Ropivacaine: An Update of its Use in Regional Anaesthesia

RopivacaineAn Update of its Use in Regional Anaesthesia

Karen J. McClellan and Diana FauldsAdis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by:A.R. Binning, Department of Anaesthesia, Western Infirmary, Glasgow, Scotland; E. Bjørnestad,Department of Anaesthesia and Intensive Care, Haukeland University Hospital, Bergen, Norway; W.R.Camann, Department of Anesthesia, Brigham and Women’s Hospital, Boston, Massachusetts, USA; G.Capogna, Fatebenefratelli General Hospital, Rome, Italy; A. Casati, Department of Anesthesiology,University of Milan, Hospital San Raffaele, Milan, Italy; M.J. Da Conceicao, Joana de Gusmao ChildrenHospital, Florianopolis, Brazil; M. De Kock, Department of Anesthesiology, St. Luc Hospital, Brussels,Belgium; G. Ivani, Department of Anaesthesia and Intensive Care, Regina Margherita Children’s Hospital,Turin, Italy; C-G. Krenn, Department of Anesthesiology and General Intensive Care Medicine, Universityof Vienna, Vienna, Austria; M.D. Owen, Department of Anesthesiology, The Bowman Gray School ofMedicine of Wake Forest University, Winston-Salem, North Carolina, USA; L.S. Polley, Department ofAnesthesiology, University of Michigan Medical Center, Mott Hospital, Ann Arbor, Michigan, USA; D.A.Scott, Department of Anaesthesia, St. Vincent’s Hospital, Melbourne, Victoria, Australia; H. Wulf, Hospitalof the Christian-Albrechts-University Kiel, Kiel, Germany.

Contents

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10661. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10692. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1070

2.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10702.2 Cardiovascular and CNS Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10712.3 Peripheral Vascular Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10712.4 MLAC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10722.5 Neonatal Outcome and Mode of Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1072

3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10733.1 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10733.2 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10733.3 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10733.4 Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10743.5 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1074

ADIS DRUG EVALUATION Drugs 2000 Nov; 60 (5): 1065-10930012-6667/00/0011-1065/$25.00/0

© Adis International Limited. All rights reserved.

Data SelectionSources:Medical literature published in any language since 1996 on ropivacaine, identified using AdisBase (a proprietary database of AdisInternational, Auckland, New Zealand) and Medline. Additional references were identified from the reference lists of published articles.Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.Search strategy: AdisBase search terms were ‘ropivacaine’. Medline search terms were ‘ropivacaine’. Searches were last updated 9 Oct,2000.Selection: Studies in patients requiring regional anaesthesia or analgesia who received ropivacaine. Inclusion of studies was based mainlyon the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred.Relevant pharmacodynamic and pharmacokinetic data are also included.Index terms: ropivacaine, pharmacodynamics, pharmacokinetics, therapeutic use, drug interactions, tolerability.

4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10744.1 Labour Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1074

4.1.1 Epidural Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10754.1.2 Intrathecal Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1075

4.2 Postoperative Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10764.2.1 Epidural Infusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10764.2.2 Local Infiltration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10794.2.3 Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1080

4.3 Surgical Anaesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10814.3.1 Lumbar Epidural Anaesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10814.3.2 Peripheral Nerve Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10824.3.3 Peribulbar Anaesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085

5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10865.1 Epidural Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10865.2 Other Routes of Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10865.3 CNS and Cardiovascular Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1087

6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10877. Place of Ropivacaine in Regional Anaesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1088

SummaryAbstract Ropivacaine is a long-acting, enantiomerically pure (S-enantiomer) amide local

anaesthetic with a high pKa and low lipid solubility which blocks nerve fibresinvolved in pain transmission (Aδ and C fibres) to a greater degree than thosecontrolling motor function (Aβ fibres). The drug was less cardiotoxic than equalconcentrations of racemic bupivacaine but more so than lidocaine (lignocaine) invitro and had a significantly higher threshold for CNS toxicity than racemicbupivacaine in healthy volunteers (mean maximum tolerated unbound arterialplasma concentrations were 0.56 and 0.3 mg/L, respectively).Extensive clinical data have shown that epidural ropivacaine 0.2% is effective

for the initiation and maintenance of labour analgesia, and provides pain reliefafter abdominal or orthopaedic surgery especially when given in conjunctionwithopioids (coadministration with opioids may also allow for lower concentrationsof ropivacaine to be used). The drug had efficacy generally similar to that of thesame dose of bupivacaine with regard to pain relief but caused less motor block-ade at low concentrations.Lumbar epidural administration of 20 to 30ml ropivacaine 0.5% provided

anaesthesia of a similar quality to that achieved with bupivacaine 0.5% in womenundergoing caesarean section, but the duration of motor blockade was shorterwith ropivacaine. For lumbar epidural anaesthesia for lower limb or genitourinarysurgery, comparative data suggest that higher concentrations of ropivacaine (0.75or 1.0%) may be needed to provide the same sensory and motor blockade asbupivacaine 0.5 and 0.75%. In patients about to undergo upper limb surgery, 30to 40ml ropivacaine 0.5% produced brachial plexus anaesthesia broadly similarto that achieved with equivalent volumes of bupivacaine 0.5%, although the timeto onset of sensory block tended to be faster and the duration of motor blockshorter with ropivacaine.Ropivacaine had an adverse event profile similar to that of bupivacaine in

clinical trials. Several cases of CNS toxicity have been reported after inadvertentintravascular administration of ropivacaine, but only 1 case of cardiovascular

1066 McClellan & Faulds

© Adis International Limited. All rights reserved. Drugs 2000 Nov; 60 (5)

toxicity has been reported to date. The outcome of these inadvertent intravascularadministrations was favourable.Conclusion: Ropivacaine is a well tolerated regional anaesthetic with an ef-

ficacy broadly similar to that of bupivacaine. However, it may be a preferredoption because of its reduced CNS and cardiotoxic potential and its lower pro-pensity for motor block

PharmacodynamicProperties

The amide local anaesthetic ropivacaine reversibly blocks nerve impulse con-duction by reducing nerve cell membrane permeability to sodium ions. In vitrostudies have shown that, because of its high pKa (≈8.2) and low lipid solubility,the drug preferentially blocks nerve fibres responsible for pain transmission(Aδ and C fibres) rather than motor function (Aβ fibres). In isolated rabbitvagus nerve, ropivacaine caused significantly less blockade of motor fibres thanbupivacaine (p = 0.0001) but had a similar effect on sensory fibres.Ropivacaine appears to be less cardiotoxic than equal concentrations of

racemic bupivacaine because of its faster dissociation from cardiac Na+ channels,but more cardiotoxic than lidocaine (lignocaine). The drug had a smaller effecton QRS prolongation than bupivacaine in healthy volunteers (+2.4 vs +6%; p <0.05). CNS toxicity occurs at lower plasma concentrations than cardiotoxicitywith all local anaesthetics; ropivacaine and bupivacaine caused seizures at lowerconcentrations than lidocaine in dogs.In healthy volunteers, ropivacaine had a significantly higher threshold forCNS

toxicity (lightheadedness, tinnitus and numbness of the tongue) than bupivacaine,with mean maximum tolerated unbound arterial plasma concentrations of 0.56and 0.3 mg/L, respectively (p < 0.001).Ropivacaine has a biphasic vascular effect, causing vasoconstriction at low

concentrations but not at higher concentrations. Importantly, epidural ropivacaine0.5% did not compromise uteroplacental circulation in healthy pregnant women.

PharmacokineticProperties

After epidural administration in women undergoing caesarean section, meanmaximum plasma concentrations (Cmax) of 1.1 to 1.6 mg/L were reached afteradministration of 20 to 28ml ropivacaine 0.5 or 0.75%. The drug also underwenta degree of systemic absorption after intercostal, subclavian perivascular, peri-bulbar, intra-articular or local administration. However, because ropivacaine isextensively (90 to 94%) bound to plasma proteins (mostly α1-acid glycoprotein)after systemic absorption, Cmax for unbound drug remained well below thethreshold for CNS toxicity reported in volunteers (≈0.6 mg/L) regardless ofthe route of administration. Like bupivacaine, ropivacaine crosses the humanplacenta.Mean total body clearance and terminal elimination half-life of ropivacaine

after epidural administration in pregnant women ranged from 13.4 to 19.8 L/hand 5 to 7h, respectively.Ropivacaine undergoes extensive hepatic metabolism after intravenous ad-

ministration, with only 1% of the drug eliminated unchanged in the urine. Twocytochrome P450 (CYP450) isoenzymes, CYP1A2 and CYP3A4 are responsiblefor the formation of major (3-hydroxy-ropivacaine) and minor metabolites, re-spectively. Agents which inhibit these isozymes (particularly CYP1A2) have thepotential to affect the pharmacokinetic profile of ropivacaine. Accordingly,coadministration of fluvoxamine, a CYP1A2 inhibitor, significantly increasedtotal plasma concentrations of intravenous ropivacaine by 16% and delayed itselimination.

