth Pain Med 1994; 19: 264–9[ISI][Medline]

54 Griffin RP, Reynolds F. Extradural anaesthesia for caesarian section: a double-blind comparison of 0.5% ropivacaine and 0.5% bupivacaine. Br J Anaesth 1995; 74: 512–6[Abstract/Free Full Text]

55 Haas D, Harper D, Saso M, Young E. Comparison of articaine and prilocaine anesthesia in maxillary and mandibular arches. Anesth Prog 1990; 37: 230–3[Medline]

56 Hickey R, Blanchard J, Hoffman J, Sjövall J, Ramamurthy S. Plasma concentrations of ropivacaine given with or without epinephrine for brachial plexus block. Can J Anaesth 1990; 37: 878–82[Abstract]

57 Hickey R, Candido KD, Ramamurthy S, et al. Brachial plexus block with a new local anaesthetic: 0.5% ropivacaine. Can J Anaesth 1990; 37: 732–8[Abstract]

58 Hickey R, Hoffman J, Ramamurthy S. A comparison of ropivacaine 0.5% and bupivacaine 0.5% for brachial plexus block. Anesthesiology 1991; 74: 639–642[ISI][Medline]

59 Hickey R, Rowley CL, Candido KD, Hoffman J, Ramamurthy S, Winnie AP. A comparative study of 0.25% ropivacaine and 0.25% bupivacaine for brachial plexus block. Anesth Analg 1992; 75: 602–6[Abstract]

60 Huang YF, Pryor ME, Veering BT, Mather LE. Cardiovascular and central nervous system effects of intravenous levobupivacaine and bupivacaine in sheep. Anesth Analg 1998; 86: 797–804[Abstract]

61 Johansson B, Glise H, Hallerback B, Dalman P, Kristofferson A. Preoperative local infiltration with ropivacaine for postoperative pain relief after cholecystectomy. Anesth Analg 1994; 78: 210–4[Abstract]

62 Katz JA, Knarr D, Bridenbaugh PO. A double-blind comparison of 0.5% bupivacaine and 0.75% ropivacaine administered epidurally in humans. Reg Anesth Pain Med 1990; 15: 250–2[ISI][Medline]

63 Kerkkamp HEM, Gielen MJM, Edström HH. Comparison of 0.75% ropivacaine with epinephrine and 0.75% bupivacaine with epinephrine in lumbar epidural anaesthesia. Reg Anesth Pain Med 1990; 15: 204–7[ISI][Medline]

64 Kingsnorth A, Bennet D, Cummings C. A randomised, double blind study to compare the efficacy of 0.25% levobupivacaine with 0.25% bupivacaine (racemic) infiltration anaesthesia in elective inguinal hernia repair. Reg Anesth Pain Med 1998; 23(suppl.): 106

65 Knudsen K, Beckman-Suurkula M, Blomberg S, Sjövall J, Edvardsson N. Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth 1997; 78: 507–14[Abstract/Free Full Text]

66 Kopacz DJ, Carpenter RL, Mackey DC. Effect of ropivacaine on cutaneous capillary blood flow in pigs. Anesthesiology 1989; 71: 69–74[ISI][Medline]

67 Kopacz DJ, Allen HW, Thompson GE. A comparison of epidural levobupivacaine 0.75% with racemic bupivacaine for lower abdominal surgery. Anesth Analg 2000; 90: 642–8[Abstract/Free Full Text]

68 Korsten HH, Ackerman EW, Grouls RJ, et al. Long-lasting sensory blockade by n-butyl-p-aminobenzoate in the terminally ill intractable cancer pain patient. Anesthesiology 1991; 75: 950–60[ISI][Medline]

69 Luduena FP, Bogado EF, Tullar BF. Optical isomers of mepivacaine and bupivacaine. Arch Int Pharmacodyn 1972; 200: 359–69[ISI]

70 Lyons G, Columb M, Wilson RC, Johnson RV. Epidural pain relief in labour: potencies of levobupivacaine and racemic bupivacaine. Br J Anaesth 1998; 81: 899–901[Abstract/Free Full Text]

71 Mashimo T, Uchida I, Pak M, et al. Prolongation of canine epidural anesthesia by liposome encapsulation of lidocaine. Anesth Analg 1992; 74: 827–34[Abstract]

72 Mazoit JX, Boico O, Samii K. Myocardial uptake of bupivacaine: pharmacodynamics of bupivacaine enantiomers in the isolated perfused rabbit heart. Anesth Analg 1993; 77: 477–82[Abstract]

