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Developments in local anaesthetic drugs

2001; Elsevier BV; Volume: 87; Issue: 1 Linguagem: Inglês

10.1093/bja/87.1.27

1471-6771

J.B. Whiteside, J.A.W. Wildsmith,

Intraocular Surgery and Lenses

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.5Albright GA Cardiac arrest following regional anaesthesia with etidocaine or bupivacaine.Anesthesiology. 1979; 51: 285-287Crossref PubMed Scopus (760) Google Scholar 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.33Covino BG Wildsmith JAW Clinical pharmacology of local anesthetic agents.in: Cousins MJ Bridenbaugh PO Neural Blockade in Clinical Anesthesia and Management of Pain. Lippincott-Raven, Philadelphia1998: 97-128Google Scholar 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.49Friedman GA Rowlingson JC DiFazio CA Donegan MF Evaluation of the analgesic effect and urinary excretion of sytemic bupivacaine in man.Anesth Analg. 1982; 61: 23-27Crossref PubMed Scopus (9) Google Scholar 110Yamashiro H Bupivacaine-induced seizure after accidental intravenous injection, a complication of epidural anesthesia.Anesthesiology. 1977; 47: 472-473Crossref PubMed Scopus (9) Google Scholar 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.29Clarkson 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: 396-405Crossref PubMed Scopus (324) Google Scholar 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'.99Vanhoutte 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: 1275-1281Crossref PubMed Scopus (136) Google Scholar 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.1Aberg G Toxicological and local anaesthetic effects of optically active isomers of two local anaesthetic compounds.Acta Pharmacol Toxicol. 1972; 31: 444-450Google Scholar 97Valenzuela 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: A205Abstract Full Text PDF Scopus (58) Google Scholar 99Vanhoutte 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: 1275-1281Crossref PubMed Scopus (136) Google Scholar 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,20Buchi 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. Pergamon Press, Oxford1971: 39-130Google Scholar 103Wildsmith 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: 444-452Crossref PubMed Scopus (80) Google Scholar 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-benzoate68Korsten 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: 950-960Crossref PubMed Scopus (39) Google Scholar 91Shulman M Treatment of cancer pain with epidural Butyl-Amino-Benzoate suspension.Reg Anesth Pain Med. 1987; 12: 1-4Google Scholar 92Shulman 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: 395-401PubMed Google Scholar) 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,16Boogaerts 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: 315-320Abstract Full Text PDF PubMed Scopus (98) Google Scholar 38Djordjevich L Ivankovich AD Chiguupati R Woronowicz A McCarthy R Efficacy of liposome encapsulated bupivacaine.Anesthesiology. 1986; 65: A185Crossref Google Scholar 53Grant GJ Vermuelen K Langerman L Zakowski M Turndorf H Prolonged analgesia with liposomal bupivacaine in a mouse model.Reg Anesth Pain Med. 1994; 19: 264-269Google Scholar 71Mashimo T Uchida I Pak M et al.Prolongation of canine epidural anesthesia by liposome encapsulation of lidocaine.Anesth Analg. 1992; 74: 827-834Crossref PubMed Scopus (83) Google Scholar but this review will concentrate on drugs. Problems with the liposome method have been reported.39Duncan LA Wildsmith JAW Liposomal local anaesthetics [editorial].Br J Anaesth. 1995; 75: 260-261Crossref PubMed Scopus (13) Google Scholar 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.17Brinklov M Clinical effects of carticaine, a new local anaesthetic.Acta Anaesthesiol Scand. 1977; 21: 5-16Crossref PubMed Scopus (16) Google Scholar 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.95Tucker GT Ropivacaine: human pharmacokinetics.Am J Anesthesiol. 1997; 24: 8-13Google Scholar 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'.25Cahn RS Ingold CK Pelog V The specification of asymmetric configuration in organic chemistry.Experentia. 1956; 12: 81-124Crossref Scopus (445) Google Scholar 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). 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,2Åckerman B Persson H Tegner C Local anaesthetic properties of the optically active isomers of prilocaine (Citanest®).Acta Pharmacol Toxicol. 1967; 25: 233-241Crossref PubMed Scopus (23) Google Scholar 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,1Aberg G Toxicological and local anaesthetic effects of optically active isomers of two local anaesthetic compounds.Acta Pharmacol Toxicol. 