Ropivacaine: An Update 1067


Therapeutic Efficacy Ropivacaine has been extensively evaluated for use as an analgesic (for labouror postoperative pain) and as a regional anaesthetic during a variety of surgicalprocedures.AnalgesiaEpidural ropivacaine 0.2% provided adequate pain relief when used for the

initiation (10 to 18ml) and maintenance (4 to 10 ml/h) of labour analgesia andhad efficacy generally similar to that of the same dose bupivacaine with regardto pain relief and motor blockade (mild) in comparative studies. Ropivacaine,like bupivacaine, had no significant effects on neonatal outcome. Coadministra-tion with opioids such as fentanyl and sufentanil improved labour analgesia andallowed a lower concentration of the anaesthetic to be used (at these lower con-centrations ropivacaine caused less motor blockade than bupivacaine).Lumbar or thoracic epidural ropivacaine 0.1, 0.2 and 0.3% infused at 10 ml/h

for 21 hours after abdominal or orthopaedic surgery reduced morphine require-ments (the primary end-point) compared with placebo. The incidence of motorblock increased with increasing dose but did not differ significantly from thatreported in placebo recipients. Results from comparative studies suggest thatepidural ropivacaine 0.2% is more effective than patient-controlled intravenousmorphine for postoperative pain relief. As for labour pain, combination withopioids is effective and may allow a lower concentration of ropivacaine to beused for the same level of pain relief.Preoperative (along the intended line of the incision) or postoperative wound

infiltration of 30 to 40ml ropivacaine 0.25 or 0.5% dose-dependently relievedpostoperative pain after hernia repair; a higher concentration (0.75%) was aseffective as bupivacaine 0.25%. Evidence published in abstract form suggeststhat preoperative infiltration of the incision line using ropivacaine may also pro-vide pain relief after thoracic surgery, breast reconstruction or lower back surgery,and postoperative wound infiltration alleviates pain after shoulder surgery.Evidence indicates that epidural ropivacaine 0.2 and 0.25% (2 and 2.5 mg/kg)

may provide effective postoperative analgesia when given via the caudal routein children undergoing minor surgery, and by the lumbar route in those undergo-ing major surgery. Importantly, motor block upon awakening was minimal withropivacaine in these studies.AnaesthesiaLumbar epidural administration of 20 or 30ml ropivacaine 0.5% provided

anaesthesia of a similar quality to that achieved with bupivacaine 0.5% in womenundergoing caesarean section, without affecting neonatal outcome. The drugs hadcomparable effects on sensory blockade, but motor blockade tended to be shorterwith ropivacaine. Lumbar epidural ropivacaine 0.5 to 1% also provided effectiveanaesthesia for lower limb or genitourinary surgery, although comparative datasuggests that higher doses of ropivacaine (0.75 or 1%) may be needed to providethe same pattern of sensory and motor blockade as bupivacaine 0.5 and 0.75% inthese patients.In patients about to undergo upper limb surgery, 30 to 40ml ropivacaine 0.5%

produced a pattern of brachial plexus anaesthesia broadly equivalent to thatachieved with bupivacaine 0.5% whether administered via the subclavian peri-vascular, axillary or interscalenic approach. The onset of sensory blockade tendedto be faster and the duration of motor blockade shorter with ropivacaine, butbetween-group differences only reached statistical significance in 1 study. In



noncomparative studies, anaesthesia of brachial plexus dermatomeswas achievedin ≥86% of patients who received 30 to 33ml ropivacaine 0.5% via the subclavianperivascular route.Limited data indicate that 25 to 30ml ropivacaine 0.75% had an onset of

sensory block similar to that of the fast onset/medium duration local anaestheticmepivacaine 2% (≈25ml) when used for combined sciatic-femoral nerve blockfor lower limb surgery, but provided longer postoperative analgesia. This advan-tage was offset by a longer time to resolution of foot motor block. Limited datasuggest that ropivacaine 0.5% has an anaesthetic efficacy similar to that ofbupivacaine 0.5% when used for combined lumbar plexus-sciatic nerve block(for knee surgery) and 3-in-1 block (for hip surgery after trauma).Results from a number of well controlled trials suggest that 5 to 10ml ropi-

vacaine 1% (alone or with lidocaine) provides a quality of peribulbar anaesthesiaat least similar to that achieved with 5 to 10ml bupivacaine 0.5 or 0.75% (aloneor with lidocaine) in patients undergoing eye surgery.

Tolerability Ropivacaine was well tolerated in clinical trials, although few studies provideddetailed tolerability data. Hypotension was the most commonly reported adverseevent in studies of epidural ropivacaine but this was most likely a consequenceof sympathetic block (common to all local anaesthetics). Other reported eventsincluded nausea, vomiting, paraesthesia, urinary retention and bradycardia. Thetolerability profile of ropivacaine was similar to that of bupivacaine in compar-ative studies. Limited evidence also suggests that the drug is well tolerated afterbrachial plexus block, intrathecal administration, lumbar plexus-sciatic nerveblock, local wound infiltration and peribulbar administration. The clinical expe-riences from 60 studies involving 3000 patients showed that accidental intra-vascular administration of ropivacaine occurred in 6 patients. Only 1 patientconvulsed and none showed signs of cardiotoxicity at doses of 75 to 200mg. Theoutcome of all 6 patients to these reactions was good. Consistent with preclinicalevidence that cardiovascular toxicity occurs at higher plasma concentrations thanCNS toxicity, only 1 case of cardiovascular toxicity after intravascular adminis-tration of ropivacaine has been reported to date.

Dosage andAdministration

Ropivacaine 0.2% is recommended for epidural analgesia, administered via eitherlumbar or thoracic routes (6 to 14 ml/h) after surgery for postoperative pain andvia the lumbar route for labour pain (10 to 20ml bolus then 6 to 14 ml/h plustop-up if required). For anaesthesia during caesarean section, ropivacaine 0.75%(15 to 20ml) is recommended. This concentration is also recommended for majoror minor nerve block and wound infiltration whereas ropivacaine 0.75 and 1.0%can be used for lumbar epidural anaesthesia during other types of surgery.Administration of ropivacaine to children <12 years of age or for spinal anaes-

thesia in adults is not yet recommended.

1. Introduction

Local anaesthetics reversibly inhibit regionalsensory nerve impulse conduction without affect-ing consciousness[1] and are therefore useful forperi- and postoperative pain relief.[2] Racemicbupivacaine, an amide local anaesthetic belonging

to the pipecoloxylidide group, has been the mostwidely used long-acting local anaesthetic for a num-ber of years.[2] In 1979 however, Albright alertedanaesthesiologists to the fact that bupivacainemight cause cardiac arrest after inadvertent intra-vascular administration.[3] Excessive administration



of bupivacainehas subsequently been associatedwithCNS as well as cardiovascular toxicity, problemslinked to the drug’s R-enantiomer.[4] These findingsprompted the development of ropivacaine, an en-antiomerically pure (S-enantiomer) pipecoloxylidideamide local anaesthetic. The use of ropivacaine forlocal anaesthesia has been discussed previously inDrugs.[5] This review re-examines the role of ropi-vacaine for regional analgesia and anaesthesia inthe light of more recent data.

2. Pharmacodynamic Properties

Table I presents an overview of the pharmaco-dynamic properties of ropivacaine discussed in thissection.

2.1 Mechanism of Action

Like other local anaesthetics, ropivacaine revers-ibly blocks nerve impulse conduction by reducingnerve cell membrane permeability to sodium ions.[6]

Nerve fibres are categorised as A, B (both myeli-nated) or C (nonmyelinated) fibres. Pain is trans-mitted via Aδ and C fibres; while motor functionis controlled by Aα and Aβ fibres.[23] Amide localanaesthetics, which have a high pKa and low lipidsolubility, preferentially block C rather than A fi-bres.[24] Ropivacaine has a pKa similar to that ofbupivacaine (≈8.2) but, because of its differentstructure, is less lipid soluble (table I)[7] and there-fore less likely to penetrate large myelinated motornerve fibres. In isolated rabbit vagus nerve, ropi-vacaine caused 16% less blockade of motor fibresthan bupivacaine (p = 0.0001) but had a similareffect on sensory fibres.[9] Another isolated nervestudy showed that ropivacaine was more selectivefor Aδ and C fibres than it was for Aβ fibres.[8]In a double-blind study in 38 volunteers,[10] epi-

dural ropivacaine 0.1, 0.2 and 0.3% (infused at arate of 10 ml/h for 21 hours) tended to have dose-dependent effects on sensory and motor function.

Table I. Summary of the pharmacodynamic properties of ropivacaine

Mechanism of Action• Reversibly blocks the conduction of nerve impulses by decreasing the permeability of the nerve cell membrane to sodium ions[6]

• Similar pKa to bupivacaine (≈8.2) but lower lipid solubility (octanol/buffer partition coefficient 115 vs 346)[7]

• More selective for nerve fibres responsible for pain transmission (Aδ and C fibres) than motor function (Aβ fibres)[8]

• Caused significantly less blockade of motor fibres than equimolar concentrations of bupivacaine (p = 0.0001) in isolated rabbitvagus nerve but had a similar effect on sensory fibres[9]

• Time to mobilisation was significantly shorter with ropivacaine 0.2 and 0.3% than bupivacaine 0.25% (p < 0.004) after a 21-hourepidural infusion (10 ml/h) in volunteers[10]

Cardiovascular Effects• Ropivacaine-induced blockade of sodium channels in isolated guinea-pig cardiac (papillary) muscle dissipated faster than

bupivacaine-induced blockade but slower than lidocaine-induced blockade at equimolar concentrations[11]

• Ropivacaine caused less impairment of mitochondrial energy metabolism than bupivacaine in isolated rat cardiac[12]

and liver[13] mitochondria• Ropivacaine was a less potent blocker of cloned human cardiac K+ channels than bupivacaine[14]

• Depressed cardiac excitability and conduction less than bupivacaine but to a similar degree as lidocaine in isolated rabbitPurkinje fibres[15] and rat cardiomyocytes[16]

• Caused less prolongation of QRS duration than bupivacaine (but not lidocaine) in anaesthetised pigs[17] and had cardiotoxicpotential approximately half that of bupivacaine and levobupivacaine in the same model[18]

• Smaller effects on QRS duration than bupivacaine in volunteers (+2.4 vs +6%; p < 0.05)[19]

• Clinical signs of cardiovascular toxicity occurred at plasma concentrations higher than those causing CNS toxicity[20]

CNS Effects• Higher threshold for CNS toxicity than bupivacaine in healthy volunteers[19,20] (mean maximum tolerated free plasma

concentration ≈0.6 vs 0.3 mg/L; p < 0.001)[19]

Peripheral/Vascular Effects• Biphasic vascular effects i.e. causes vasoconstriction at low (0.063 to 0.5%) but not high (1%) concentrations[21]

• No significant effects on uteroplacental circulation in healthy pregnant women after epidural administration (0.5%)[22]



Time to mobilisation was significantly shorter forropivacaine 0.2 and 0.3% than bupivacaine 0.25%(p < 0.004).