73 McClure JH. Ropivacaine. Br J Anaesth 1996; 76: 300–7[Free Full Text]

74 McClure JH. The obstetric challenge. Am J Anesthesiol 1997; 24 (5; Suppl): 18–21

75 McCrae AF, Jozwiak H, McClure JH. Comparison of ropivacaine and bupivacaine in extradural analgesia for the relief of pain in labout. Br J Anaesth 1995; 74: 261–5[Abstract/Free Full Text]

76 McCrae AF, Westerling P, McClure JH. Pharmacokinetic and clinical study of ropivacaine and bupivacaine in women receiving extradural analgesia in labour. Br J Anaesth 1997; 79: 558–62[Abstract/Free Full Text]

77 McDonald SB, Liu SS, Kopacz DJ, Stephenson CA. Hyperbaric spinal ropivacaine: A comparison to bupivacaine in volunteers. Anesthesiology 1999; 90: 971–77[ISI][Medline]

78 Moller R, Covino BG. Cardiac electrophysiologic properties of bupivacaine and lidocaine compared with thosw of ropivacaine, a new amide local anaesthetic. Anesthesiology 1990; 72: 322–9[ISI][Medline]

79 Morrisson LMM, Emanuelsson BM, McClure JH, et al. Efficacy and kinetics of extradural ropivacaine: Comparison with bupivacaine. Br J Anaesth 1994; 72: 269–73

80 Mulroy MF, Burgess FW, Emanuelson BM. Ropivacaine 0.25% and 0.5%, but not 0.125% provide effective wound infiltration analgesia after outpatient hernia repair, but sustained plasma drug levels. Reg Anesth 1999; 23: 136–41

81 Nolte H, Fruhstorfer H, Edström HH. Local anaesthetic efficacy of ropivacaine (LEA 103) in ulnar nerve block. Reg Anesth Pain Med 1990; 15: 118–24[ISI][Medline]

82 Owen MD, D’Angelo R, Gerancher JC, Thompson JM, Foss ML, Babb JD, Eisenach JC. 0.125% ropivacaine is similar to 0.125% bupivacaine for labor analgesia using patient-controlled epidural infusion. Anesth Analg 1998; 86: 527–31[Abstract]

83 Pitkanen M, Covino BG, Feldman HS, Arthur GR. Chronotropic and inotropic effects of ropivacaine, bupivacaine and lidocaine in the spontaneously beating and electrically paced isolated, perfused rabbit heart. Reg Anesth 1992; 17: 183–92[ISI][Medline]

84 Polley LS, Columb MO, Naughton NN, Wagner DS, Cosmas JM. Relative analgesic potencies of ropivacaine and bupivacaine for epidural analgesia in labour. Anesthesiology 1999; 90 944–50[ISI][Medline]

85 Reiz S, Haggmark S, Johansson G, Nath S. Cardiotoxicity of ropivacaine – a new amide local anaesthetic agent. Acta Anaesthesiol Scand 1989; 33: 93–8[Medline]

86 Rosenberg PH, Heinonen E. Differential sensitivity of A and C nerve fibres to long-acting amide local anaesthetics. Br J Anaesth 1983; 55: 163–7[Abstract]

87 Santos AC, Karpel B, Noble G. The placental transfer and fetal effects of levobupivacaine, racemic bupivacaine and ropivacaine. Anesthesiology 1999; 90: 1698–703[ISI][Medline]

88 Scott DB, Lee A, Fagan D, Bowler GMR, Bloomfield P, Lundh R. Acute toxicity of ropivacaine compared with that of bupivacaine. Anesth Analg 1989; 69: 563–9[Abstract]

89 Scrutton MJ, Srikantharajah L, Williams H, Porter J, O’Sullivan G. Comparison of ropivacaine with bupivacaine for epidural analgesia in labour. Anesthesiology 1994; 90 (suppl.): A34

90 Simon MA, Vree TB, Gielen MJ, Booij LH. Comparison of the effects and disposition kinetics of articaine and lidocaine in 20 patients undergoing intravenous regional anaesthesia during day case surgery. Pharm World Sci 1998; 20: 88–92[ISI][Medline]

91 Shulman M. Treatment of cancer pain with epidural Butyl-Amino-Benzoate suspension. Reg Anesth Pain Med 1987; 12: 1–4

92 Shulman M, Lubenow TR, Nath HA, Blazek W, McCarthy RJ, Ivankovich AD. Nerve blocks with 5% butamben suspension for the treatment of chronic pain syndromes. Reg Anesth Pain Med 1998; 23: 395–401[ISI]