1972; 31: 444-450Google Scholar 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.60Huang YF Pryor ME Veering BT Mather LE Cardiovascular and central nervous system effects of intravenous levobupivacaine and bupivacaine in sheep.Anesth Analg. 1998; 86: 797-804Crossref PubMed Google Scholar 72Mazoit JX Boico O Samii K Myocardial uptake of bupivacaine: pharmacodynamics of bupivacaine enantiomers in the isolated perfused rabbit heart.Anesth Analg. 1993; 77: 477-482Crossref PubMed Google Scholar 99Vanhoutte 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: 1275-1281Crossref PubMed Scopus (136) Google Scholar Human studies have also shown that larger doses of S(–) bupivacaine than racemic bupivacaine are required before the onset of neurological symptoms.12Bardsley 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: 245-249Crossref PubMed Scopus (365) Google Scholar 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,4Af Ekenstam B Egner B Petersson G Local anaesthetics: 1. N-alkyl pyrrolidine and N-alkyl piperidine carboxylic amides.Acta Chem Scand. 1957; 11: 1183-1190Crossref Google Scholar 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(+),3Åckerman 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: 571-578Crossref PubMed Scopus (200) Google Scholar 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.7Arlock P Actions of three local anaesthetics: lidocaine, bupivacaine and ropivacaine on guinea pig papillary muscle sodium channels (Vmax).Pharmacol Toxocol. 1988; 63: 96-104Crossref PubMed Scopus (83) Google Scholar 78Moller R Covino BG Cardiac electrophysiologic properties of bupivacaine and lidocaine compared with thosw of ropivacaine, a new amide local anaesthetic.Anesthesiology. 1990; 72: 322-329Crossref PubMed Scopus (129) Google Scholar 85Reiz S Haggmark S Johansson G Nath S Cardiotoxicity of ropivacaine – a new amide local anaesthetic agent.Acta Anaesthesiol Scand. 1989; 33: 93-98Crossref PubMed Scopus (213) Google Scholar Infusion studies in human volunteers have confirmed that larger doses are required to produce early features of neurotoxicity and cardiotoxicity than racemic bupivacaine.65Knudsen 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: 507-514Crossref PubMed Scopus (792) Google Scholar 88Scott DB Lee A Fagan D Bowler GMR Bloomfield P Lundh R Acute toxicity of ropivacaine compared with that of bupivacaine.Anesth Analg. 1989; 69: 563-569Crossref PubMed Scopus (651) Google Scholar The commercial preparation has an enantiomeric purity of 99.5%.44Federsel H Jaksch P Sanberg R An efficient synthesis of a new, chiral 2′,6′-pipecoloxylidide local anaesthetic agent.Acta Chemica Scandanavica. 1987; B41: 757-761Crossref Google Scholar 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.73McClure JH Ropivacaine.Br J Anaesth. 1996; 76: 300-307Crossref PubMed Scopus (425) Google Scholar 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.9Arthur GR Covino BG What's new in local anesthetics?.Anesth Clin North Am. 1988; 6: 357-370Google Scholar 45Feldman 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: 373-384Crossref PubMed Scopus (129) Google Scholar 83Pitkanen 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: 183-192PubMed Google Scholar 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.Table 1Physico-chemical properties and plasma protein binding characteristics of local anaesthetic agents.95 104 PKa=dissociation constantDrugPKaPartition coefficientPercentage protein boundLidocaine7.84364Prilocaine7.82555Mepivacaine7.82177Bupivacaine8.234695.5Levobupivacaine8.234693.4Ropivacaine8.211594 Open table in a new tab 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,10Bader 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: 724-727Crossref PubMed Google Scholar 86Rosenberg PH Heinonen E Differential sensitivity of A and C nerve fibres to long-acting amide local anaesthetics.Br J Anaesth. 1983; 55: 163-167Crossref PubMed Scopus (90) Google Scholar 103Wildsmith 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: 444-452Crossref PubMed Scopus (80) Google Scholar 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.28Cederholm 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: 322-327Crossref PubMed Scopus (61) Google Scholar 36Dahl JB Simonsen L Mogensen T Henriksen JH Kehlet H The effect of 0.5% ropivacaine on epidural blood flow.Acta Anaesthesiol Scand. 1990; 34: 308-310Crossref PubMed Scopus (61) Google Scholar 66Kopacz DJ Carpenter RL Mackey DC Effect of ropivacaine on cutaneous capillary blood flow in pigs.Anesthesiology. 