2.2 Cardiovascular and CNS Effects

Local anaesthetics can produce CNS toxicity(e.g. seizures) and cardiovascular toxicity (e.g. ar-rhythmias and a reduction in myocardial contrac-tility) at the high plasma concentrations seen afterlarge doses or inadvertent intravascular injectionof the drug.[25] Clinical signs of cardiovascular tox-icity occur at plasma drug concentrations higherthan those causing CNS toxicity.[20,26] Evidencesuggests that ropivacaine has a higher threshold forcardiovascular and CNS toxicity than bupivacaineand a lower threshold than lidocaine (lignocaine).Local anaesthetic-induced cardiotoxicity may

be linked to slow dissociation of the drug fromcardiac Na+ channels (resulting in accumulation ofNa+ channel block)[27] and from impairment ofcardiac mitochondrial energy metabolism. Two invitro studies[12,13] found that ropivacaine causedless disturbance of mitochondrial energy metabo-lism than bupivacaine, possibly because of itslower lipid solubility. Toxic symptoms such asdysrhythmia, seizure, bradycardia and hypoten-sion occurred at significantly higher doses ofropivacaine than bupivacaine in anaesthetised rats (p< 0.05).[28]Blockade of potassium channels may also con-

tribute to the cardiotoxic effects of local anaes-thetics by increasing cardiac action potential dura-tion; limited evidence indicates that ropivacainehas a lower affinity for human cardiac K+ channelsthan bupivacaine.[14]Ropivacaine caused less prolongation of QRS

duration than bupivacaine (but not lidocaine) inanaesthetised pigs.[17,29] In the same model, ropi-vacaine had cardiotoxic potential (assessed bydP/dtmax, ejection fraction and peak ejection rate)approximately half that of both bupivacaine andlevobupivacaine;[18] the lethal dose of ropivacainewas ≈50% higher than that of bupivacaine.[29]In a dog study designed tomimic accidental intra-

vascular overdose of local anaesthetics, ropiva-

caine and bupivacaine caused seizures at lowerdoses than lidocaine (p < 0.05).[30] No significantdifferences were observed between ropivacaineand bupivacaine, although the incidence of ven-tricular arrhythmias at twice the convulsive dosewas significantly lower with ropivacaine (33 vs83%; p-value not reported).In a randomised double-blind crossover study

involving 12 volunteers,[19] intravenous ropiva-caine had a significantly higher threshold for CNStoxicity than bupivacaine. Both drugs were infusedat a rate of 10 mg/min to a maximum cumulativedose of 250mg if tolerated; maximum tolerated un-bound arterial plasma concentrations ranged from0.34 to 0.85 (mean 0.56) mg/L for ropivacaine andfrom 0.13 to 0.51 (mean 0.3) mg/L for bupivacaine(p < 0.001) [fig. 1].[19] Ropivacaine also appearedto be less cardiotoxic than bupivacaine in thisstudy: QRS width during sinus rhythm increasedsignificantly with bupivacaine (+6%) comparedwith ropivacaine (+2.4%; p < 0.05) and placebo(–0.4%; p < 0.05). In a similar study,[20] the sever-ity and symptoms of CNS toxicity (lightheaded-ness, tinnitus and numbness of the tongue) inhealthy volunteers were greater with bupivacaine(mean highest tolerated intravenous dose 99mg)than ropivacaine (124mg).At these doses, both drugsslightly depressed myocardial conductivity andcontractility but no arrhythmias were detected.[20]

2.3 Peripheral Vascular Effects

Ropivacaine has a biphasic vascular effect likeothers in its drug class. Low concentrations ofropivacaine (0.063 to 0.5%) injected intradermally(0.1ml) caused vasoconstriction in humans[21] buta higher concentration (1%) did not.[21] The vaso-constriction at low concentrations is likely to con-tribute to its long duration of action.Intravenous ropivacaine (0.1 or 0.2 mg/kg/min

for 15 minutes) caused no significant deteriorationin uterine blood flow in pregnant sheep.[31] Nor didepidural ropivacaine 0.5% compromise uteropla-cental circulation in healthy pregnant women.[22]



2.4 MLAC

Two studies conducted during labour have shownthat ropivacaine has a higher minimum local anal-gesic concentration (MLAC) than bupivacaine.Polley et al.[32] administered 20ml epidural ro-pivacaine (n = 25) or bupivacaine (n = 25) towomen with cervical dilation 3 to 7cm; drug con-centration was based on an up-down sequential al-location technique according to the analgesic re-sponse of the previous patient and MLAC wascalculated as the median effective concentration(EC50). Capogna et al.[33] used the same trial de-sign in 80 women with cervical dilation 2 to 5cm.Both studies found that the MLAC for ropivacaine(0.111[32] and 0.156%[33]) was higher than that forbupivacaine (0.067[32] and 0.093%[33]) [p < 0.0001].

The clinical relevance of the MLAC concept re-mains to be determined because the 2 drugs pro-duced comparable analgesia when administeredat higher concentrations in clinical studies (section4.1).

2.5 Neonatal Outcome and Mode of Delivery

Ropivacaine did not significantly affect neo-natal outcome or mode of delivery in clinical stud-ies of the drug for labour pain or caesarean section.Neonatal outcome was evaluated by Apgar scoresat 1 and 5minutes andNeurologicAdaptiveCapacityScores (NACS) at 2 and 24 hours after delivery(NACS are numerical with a maximum of 40;scores ≥35 denote a vigorous baby). These scoreswere not significantly affected by either ropiva-caine (mean total dose range 94 to 128mg) orbupivacaine (98 to 142mg) in comparative studiesfor labour pain[34-39] although more neonates hadan NACS ≥35 after ropivacaine 0.25% (mean totaldose 128.3mg) than bupivacaine 0.25% (mean totaldose 142mg) at 15 minutes (89 vs 81%; p < 0.05)and 2 hours (95 vs 86%; p < 0.05) in 1 study.[35]The results from a prospective meta-analysis[40]

which pooled data from 6 double-blind trials of thedrug for labour pain[35,36,38,39,41] showed that fewerneonates had NACS <35 after 24 hours withropivacaine 0.25% (n = 201; mean dose 103mg)than with bupivacaine 0.25% (n = 190; mean dose110mg) [2.8 vs 7.6%; p < 0.05].[40] However, theclinical significance of this finding is probablysmall and the methodology of the meta-analysishas been questioned.[42] With regard to mode ofdelivery, the meta-analysis showed that the propor-tion of spontaneous vaginal deliveries was higherwith ropivacaine (58 vs 49%; p < 0.05) and theproportion of instrumental deliveries lower (27 vs40%; p < 0.01), but the overall rate of Caesareandeliveries did not differ between groups.[40]When used for caesarean section, the effects of

20ml epidural ropivacaine 0.5[43] or 0.75%[44] onneonatal outcome (assessed using NACS) were notsignificantly different from those of bupivacaine0.5%.

Ropivacaine Bupivacaine

Dru

g pl

asm

a co

ncen

tratio

n (m

g/L)

0.5

0.4

0.3

0.2

0.1

0

0.6

0.7

0.8

0.9

Fig. 1. Maximum tolerated free arterial plasma concentrationsof ropivacaine and bupivacaine. In a randomised, double-blindcrossover study.[19] 12 volunteers received intravenous infu-sions of each drug (10 mg/min) until signs and symptoms ofCNS toxicity developed.



3. Pharmacokinetic Properties

The pharmacokinetic profile of ropivacaine hasprimarily been examined after epidural administra-tion in patients undergoing surgery, although someabsorption data are available after intercostal, bra-chial plexus, peribulbar and intra-articular admin-istration, and wound infiltration.

3.1 Absorption

After epidural administration of 20 to 28mlropivacaine 0.5 or 0.75% in patients undergoingcaesarean section, meanmaximum plasma concen-trations (Cmax) of 1.1 to 1.6 mg/L were reached(table II).The drug also undergoes a small degree of sys-

temic absorption after intercostal,[48] subclavianperivascular (for brachial plexus block),[49] peri-bulbar,[52] intra-articular[53] or local (wound infil-tration)[50,51] administration (table II). However,considering that only a fraction of circulatingropivacaine is unbound (section 3.2), ropivacaineCmax values remained well below the reportedthreshold for CNS toxicity (arterial plasma un-bound ropivacaine concentrations ≈0.6 mg/L).[19]

3.2 Distribution

Ropivacaine is extensively (90 to 94%) boundto plasma proteins[45-47,54,55] (primarily α1-acidglycoprotein); the level of binding is slightly lessthan that reported with bupivacaine (96%).[55]During prolonged (21,[56] 24[57] or 72h)[58,59] post-operative epidural infusion of ropivacaine, unboundplasma drug concentrations plateaued or graduallydeclined despite a progressive increase in totalconcentrations. The reduction in unbound concen-trations was attributed to an increase in plasma α1-acid glycoprotein levels which accompanies thestress response to surgery.[57,58]Clinical studies[45-47] have shown that ropivacaine

crosses the placenta after epidural administra-tion.[45-47] In 1 study, unbound ropivacaine concen-trations in maternal and umbilical veins at deliverywere higher than those reported with bupivacaine

(0.072 vs 0.032 mg/L for maternal vein and 0.06 vs0.03 mg/L for umbilical vein; both p ≤ 0.002).[45]

3.3 Metabolism and Elimination

Mean apparent total body clearance (CL) andterminal elimination half-life (t1⁄2) of ropivacaineafter epidural administration have been evaluatedin a number of studies in pregnant women[45,47,54]and ranged from 13.4 to 19.8 L/h and 5 to 7h, respec-tively, regardless of dose. The t1⁄2 after intravenousadministration was shorter (≈2h),[60] indicatingthat the drug undergoes absorption-dependent elimi-nation.Ropivacaine undergoes extensive hepatic meta-

bolism after intravenous administration, with only1% of the drug eliminated unchanged in theurine.[61] Biotransformation occurs via oxidativemetabolism and dealkylation; the major meta-