93 Stienstra R. A closer look at the new local anesthetics. Acta Anaesth Belg 1999; 50: 211–6[Medline]

94 Tetzlaff JE. Ropivacaine. In: Tetzlaff JE, ed. Clinical Pharmacology of Local Anesthetics. Boston: Butterworth Heinemann, 2000; 125–31

95 Tucker GT. Ropivacaine: human pharmacokinetics Am J Anesthesiol 1997; 24 (5; Suppl): 8–13

96 Vainionpää VA, Haavisto ET, Huha TM, Korpi KJ, Nuutinen LS, Hollmén AI, Jozwiak HM, Magnusson M. A clinical and pharmacokinetic comparison of ropivacaine and bupivacaine in axillary plexus block. Anesth Analg 1995; 81: 534–8[Abstract]

97 Valenzuela C, Delpon E, Perez O, Tamkun MM, Tamargo J, Snyders DJ. Stereoselective bupivacaine block of human cardiac delayed rectifier hKv1.5 channel. Biophys J 1994; 66: A205

98 van Kleef JW, Veering BT, Burm AGL. Spinal anaesthesia with ropivacaine: a double-blind study on the efficacy and safety of 0.5% and 0.75% solutions in patients undergoing minor lower limb surgery. Anesth Analg 1994; 78: 1125–30[Abstract]

99 Vanhoutte F, Vereecke J, Verbeke N, Carmeliet E. Stereoselective effects of the enantiomers of bupivacaine on electrophysiological properties of the guinea-pig papillary muscle. Br J Pharmacolol 1991; 103: 1275–81[Abstract]

100 Wahedi W, Nolte H, Klein P. Ropivacaine in spinal anaesthesia. Anaesthesist 1996; 45: 737–44[ISI][Medline]

101 Whitehead E, Arrigoni B, Bannister J. An open study of ropivacaine in extradural anaesthesia. Br J Anaesth 1990; 64: 67–71[Abstract]

102 Whiteside JB, Burke D, Wildsmith JAW. Spinal anaesthesia with ropivacaine 5 mg ml–1 in glucose 10 mg ml–1 or 50 mg ml–1. Br J Anaesth 2001; 86: 241–4[Abstract/Free Full Text]

103 Wildsmith JAW, Brown DT, Paul D, Johnson S. Structure-activity relationships in differential nerve block at high and low frequency stimulation. Br J Anaesth 1989; 63: 444–52[Abstract]

104 Wildsmith JAW. Peripheral nerve block and ropivacaine. Am J Anesthesiol 1997; 24 (5; Suppl): 14–17

105 Wildsmith JAW. Relative potencies of ropivacaine and bupivacaine. Anesthesiology 2000; 92: 283[Medline]

106 Winther JE, Patirupanusara B. Evaluation of carticaine – a new local analgesic. Int J Oral Surg 1974; 3: 422–7[Medline]

107 Wolff AP, Hasselstrom L, Kerkkamp HE, Gielen MJ. Extradural ropivacaine and bupivacaine in hip surgery. Br J Anaesth 1995; 74: 458–60[Abstract/Free Full Text]

108 Wood MB, Rubin AP. A comparison of epidural 1% ropivacaine and 0.75% bupivacaine for lower abdominal gynaecological surgery. Anesth Analg 1993; 76: 1274–8[Abstract]

109 Writer WDR, Stienstra R, Eddleston JM, et al. Neonatal outcome and mode of delivery after epidural analgesia for labour with ropivacaine and bupivacaine: a prospective meta-analysis. Br J Anaesth 1998; 81: 713–7[Abstract/Free Full Text]

110 Yamashiro H. Bupivacaine-induced seizure after accidental intravenous injection, a complication of epidural anesthesia. Anesthesiology 1977; 47: 472–3[ISI][Medline]

111 Zaric D, Axelsson K, Nydahl PA, Philipsson L, Larsson P, Jansson JR. Sensory and motor blockade during epidural analgesia with 1.0%, 0.75% and 0.5% ropivacaine – a double-blind study. Anesth Analg 1991; 72: 509–15[Abstract]

112 Zaric D, Axelsson K, Nydahl PA, Philipsson L, Samuelsson L. Sensory and motor blockade during continuous epidural infusion of ropivacaine 0.1%, 0.2% and 0.3% in volunteers – a double-blind study. Reg Anesth Pain Med 1994; 19(Suppl 2S): 60