1989; 71: 69-74Crossref PubMed Scopus (120) Google Scholar Epinephrine was found to have little effect on the local action or the resultant systemic concentrations of ropivacaine in human studies.28Cederholm 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: 322-327Crossref PubMed Scopus (61) Google Scholar 56Hickey 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: 878-882Crossref PubMed Scopus (76) Google Scholar 81Nolte H Fruhstorfer H Edström HH Local anaesthetic efficacy of ropivacaine (LEA 103) in ulnar nerve block.Reg Anesth Pain Med. 1990; 15: 118-124Google Scholar 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.27Capogna G Celleno D Fusco P Lyons G Columb M Relative potencies of bupivacaine and ropivacaine for analgesia in labour.Br J Anaesth. 1999; 82: 371-373Crossref PubMed Scopus (230) Google Scholar 84Polley LS Columb MO Naughton NN Wagner DS Cosmas JM Relative analgesic potencies of ropivacaine and bupivacaine for epidural analgesia in labour.Anesthesiology. 1999; 90: 944-950Crossref PubMed Scopus (321) Google Scholar 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.8Arthur GR Wildsmith JAW Tucker GT Pharmacology of local anaesthetic drugs.in: Wildsmith JAW Armitage EN Principles and Practice of Regional Anaesthesia. Churchill Livingstone, London1993: 29-45Google Scholar Thus, each clinical application must be considered in turn. Ropivacaine has been used successfully for post-operative analgesia in patients undergoing inguinal herniorrhaphy80Mulroy 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: 136-141Google Scholar and open cholecystectomy.61Johansson B Glise H Hallerback B Dalman P Kristofferson A Preoperative local infiltration with ropivacaine for postoperative pain relief after cholecystectomy.Anesth Analg. 1994; 78: 210-214Crossref PubMed Scopus (95) Google Scholar Equal doses (100 mg) of ropivacaine and bupivacaine have been shown to provide similar analgesia after inguinal hernia surgery.41Erichsen CJ Vibits H Dahl JB Kehlet H Wound infiltration with ropivacaine and bupivacaine for pain after inguinal herniotomy.Acta Anaesthesiol Scand. 1995; 39: 67-70Crossref PubMed Scopus (57) Google Scholar 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.28Cederholm 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: 322-327Crossref PubMed Scopus (61) Google Scholar Some authors have questioned the safety of this because of the possibility of inducing microcirculatory insufficiency or compromising end-arterial blood supply.94Tetzlaff JE Ropivacaine.in: Tetzlaff JE Clinical Pharmacology of Local Anesthetics. Butterworth Heinemann, Boston2000: 125-131Google Scholar 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.21Burke D Joypaul V Thomson MF Circumcision supplemented by dorsal penile nerve block with 0.75% ropivacaine: a complication.Reg Anesth Pain Med. 2000; 25: 424-427PubMed Google Scholar Therefore, ropivacaine may be unsuitable for infiltration in tissues without collateral blood supply. A large number of studies on the use of ropivacaine for brachial plexus anaesthesia, utilizing a variety of techniques, have been published.43Fanelli 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: 597-600PubMed Google Scholar 57Hickey R Candido KD Ramamurthy S et al.Brachial plexus block with a new local anaesthetic: 0.5% ropivacaine.Can J Anaesth. 1990; 37: 732-738Crossref PubMed Scopus (56) Google Scholar The majority of studies suggest that the clinical outcome is similar to that of equivalent doses of bupivacaine,58Hickey R Hoffman J Ramamurthy S A comparison of ropivacaine 0.5% and bupivacaine 0.5% for brachial plexus block.Anesthesiology. 1991; 74: 639-642Crossref PubMed Scopus (103) Google Scholar 59Hickey 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: 602-606Crossref PubMed Scopus (58) Google Scholar 96Vainionpää 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: 534-538PubMed Google Scholar 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.15Bertini 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: 514-518PubMed Google Scholar 43Fanelli 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: 597-600PubMed Google Scholar Bertini and colleagues also demonstrated a better quality of block with ropivacaine as indicated by intra-operative opioid requirements and patient satisfaction scores.15Bertini 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: 514-518PubMed Google Scholar 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. 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.98van 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: 1125-1130PubMed Google Scholar 100Wahedi W Nolte H Klein P Ropivacaine in spinal anaesthesia.Anaesthesist. 1996; 45: 737-744Crossref PubMed Scopus (42) Google Scholar 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.51Gautier 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: 1239-1245Crossref PubMed Scopus (144) Google Scholar 77McDonald SB Liu SS Kopacz DJ Stephenson CA Hyperbaric spinal ropivacaine: A comparison to bupivacaine in volunteers.Anesthesiology. 1999; 90: 971-977Crossref PubMed Scopus (139) Google Scholar Gautier and colleagues51Gautier