Table II. Mean total (bound and unbound) maximum plasmaconcentrations (Cmax) of ropivacaine after various routes of ad-ministration in adults

Route of administration Regimen(dose)

Cmax(mg/L)

Epidural[45] 23-28ml of 0.5%(115-140mg)

1.24

Epidural[46] 20ml of 0.75%(150mg)

1.47

Epidural[47] 20ml of 0.75%(150mg)

1.1

25ml of 0.75%(187.5mg)

1.6

Intercostal[48] 56ml of 0.25%(140mg)

1.06

Subclavianperivascular[49]

38ml of 0.5%(190mg)

1.26

Wound infiltration[50] 30ml of 0.125%(37.5)

0.11

30ml of 0.25%(75mg)

0.24

30ml of 0.5%(150mg)

0.38a

Wound infiltration[51] 30ml of 0.75%(225mg)

1.42

Peribulbar[52] 7ml of 1%(70mg)

1.42

Intra-articular[53] 100mg 0.6150mg 0.7

a Value estimated from graph.



bolite in urine is 3-hydroxy-ropivacaine (37% ofthe administered dose). Minor metabolites include4-hydroxy-ropivacaine, 2-hydroxy-methyl-ropiva-caine and N-dealkylated metabolites 2′,6′-pipeco-loxylidide (PPX) and 3-hydroxy-PPX.An in vitro study in human liver microsomes

found that 2 cytochrome P450 (CYP) isoenzymes,CYP1A2 and CYP3A4, were responsible for theformation of the major and minor metabolites, re-spectively.[62]

3.4 Children

Few data are available on the pharmacokineticsof ropivacaine in children and toxic thresholdshave not been established. Mean total and freeplasma concentrations of ropivicaine ranged from0.41 to 1.11 mg/L and 0.02 to 0.03 mg/L, respec-tively, in 18 children aged 0.3 to 7.3 years whoreceived ropivicaine 0.2% at 0.4 mg/kg/h througha lumbar or thoracic epidural catheter for a meanof 61.3 hours (after a 1 mg/kg bolus dose).[63] Thevolume of distribution was 3.1 L/kg and the t1⁄2 was4.9 hours.[63]Maximum plasma[64] and serum[65] unbound

drug concentrations after lumbar epidural adminis-tration of ropivacaine 1.75 mg/kg[64] or caudal epi-dural administration of ropivacaine 1.88 or 3.75mg/kg[65] in children were below maximum toler-ated levels reported in adults (≈0.6 mg/L).[19] In9 healthy children aged 1 to 6 years who received1 ml/kg ropivacaine 0.25% via the caudal route,systemic drug exposure was similar to that seen inadults.[66]

3.5 Drug Interactions

Because CYP1A2 and CYP3A4 are the primaryisozymes responsible for oxidative hepatic meta-bolism of ropivacaine (section 3.3), agents whichinhibit these isozymes may potentially affect thepharmacokinetic profile of ropivacaine. A ran-domised, 3-way crossover study in 12 volunteers[67]found that fluvoxamine (a CYP1A2 inhibitor) sig-nificantly altered the pharmacokinetic profile ofropivacaine but ketoconazole (CYP3A4) did not.Oral fluvoxamine (25mg twice daily for 2 days)

increased total plasma concentrations of intra-venous ropivacaine 40mg by 16% (p < 0.05), de-layed its elimination (t1⁄2 3.6 vs 1.9h; p < 0.05) andreduced CLtot (6.7 vs 21.2 L/h; p < 0.05). None ofthese parameters were significantly affected byoral ketoconazole 400mg (100mg twice daily for 2days), although formation of the minor metabolitePPX was significantly reduced.

4. Therapeutic Efficacy

The use of ropivacaine as an analgesic (for labouror postoperative pain) and as a local anaestheticduring a variety of surgical procedures has beenstudied extensively. The current review incorpo-rates previously reported[5] and more recent data onropivacaine for these indications.

4.1 Labour Pain

The efficacy of lumbar epidural ropivacaine forlabour analgesia has been evaluated in nonblinddose-finding studies and in randomised double-blind comparisons with bupivacaine. The use ofepidural ropivacaine with opioids has also been ex-amined. Study design details mentioned here referto studies published in full because design datawere generally lacking in abstract reports.Women of American Society of Anaesthes-

iologists (ASA) status I or II who were in activelabour (cervical dilatation generally <5 or 7cm)were included in the studies. Those who had al-ready received opioid or sedative medication wereusually excluded.Test doses of ropivacaine or lidocaine were ad-

ministered in some studies to reduce the likelihoodof inadvertent intravascular or intrathecal admin-istration (section 6). The drug was then given asa single dose for initiation of analgesia, then asintermittent bolus doses, continuous infusion orpatient-controlled epidural anaesthesia (PCEA) formaintenance of analgesia (drug administration com-menced within 15 minutes of the initial dose inmaintenance studies). Primary end-points includedpatient-reported pain relief [evaluated using a lin-ear visual analogue scale (VAS)] and motor block



(generally rated according to the modified Brom-age scale; table III).

4.1.1 Epidural Administration

Dose-Finding StudiesEpidural ropivacaine 0.2% provides adequate

pain relief when used for the initiation (10 to 18ml)andmaintenance (4 to 10ml/h) of labour analgesia.In a double-blind trial,[68] women who requestedlabour analgesia received 13ml of epidural ro-pivacaine 0.1, 0.15 or 0.2%, with a 5ml top-upavailable after 15 minutes if necessary. Acceptablepain reliefwas reported in significantlymore patientsreceiving ropivacaine 0.2% than ropivacaine 0.1%or 0.15% (p < 0.05) [table IV]. The duration ofeffect in women who received adequate analgesiaincreased with increasing dose (64, 96 and 110minutes, respectively; p < 0.011 for ropivacaine0.2 vs 0.1%). The incidence and intensity of motorblock with ropivacaine was low and tended to bedose related (table IV).After establishing adequate analgesia with

ropivacaine 0.2%, continuous infusion at a fixedrate of 4 to 10 ml/h provided satisfactory labouranalgesia and minimal motor block in 2 nonblindstudies[69,70] (table IV). More than 70% of patientsin each of the 4 groups in both studies rated thequality of analgesia before delivery to be eithergood or excellent; the quality of analgesia duringlabour did not differ between groups. Additionalbolus doses of ropivacaine were required in allgroups, although more were required in womenreceiving ropivacaine 0.2% 4 ml/h than in thosereceiving the other regimens (p < 0.05).[69,70] Theuse of PCEA ropivacaine 0.2% (5ml bolus on de-mand with a 15-min lockout) was as effective as a

continuous infusion of ropivacaine 0.2% 8 ml/hduring active labour in a study in 30 women.[71]Pain relief did not differ significantly betweengroups but the maternal satisfaction score was sig-nificantly superior in the PCEA group (p < 0.05)and fewer PCEA recipients had modified Bromagegrade 1 or 2 motor block (30 vs 70%; p < 0.05).

Comparisons with BupivacaineThe analgesic effects of epidural ropivacaine

0.1 to 0.25% during labour were generally similar tothose of equivalent concentrations of bupivacaine,whether used as monotherapy or in combinationwith the opioids sufentanil or fentanyl (tableV).[34-39,72-74] The onset and quality of pain reliefdid not differ significantly between drugs, the degreeof motor block was mild in most patients (table V),and there were no significant effects on neonataloutcome (section 2.5).Coadministration of ropivacaine with opioids

such as fentanyl[74,75] and sufentanil[72,73,76] hasbeen shown to improve labour analgesia and allowa lower concentration of ropivacaine to be used.Studies reported in table V which employed theseregimens found that the ropivacaine-based regi-men caused significantly less motor block than thebupivacaine-based regimen.[72,74]

4.1.2 Intrathecal AdministrationA number of randomised, double-blind studies

have evaluated the effects of intrathecal ropiva-caine for combined spinal-epidural analgesia dur-ing the early stages of labour.[77-80] Although yetto be published in full, the results of these studiessuggest that low doses of ropivacaine (≤4mg) incombination with either sufentanil or fentanyl pro-vide effective labour analgesia withminimalmotorblockade when administered via this route. Theonly full study published to date[81] found thatropivacaine 2mg (n = 15) and 4mg (n = 15) wereas effective as bupivacaine 2.5mg (n = 15) whenadministered intrathecally with sufentanil 10μg inpatients requesting labour analgesia. No signifi-cant between-group differences in duration of an-algesia were reported and motor block was not ob-served in any of the groups.

Table III. Modified Bromage Scale

Grade Definition0 No motor block1 Unable to raise extended leg but able to move knees

and foot2 Unable to raise extended leg or knees but able to

move foot3 Complete motor block of lower limb



4.2 Postoperative Pain

4.2.1 Epidural InfusionThe effects of epidural ropivacaine (alone or

with epidural opioids) on postoperative pain havebeen examined in patients undergoing abdominalor orthopaedic surgery. Lumbar or thoracic infu-sion of ropivacaine was started after surgery andcontinued for between 21 and 72 hours, and patient-controlled intravenous opioid consumption wasthe primary indicator of analgesic efficacy. VASpain scores (ranging from 0mm ‘no pain’ to100mm ‘worst possible pain’) were also evaluated,

although these are not a particularly reliable indi-cator of efficacy in studies which permit concom-itant opioid use. All studies reported in this sectionwere randomised and double-blind, with the excep-tion of 1 study[82] which employed a single-blind de-sign.

MonotherapyEpidural ropivacaine 0.1, 0.2 or 0.3% infused at

a rate of 10 ml/h for 21 hours after abdominal ororthopaedic surgery reduced patient-controlled in-travenous morphine use compared with placebo

Table IV. Dose-finding studies of epidural ropivacaine (ROP) when used for the initiation and/or maintenance of labour analgesiaReference(study design)

No. ofpts

Regimena

(median totaldose)

Pts with good orexcellent painrelief (%)b

Bromage gradec motor block before delivery (% pts)0 1 2 3

Beilin et al.(r, db, pg)[68]

12 13 or 18ml ROP0.1%

33 100 0 0 0

28 13 or 18ml ROP0.15%

64 93 7 0 0

28 13 or 18ml ROP0.2%

93* 86 14 0 0

Benhamou et al.(r, nb, pg)[69]

34 10ml ROP 0.2%then 4 ml/h(86.4mg)

74 64 24 9 3


88 58 23 19 0


85 57 28 11 4

32 10ml ROP 0.2%then 10 ml/h(127.6mg)

88 42 39 16 3

Cascio et al.(r, nb, pg)[70]

33 15mld ROP 0.2%then 4 ml/h(74.8mg)

82 90e* 6e 4e 0e


91 60e 35e 5e 0e


97 50e 33e 15e 2e


84 58e 32e 10e 0e

a The maintenance infusion was started within 15 min of the initial dose and was continued until delivery.b Rated by the patient.c See table III for description of modified Bromage grades.d Median initial dose for entire study population.e Value estimated from graph.db = double-blind; nb = nonblind; pg = parallel group; pts = patients; r = randomised; * p < 0.05 vs other regimens.



Table V. Randomised, double-blind studies which compared the efficacies of epidural ropivacaine (ROP) and bupivacaine (BUP) for labouranalgesia when used alone or in combination with opioids

Reference No. ofpts

Regimena (mean total dose) Onset ofpain relief(min)

Pts with goodor excellentpain relief (%)

Bromage gradeb motor block(% pts evaluated)0 1 2 3

MonotherapyEddleston et al.[38] 51 ROP 0.25% 10-15ml then

10ml prnc (94.2mg)median 12 91 40 34 18 8

50 BUP 0.25% 10-15ml then10ml prnc (100mg)

median 10.5 95 24 38 24 14

Gaiser et al.[35] 37 ROP 0.25% 8-12ml then8-12 ml/h (128.3mg)

mean 11.4 23 43 20 14

38 BUP 0.25% 8-12ml then8-12 ml/h (142.0mg)

mean 12.4 47 18 22 13

McCrae et al.[37] 20 ROP 0.5% 10ml thenROP 0.25% 10ml top-upd

median 9.5 85 10 50 40 0

18 BUP 0.5% 10ml thenBUP 0.25% 10ml top-upd

median 8 78 22 44 33 0

Muir et al.[36] 34 ROP 0.25% 10-15ml then10ml prnc (NR)

97 79 15 3 3

26 BUP 0.25% 10-15ml then10ml prnc (NR)

100 58 35 8 0

Owen et al.[34] 26 ROP 0.125% 6 ml/h + PCEAe

(123mg)96 23 46 27 4

25 BUP 0.125% 6 ml/h + PCEAe

(98mg)100 12 52 36 0

Stienstra et al.[39] 39 ROP 0.25% 10ml then 6-12 ml/h andtop-up doses of 6-10ml prnc (128mg)

median 10 94f

37 BUP 0.25% 10ml then 6-12 ml/h andtop-up doses of 6-10ml prnc (124mg)

median 10 94f

In combination with opioidsFischer et al.[72] 95 ROP 0.1% + SUF 0.5 mg/L 10ml then

PCEAg (median 72.8ml)89* 11h

94 BUP 0.1% + SUF 0.5 mg/L 10ml thenPCEAg (median 67.5ml)

80 20h

Gautier et al.[73] 14 ROP 0.125% + SUF 7.5μg 10ml then10ml prn (49.4mg)

mean 14 99

16 BUP 0.125% + SUF 7.5μg 10ml then10ml prn (53.1mg)

mean 16 97

Meister et al.[74] 25 ROP 0.125% + FEN 2 mg/L 15mlthen 6 ml/h + PCEAe (113.0mg ROP+ 180.8mg FEN)

96 68* 32 0 0

25 BUP 0.125% + FEN 2 mg/L 15ml then6 ml/h + PCEAe (102.5mg BUP +164.0mg FEN)

96 28 68 4 0

a The maintenance infusion was started within 15 min of the initial dose and was continued until delivery.b See table III for description of modified Bromage grades.c Intermittent top-up doses of 10ml were given when requested to a maximum of 8 top-ups or 175mg in 3h.d All parameters were measured after the top-up dose.e PCEA was used to supplement the basal infusion rate of 6 ml/h. 5ml boluses were available to patients every 10 min with a 30 ml/h limit.f n = 31.g 5ml doses were injected via the PCEA pump until the patient felt comfortable; patients were then able to self-administer a demand dose

of 5ml every 10 min as needed.h Grades 1 to 3 motor block.FEN = fentanyl; PCEA = patient-controlled epidural administration; prn = as required; pts = patients; SUF = sufentanil; * p < 0.05 vs BUPregimen.



(the primary end-point, table VI); efficacy tendedto be dose related.[83-85]The proportion of patients without motor block

decreased as the ropivacaine dose increased (tableVI). The degree of motor block was also relatedto dose: patients receiving ropivacaine 0.3% gen-erally had worse motor block (particularly at 4 and8 hours) than those in the other groups.[83,85,86]Studies of various infusion rates of ropivacaine

0.2% administered for 21 hours after lower ab-dominal[87] or orthopaedic[88] surgery found thatrates of 10 to 14 ml/h significantly reduced patient-controlled intravenous morphine use comparedwith placebo[87] or untreated controls;[88] the effectof ropivacaine tended to be rate related.In a comparative study,[89] ropivacaine 0.2%

provided slightly less pain control than bupiva-caine 0.2% (both infused at a rate of 8 ml/h) afterknee surgery. More ropivacaine than bupivacainerecipients had a VAS pain score >30mm on move-ment (21 out of 26 vs 14 out of 26; p = 0.04) in the

8- to 24-hour period postoperatively, and overallmorphine consumption tended to be greater (median30.7 vs 20.5mg; p = NS). However, the degree ofmotor block was lower with ropivacaine (88 vs56% of patients were free from motor block after24 hours).

Compared with Patient-Controlled MorphineEpidural ropivacaine 0.2% is more effective

than patient-controlled intravenous morphine forpostoperative pain relief.A study in 130 patients who had undergone ma-

jor abdominal surgery[90] showed that patients whoreceived ropivacaine 0.2% (20ml epidural bolus then10 ml/h for 24h) alone or with patient-controlledintravenousmorphine had significantly lower VASpain scores both at rest and on coughing in the 24-hour period after surgery than those who used mor-phine alone (p < 0.02). Furthermore, the quality ofpain relief at 2200h on the day of surgery was ratedas good or excellent in ≥84% of patients receiving

Table VI. Randomised, double-blind placebo (PL)-controlled studies comparing the efficacies of different concentrations of epiduralropivacaine (ROP) for postoperative pain when administered at a rate of 10 ml/h for 21 hours after major orthopaedic[83,85] or upper[84] orlower[86] abdominal surgery

Reference Regimen No. ofpts

Morphine consumption (mg)a Pts without motor blockb

(%)0-4h 4-8h 8-21h 0-21h 4h 8h 21h

Badner et al.[83] PL 10 mean 9c mean 15c mean 33c mean 57c

ROP 0.1% 12 mean 2c mean 6c mean 14c mean 22c**ROP 0.2% 11 mean 5c mean 2c mean 17c mean 24c**ROP 0.3% 11 mean 4c mean 1c mean 11c mean 16c**

Muldoon et al.[85] PL 12 9.0 10.5 17.5 67 92 100ROP 0.1% 11 2.0 3.0 12.6 64 82 82ROP 0.2% 12 0.5* 1.5* 25.8 25 42 42ROP 0.3% 11 0 0* 4.0 36 46 45

Schug et al.[84] PL 9 75 100 100 100ROP 0.1% 10 32* 100 100 100ROP 0.2% 10 39* 90 90 90ROP 0.3% 10 13*† 90 90 90

Scott et al.[86] PL 10 7c 10c 27c 44c 80 89 90ROP 0.1% 10 2c 4c 13c 19c 100 100 100ROP 0.2% 10 0c 1c* 7c 8c* 70 80 80ROP 0.3% 10 5c 0c* 14c 19c 30 13 70

a Median value unless stated otherwise.b Bromage grade 0 (see table III for description).c Value estimated from graph.pts = patients; * p < 0.05, ** p < 0.01 vs PL; † p < 0.05 vs ROP 0.1%.



ropivacaine (alone or with morphine) comparedwith 64% of those receiving morphine alone (p <0.05). A similarly designed study compared the useof epidural ropivacaine for both surgical anaest-hesia (15 to 25ml bolus dose of ropivacaine 1%)and postoperative analgesia (4 to 6 ml/h of ro-pivacaine 0.2% for 24h, and top-up doses of 6 to10ml for 48h) with the use of general anaesthesiafollowed by patient controlled intravenous mor-phine after hip replacement surgery. Ropivacainerecipients (n = 43) had significantly greater painrelief in the first 24 hours (p = 0.007) andmet criteriafor discharge from the postanaesthesia care unitconsiderably faster (mean 5.6 vs 39.7 minutes)compared with general anaesthetic/morphine re-cipients (n = 45).[91]

In Combination with Epidural OpioidsCoadministration of ropivacaine with opioids

such as sufentanil or fentanyl improves the qualityof postoperative epidural analgesia.In a randomised, double-blind study which did

not permit the use of additional analgesics otherthan paracetamol, administration of ropivacaine0.2% with fentanyl 4 mg/L (mean rate 10 ml/h;n = 63) for 72 hours after major abdominal surgeryprovided significantly more effective pain relief(assessed by VAS pain scores) at rest or whencoughing than ropivacaine with fentanyl 1 mg/L(n = 59) or 2 mg/L (n = 62), or ropivacaine alone(n = 60).[92] The degree of motor block did not differsignificantly between groups: >80% of patientshad no motor block within 8 hours.A comparative study found that ropivacaine

0.2% with fentanyl 2 mg/L (n = 16) was more ef-fective than bupivacaine 0.125% with fentanyl 2mg/L (n = 16) after major abdominal surgery whenadministered at a basal rate of 4 to 6 ml/h withpatient-supplemented 1.5ml incremental doses ifrequired.[93] Overall pain relief did not differ signifi-cantly between groups, but bupivacaine/fentanyl re-cipients requested significantly more supplementaldoses over the 48-hour follow-up period thanropivacaine/fentanyl recipients (10 vs 5; p < 0.03).Like fentanyl, sufentanil also improves the

postoperative analgesic efficacy of ropivacaine.[82]

30 patients who had undergone total hip replace-ment received ropivacaine 0.1% alone or withsufentanil 1 mg/L at a rate of 5 to 9 ml/h. Combi-nation therapy resulted in a 6-fold reduction in theuse of supplemental opioid (piritramide) over the48-hour follow-up period (p < 0.001 vs ropivacainealone); motor block was minimal in both groupsand resolved rapidly. A higher dosage combination(ropivacaine 0.2% plus sufentanil 1 mg/L) pro-vided a degree of postoperative analgesia similarto that achieved with bupivacaine 0.175% andsufentanil 1 mg/L in 86 patients after major ab-dominal surgery.[94] The rate of the epidural infu-sion was adjusted according to individual require-ments, and was gradually tapered after 3 days. Theincidence of motor block did not differ signifi-cantly between groups, but postoperative mobilitywas restored faster in patients receiving ropivaca-ine (fig. 2).[94] The optimal dose of sufentanil forcombination with ropivacaine has yet to be clearlyestablished.[95]

0

20

40

60

80

100

1 2 3 4Postoperative day

Unl

imite

d w

alki

ng (%

pat

ient

s) *

*ROP + SUFBUP + SUF

Fig. 2. Postoperative mobilisation after analgesia with ropiva-caine (ROP) or bupivacaine (BUP). In a randomised, double-blind study, 86 patients who had undergone abdominal surgeryreceived ROP 0.2% plus sufentanil (SUF) 1 mg/L or BUP0.175% plus SUF 1 mg/L (rate adjusted according to individualrequirements) for 3 or 4 days for epidural postoperative anal-gesia.[94] Postoperative mobilisation was assessed for 4 days.* p < 0.05 vs BUP + SUF.



4.2.2 Local InfiltrationA number of well controlled studies have dem-

onstrated that preoperative[96] (along the intendedline of the incision) or postoperative[50,97,98] woundinfiltration of ropivacaine dose-dependently re-lieves postoperative pain, at least in the short term,after inguinal hernia repair. In 1 of these studies,30ml of either ropivacaine 0.5% (n = 27) or 0.25%(n = 25) provided significantly greater pain reliefthan ropivacaine 0.125% (n = 26) and saline (n =24) when assessed by the time taken to the firstrequest for a supplementary analgesic and VASpain scores.[50] These dose-related effects wereconfirmed in a study in 126 patients undergoinghernia repair[96] in which significantly fewer pa-tients who received preoperative wound infil-tration with 40ml ropivacaine 0.5% or 0.25% re-quested supplementary analgesia compared withthose who received saline (51 and 74 vs 88% ofpatients; p ≤ 0.05).[96]Based on a nonblind study[98] which found that

ropivacaine 0.75% relieved pain after hernia re-pair, the effects of 40ml ropivacaine 0.75% were

compared with those of 40ml bupivacaine 0.25%in a randomised, double-blind study in 144 pa-tients.[97] No significant between-group differ-ences in postoperative relief were observed at rest(fig. 3), on mobilisation or during coughing.In addition to relieving pain after hernia repair,

preoperative infiltration of the incision line withropivacaine appears to reduce pain after thoracicsurgery,[99] breast reconstruction[100] or lower backsurgery[101,102] and postoperative wound infiltra-tion alleviates pain after shoulder surgery.[51] How-ever, only 1 of these studies has been published infull;[51] the findings of the remaining studies needto be interpreted with care.

4.2.3 ChildrenEpidural ropivacaine appears to relieve post-

operative pain when given via the caudal route inchildren undergoing minor surgery and limitedevidence suggests it may also be effective whengiven by the lumbar route in those undergoingmajor surgery.Randomised, double-blind studies[103-106] found

that caudal administration of ropivacaine 0.2% (2mg/kg) or 0.25% (2.5 mg/kg) provided similar orbetter postoperative analgesia to bupivacaine0.25% (2.5 mg/kg) in children undergoing minorsurgery (table VII).The onset time, duration of analgesia and need

for supplemental analgesia were similar for bothdrugs in most studies, although 1 study[104] foundropivacaine 0.2% (2 mg/kg) to be significantlymore effective than bupivacaine 0.25% (2 mg/kg)for all 3 parameters (table VII). Importantly, motorblock upon wakening was minimal with ropiva-caine 0.2 and 0.25%, as it was with bupivacaine0.25%.Ropivacaine 0.5% (3.75 mg/kg) was signifi-

cantly more effective than both ropivacaine 0.25%(1.88 mg/kg) and bupivacaine 0.25% (1.88 mg/kg)in terms of analgesia (table VII),[65] but was asso-ciated with greater impairment of motor functionas documented by a significantly longer time takento first observation of the patients either standingor voiding.

0

2

4

6

8

10

12

0-4 4-8 8-12 24Time after hernia surgery (h)

Pai

n sc

ore

at re

st

ROP 0.75%BUP 0.25%

Fig. 3. Effects of wound infiltration with ropivacaine 0.75%(ROP) or bupivacaine 0.25% (BUP) on pain after hernia repair.Patients undergoing hernia repair were randomised to receivewound infiltration with 40ml of either ROP 0.75% (n = 73) or BUP0.25% (n = 71) in a double-blind trial.[97] Postoperative pain reliefwas measured using a visual analogue scale ranging from 0mm(no pain) to 100mm (worst pain imaginable).



One study[107] has examined the use of lumbaradministration of ropivacaine for postoperative an-algesia in children after major surgery. In thisstudy, ropivacaine 0.2% (1.4 mg/kg) provided adegree of postoperative analgesia similar to thatachieved with bupivacaine 0.25% (1.75 mg/kg).[107]Preliminary evidence suggests that coadministra-

tion of clonidine (as a single dose[108,109] or contin-uous infusion[110]) prolongs the postoperative an-algesic effect of ropivacaine in children and allowsa lower concentration of ropivacaine to be used.[109]

4.3 Surgical Anaesthesia

This section contains updated information onthe use of ropivacaine for regional anaesthesia viaepidural or peripheral nerve administration, as well

as new data on alternative routes of administrationto patients undergoing surgical procedures.

4.3.1 Lumbar Epidural AnaesthesiaA large number of studies have evaluated the

efficacy of ropivacaine for surgical anaesthesiaafter lumbar epidural administration. The main de-terminants of efficacy in these studies were sensoryblockade (measured by pinprick tests) and motorblockade (generally measured using the Bromagescale). Ropivacaine was administered via the L2 toL3 or the L3 to L4 interspace.

Caesarean SectionEpidural ropivacaine 0.5% provided anaesthe-

sia of a similar quality to that achieved withbupivacaine 0.5% in women undergoing caesareansection, without affecting neonatal outcome. Sev-eral randomised, double-blind studies[22,43,111,112]

Table VII. Randomised, double-blind studies comparing the efficacies of ropivacaine (ROP) and bupivacaine (BUP) when administered bycaudal[65,103-106] or lumbar[107] routes for postoperative analgesia in children after general anaesthesia

Reference Regimen No. of pts(mean age)

Type of surgery(mean duration)

Analgesia (min)a Pts not needingadditionalanalgesia in24h (%)

onset durationb

Caudal blockDa Conceicaoet al.[103]

ROP 0.25% (2.5 mg/kg)BUP 0.25% (2.5 mg/kg)

40 (4y)40 (4y)

Herniorrhaphy (60 min)Herniorrhaphy (60 min)

NRNR

300300

NRNR

Ivani et al.[104] ROP 0.2% (2 mg/kg) 20 (4y) Subumbilical (40 min) 9* 520* 90*BUP 0.25% (2 mg/kg) 20 (4y) Subumbilical (38 min) 12 253 50

Ivani et al.[105] ROP 0.2% (2 mg/kg) 122 (4.2y) Subumbilical (37.3 min) 9.7 271.9 40BUP 0.25% (2.5 mg/kg) 123 (4.1y) Subumbilical (38 min) 10.4 233.2 40

Khalil et al.[106] ROP 0.25% (2.5 mg/kg) 39 (38mo) Urological, lowerabdominal or lowerextremity (43 min)

10 median 680 33

BUP 0.25% (2.5 mg/kg) 36 (44mo) Urological, lowerabdominal or lowerextremity (39 min)

9 median 680 36

Koinig et al.[65] ROP 0.25% (1.88 mg/kg) 18 (5y) Hernia repair (30 min) NR median 208 NRROP 0.5% (3.75 mg/kg) 21 (4y) Hernia repair (36 min) NR median 1440*† NR†*BUP 0.25% (1.88 mg/kg) 17 (4y) Hernia repair (29 min) NR median 220 NR

Lumbar blockIvani et al.[107] ROP 0.2% (1.4 mg/kg) 14 (7.7mo) Major abdominal

(101.5 min)11.7 456.6 57

BUP 0.25% (1.75 mg/kg) 14 (7.3mo) Major abdominal(112.3 min)

13.1 491.2 43

a Mean values unless stated otherwise.b Measured as the time to first request for analgesia (where applicable) in the first 24h after surgery (max. 1440 min).NR = not reported; pts = patients; * p < 0.05 vs BUP; † p < 0.001 vs ROP 0.25%.



have shown that ropivacaine 0.5% and bupivacaine0.5% have similar effects on sensory blockade dur-ing caesarean section, although motor blockadetended to be of shorter duration with ropivacaine.These studies involved 20 to 75 women, and usedan initial 20[22,43,112] or 30ml[111] dose (several studiesallowed the use of 1[22] or 2[43,112] 5ml top-ups ifnecessary).A higher concentration of ropivacaine (0.75%)

also produced an epidural block similar to thatachieved with bupivacaine 0.5% in a study in 122women receiving a 20ml epidural dose; no signif-icant differences in sensory or motor blockade, orthe number of patients needing 5ml top-ups, werereported.[44] Similar results were reported in 3other studies comparing ropivacaine 0.75% (20 to25ml) and bupivacaine 0.5% (20 to 30ml) but thesedata are currently available in abstract formonly.[113-115]

Orthopaedic SurgeryThe results from small (n = 20 to 25) randomised

double-blind studies which compared the anaes-thetic efficacies of lumbar epidural ropivacaineand bupivacaine for lower limb surgery showedsimilar patterns of sensory and motor blockadewhen ropivacaine 0.75 to 1.0% or bupivacaine 0.5to 0.75% were administered.[116-118] When equiva-lent doses were employed (20ml of a 0.5% solu-tion), the duration of motor and sensory blockadewith ropivacaine (n = 22) was significantly shorterthan with bupivacaine (n = 22).[119] In contrast,these doses were shown to provide equivalent an-aesthesia in 63 patients undergoing lower limborthopaedic surgery.[120] No significant between-group differences were observed in onset, durationor regression of sensory block, and intensity andduration of motor block (although median valuesof the latter were greater with bupivacaine). Inter-estingly, sensory analgesia was considered satis-factory in only 78% of ropivacaine and 62% ofbupivacaine recipients (difference not signifi-cant),[120] suggesting that lumbar epidural blockwith either of these agents alone may be insuffi-cient when 0.5% solutions are used.

Genitourinary SurgeryTwo nonrandomised, nonblind dose-finding

studies[121,122] demonstrated that ropivacaine (20mlof a 0.5, 0.75 or 1.0% solution) provides adequatesensory and motor blockade for urological surgery.The time taken to reach the maximum level ofanalgesia was not dose related, although the dura-tion of anaesthesia and the degree of motor block-ade were. A comparative trial[123] in patients under-going urological surgery showed that sensoryblockade achieved with 20ml ropivacaine 0.75%(150mg) was less intense and of a shorter durationthan that provided by the same dose of bupivacaine,but the time to onset ofmotor blockadewas similar.Studies that compared ropivacaine and bupivaca-ine at a dose ratio of up to 1.5 : 1 (ropivacaine 1%vs bupivacaine 0.75%[124] or ropivacaine 0.75% vsbupivacaine 0.5%)[125] for epidural anaesthesia dur-ing gynaecological surgery reported very similarpatterns of motor and sensory blockade with bothdrugs.

4.3.2 Peripheral Nerve Administration

Brachial Plexus BlockWhen administered via the subclavian peri-

vascular route, 30 to 33ml ropivacaine 0.5% (150to 165mg) induced satisfactory brachial plexusblock in patients about to undergo upper limb sur-gery in noncomparative studies [50% of patientsalso received epinephrine (adrenaline)].[126-128]Anaesthesia of brachial plexus dermatomes wasachieved in 86 to 100% of patients in these studies.Single doses of a lower ropivacaine concentration(0.25%) do not appear to produce satisfactory bra-chial plexus block[129] but a continuous inter-scalene infusion of ropivacaine 0.2% (5 ml/h witha patient-controlled bolus dose of 3 or 4ml; 20-minute lockout) controlled pain more effectivelythan a continuous infusion of nicomorphine (0.5mg/h with a patient-controlled bolus dose of 2 or3mg; 20-minute lockout) after major shoulder sur-gery in 2 randomised studies involving 60[130] and33[131] patients.Well controlled comparative studies have found

that 30 to 40ml ropivacaine 0.5% produces a pat-tern of brachial plexus anaesthesia broadly equiv-



Rop

ivacaine: An U

pdate

1083

© A

dis In

tern

atio

na

l Limite

d. A

ll righ

ts rese

rved

.D

rug

s 2000 No

v; 60 (5)

Table VIII. Randomised double-blind studies comparing ropivacaine (ROP) and bupivacaine (BUP) or mepivacaine (MEP) for brachial plexus anaesthesia in patients undergoingupper limb surgery (mean parameters unless otherwise stated)

Reference Regimen No. ofpts

Onset ofanaesthesia(min)a

Time toreadiness forsurgery (min)b

Analgesiaduration(h)c

Complete motor block (min) Pts requiringperioperativefentanyl (%)

onset duration

Subclavian perivascular blockHickey et al.[132] 32ml ROP 0.5% (175mg) 24 13-31 14 48 (hand);

7 (shoulder)600 (hand);720 (shoulder)

32ml BUP 0.5% (175mg) 23 18-58 13 48 (hand);9 (shoulder)

660 (hand);720 (shoulder)

Vaghadia et al.[136] 30ml ROP 0.75% (225mg) 49 16-21 median 11 15 648 2430ml BUP 0.5% (150mg) 49 21-25 median 12 20 768 29

Axillary blockBertini et al.[133] 32ml ROP 0.5% (160mg) 30 16.4* 11 NR 500* 10*

32ml ROP 0.75% (240mg) 30 14.7* 11 NR 492* 6.7*32ml BUP 0.5% (160mg) 30 22.3 11 NR 600 23.3

Casati et al.[137] 20ml ROP 0.75% (150mg) 15 median 10 median 10** median 20(hand)

median 550*(hand)

7

20ml MEP 2% (400mg) 15 median 8 median 5 median 10(hand)

median 230(hand)

13

McGlade et al.[134] 40ml ROP 0.5% (200mg) 30 median 10-20 median 7-11 median 30(elbow) 60(wrist/hand)

median 390(elbow/wrist);450 (hand)

NAd

40ml BUP 0.5% (200mg) 31 median 10-30 median 10-21 median 40 (elbow);48 (wrist);61 (hand)

median 360 (elbow);540 (wrist);498 (hand)

NAd

Interscalenic blockCasati et al.[138] 20ml ROP 0.5% (100mg) 15 23e 11.5e* NR NR 13

20ml ROP 0.75% (150mg) 15 15e† 10.7e** NR NR 020ml ROP 1% (200mg) 15 10e††* 10.6e** NR NR 1320ml MEP 2% (400mg) 15 18e 5.5e NR NR 20

Klein et al.[135] 30ml ROP 0.5% (150mg) 22 <6 11.5e 4.4 720 (shoulder)30ml ROP 0.75% (225mg) 24 <6 9.5e 3.9 780 (shoulder)30ml BUP 0.5% (150mg) 21 <6 12e 4.4 900 (shoulder)

a Value or range of values for ≤6 nerves for subclavian perivascular or axillary administration and the C5-6 dermatomes for interscalene administration (where reported).b Patients were considered ready for surgery when they had loss of sensation to pinprick and at least partial motor block in each nerve tested.

c Measured either as the time to first request for postoperative analgesia[133,135-138] the time to regaining sharp sensation[134] or not defined.[132]

d Patients were not given fentanyl but 33% of ropivacaine and 22% of bupivacaine recipients required additional nerve block with prilocaine 30mg.

e Value estimated from graph.NA = not applicable; NR = not reported; pts = patients; * p < 0.05, ** p < 0.01 vs BUP or MEP; † p < 0.05, †† p < 0.001 vs ROP 0.5%.

alent to that provided by 30 to 40ml bupivacaine0.5% whether administered via the subclavianperivascular,[132] the axillary[133,134] or the inter-scalenic[135] approach (table VIII).Although the onset of sensory blockade tended

to be faster and the duration of motor blockadeshorter with ropivacaine, differences between ro-pivacaine and bupivacaine were only statisticallysignificant in 1 study.[133]Whether or not ropivacaine 0.75% provides ad-

ditional benefits over the 0.5% concentration hasyet to be clearly determined, with 2 studies findingno significant difference[133,135] but 1 finding that20ml ropivacaine 0.75% was superior with regardto time to readiness for surgery (loss of pinpricksensation and inability to elevate the shoulder) af-ter interscalenic administration (table VIII).[138]A comparison with the fast onset/medium dura-

tion local anaesthetic mepivacaine for interscalenebrachial plexus anaesthesia found that patientswho received 20ml ropivacaine 1% were ready forshoulder surgery faster than those who received20ml mepivacaine 2% (ropivacaine 0.75% and 0.5%had an onset speed similar to that of mepivacaine;table VIII).[138] Not unexpectedly, analgesia dura-tion was longer with ropivacaine than with me-pivacaine 2% after both axillary[137] and inter-scalenic[138] administration.

Sciatic-Femoral BlockThe results from 2 randomised, double-blind

studies in patients (n = 45[139] and n = 340[140])undergoing orthopaedic lower limb proceduresindicate that, when used for combined sciatic-femoral nerve block, 25 to 30ml ropivacaine 0.75%has an onset of sensory block similar to that of≈25ml mepivacaine 2% (≈13 min), but provideslonger postoperative analgesia (≈11[139] and 15h[140]vs 4[139] and 6h;[140] p < 0.01). Both ropivacaine andmepivacaine had a faster onset of sensory and motorblock than bupivacaine (fig. 4) and a shorter dura-tion of postoperative analgesia (11.2 and 4.2 vs14.7h; p < 0.05 for ropivicaine vs bupivicaine andp < 0.01 for mepivicaine vs ropivicaine andbupivicaine).[139] Resolution of foot motor blockwas slower with ropivacaine 0.75% than mepi-

vacaine (≈10 vs 4h; p < 0.01) which needs to beconsidered in patients requiring early mobilisa-tion.[139,140]The addition of clonidine 1 μg/kg to 30ml

ropivicaine 0.75% for sciatic-femoral nerve blockprovided a 3 hour delay in the first request forpain medication after hallux valgus repair in arandomised double-blind study (time to first re-quest for pain medication was 16.8 vs 13.7 hoursin recipients of ropivicaine alone, p = 0.038).

Other Regional Anaesthetic TechniquesLimited data suggest that ropivacaine 0.5% has

an anaesthetic efficacy similar to that of bupiva-caine 0.5% when used for combined lumbar plexus-sciatic nerve block for knee arthroplasty[141] and3-in-1 block (blockade of the femoral nerve, thelateral cutaneous femoral nerve and the obturatornerve) for hip surgery after trauma.[142] In addition,4ml intrathecal (spinal) ropivacaine 0.3% (12mg)appears to provide a pattern of sensory and motorblockade similar to that achieved with 4mlbupivacaine 0.2% (8mg) in patients undergoing

0

10

20

30

40

50

60

Sensory block Motor block

Ons

et ti

me

(min

)

* * * *

ROP 0.75%MEP 2%BUP 0.25%

Fig. 4. Onset of sciatic-femoral nerve block achieved withropivacaine (ROP), mepivacaine (MEP) or bupivacaine (BUP).Patients scheduled for hallux valgus repair received combinedsciatic-femoral nerve block with 25ml of ROP 0.75% (n = 15),MEP 2% (n = 15) or BUP 0.5% (n = 15) in a randomised, double-blind trial.[139] * p ≤ 0.002 vs BUP.



knee arthroscopy.[143] This randomised dose-findingstudy in 150 patients found that ropivacaine 12mghad optimal effects; a lower dose (10mg) providedshorter anaesthesia and a higher dose (14mg) sig-nificantly increased the time to first void.In a randomised double-blind study in 60 patients

undergoing carotid endarterectomy with cervicalplexus block,[144] time to readiness for surgery wassimilar in patients receiving 0.2 ml/kg ropivacaine0.75 or 1.0%, or mepivacaine 2%. However, bothropivacaine concentrations provided longer post-operative analgesia than mepivacaine (≈10 vs 5h;p < 0.05).

4.3.3 Peribulbar AnaesthesiaA number of randomised, double-blind studies

involving between 27 and 50 patients per grouphave shown that 5 to 10ml ropivacaine 1% (aloneor with lidocaine 2%) provides a quality of peri-bulbar anaesthesia at least similar to that achievedwith 5 to 10ml bupivacaine 0.5 or 0.75% (alone orwith lidocaine 2%) in patients undergoing cataractor intraocular surgery (table IX).Hyaluronidase was administered with both

drugs to promote the spread of the anaesthetic andthereby reduce intraocular pressure. A top-up dose(≤5ml) of each drug was given between 5 and 10minutes after the first if sensory anaesthesia or aki-nesia was considered to be inadequate for surgery;

Table IX. Randomised, double-blind studies comparing ropivacaine (ROP) and bupivacaine (BUP) for peribulbar anaesthesia in patientsundergoing cataract or intraocular surgerya

Reference Initial regimen (pts) Injection site(volume)

No. of ptsneedingextra dose after10 min (%)b

Mean totalvolumeinjected(ml)c

Time toreadinessforsurgery(min)

Time toincision(min)

No. of ptsreportingperioperativepain (%)

Cataract SurgeryCorke et al.[145] 8ml ROP 1% (50) Inferolateral 15 (30%) 8-12 median 5 NR 3 (6%)

8ml BUP 0.5% + LID2% (50)

Inferolateral 13 (26%) 8-12 median 5 NR 8 (16%)

Gillart et al.[146] ROP 1% + LID 2% (50) Medial 19 (38%)* 10.6 NR 23 3 (6%)BUP 0.5% + LID 2%(50)

Medial 31 (62%) 10.5 NR 20 4 (8%)

Huha et al.[52] 7ml ROP 1% (50) Inferolateral (5ml)then medial (2ml)

9 (18%) 7.5 NR 32 6 (12%)

7ml BUP 0.75% (50) Inferolateral (5ml)then medial (2ml)

14 (28%) 8 NR 34 6 (12%)

Nicholson et al.[147] 7-10ml ROP 1% + LID2% (44)

Inferolateral 7 (16%) 7-15 median 8 NR NR

7-10ml BUP 0.75% +LID 2% (46)

Inferolateral 12 (26%) 7-15 median 8 NR NR

Intraocular SurgeryMcLure et al.[148] 5ml ROP 1% (27) Inferotemporal 18 (67%)d 8.6 7.9 23.2 NR

5ml BUP 0.75% + LID2% (27)

Inferotemporal 23 (85.2%)d 9.0 8.3 20.7 NR

Nociti et al.[149] 8ml ROP 1% (40) Double injection(5ml then 3ml)

0 (0%)e 8 NR NR NR

8ml BUP 0.75% (40) Double injection(5ml then 3ml)

2 (5%)e 8.1 NR NR NR

a All pts also received hyaluronidase 7.5 IU/ml,[52,148] 15 IU/ml,[147] 25 IU/ml,[146] 50 IU/ml[149] or 75 IU/ml.[145]

b Because of insufficient efficacy of first dose.c Includes initial and supplementary doses.d Pts in this study received a second injection after 6 min and a third injection after 12 min if necessary.e The supplementary dose was given after 5 min in this study if required.LID = lidocaine (lignocaine); NR = not reported; pts = patients; * p < 0.05 vs BUP.



overall this appeared more likely in bupivacainerecipients, although only 1 study[146] showed a sta-tistically significant between-group difference.Because there was no standard scoring system for

ocular or eyelid movement used across all studiesreported in table IX, a trend was hard to identify.Nevertheless, effects on ocular and eyelid motilityappeared to be broadly similar with the 2 drugs (theonset of ocular akinesia was faster with ropiva-caine in 2 studies,[52,149] and eyelid akinesia wasmore marked with ropivacaine in 2 studies[52,147]but no other differences were reported).Reports of perioperative pain were minimal in

each group (table IX).

5. Tolerability

Ropivacaine appears to have been well toleratedin clinical trials regardless of the route of adminis-tration. However, few details are available on itsgeneral tolerability profile because most studiespublished to date have only provided a brief over-view of adverse events.

5.1 Epidural Administration

Hypotension was the most commonly reportedadverse event in studies of epidural ropivacaine inwomen undergoing caesarean section (0.5 or0.75% solution)[43,44] and those treated for labourpain (0.125 to 0.2%)[34,35,70] or postoperative pain(0.1 to 0.3%).[83-85,87,90] The incidence of hypoten-sion increased with increasing drug dose but wasmost likely a consequence of sympathetic block(common to all local anaesthetics). Other eventsreported in these studies included nausea, vomit-ing, paraesthesia, urinary retention and brady-cardia. Coadministration with opioids may in-crease the incidence of hypotension, nausea andpruritus.[92]The maternal and neonatal tolerability profiles

of ropivacaine 0.75% did not differ significantlyfrom those of bupivacaine 0.5%when used for cae-sarean section.[43,44] A meta-analysis which pooleddata from 6 well-controlled trials of the drug forlabour pain found that the tolerability profile ofropivacaine 0.25% was not significantly different

from that of bupivacaine 0.25%.[40] Adverse eventsidentified in the meta-analysis included hypo-tension (15% for ropivacaine vs 9.5% for bupiva-caine), poor progression of labour (11 vs 12%),moderate or severe fetal bradycardia (18 vs 19%)and neonatal jaundice (9.5 vs 10%) [fig. 5].For other neonatal outcome data from this trial,

see section 2.5.Although experience with ropivacaine in children

is limited, no adverse events were reported aftercaudal[65,104-106,150] or lumbar epidural[107,110] ad-ministration in this patient group.

5.2 Other Routes of Administration

Evidence from clinical trials indicate that ropi-vacaine is well tolerated after brachial plexusblock,[132,136] combined spinal-epidural (intrathecal)administration,[81] lumbar plexus and sciatic nerveblock,[141] local wound infiltration[96,97] and peri-bulbar administration.[147,148,151] One comparativestudy found that, after peribulbar administration ofropivacaine, the postoperative incidence of dip-lopia (26%), scalp anaesthesia (19%), headache

ROPBUP

0

2

4

6

8

10

12

14

16

18

20

Maternalhypotension

Fetalbradycardia

Neonataljaundice

Inci

denc

e (%

pat

ient

s)Fig. 5. Tolerability profiles of epidural ropivacaine (ROP) 0.25%and bupivacaine (BUP) 0.25% when used for labour pain. Ameta-analysis[40] of 6 randomised, double-blind studies com-pared the effects of ROP (n = 201; mean total dose 103mg) andBUP (n = 190; mean total dose 110mg) after epidural adminis-tration for labour pain.



(15%), dizziness (15%) and nausea (7%) were sim-ilar to those reported with bupivacaine.[148]

5.3 CNS and Cardiovascular Toxicity

Clinical evidence from 60 studies involving3000 patients showed that accidental intravascularadministration of ropivacaine was suspected in 6patients. Only 1 patient convulsed and none showedsigns of cardiotoxicity at doses of 75 to 200mg.[152]The outcome of all 6 patients was good. Severalother cases of CNS toxicity have been reportedwith ropivacaine after inadvertent intravascularadministration.[153-157] Most of these patients de-veloped convulsions,[153-155] although more unusualmanifestations included anxiety, vocalisation andagitation.[156] Consistent with evidence that cardio-vascular toxicity occurs at higher plasma ropiva-caine concentrations than CNS toxicity (section2.2),[20] reports of cardiovascular toxicity after ac-cidental intravascular administration of ropiva-caine are extremely rare. In the only case reportedto date,[154] severe cardiac dysrhythmia developedin a patient with an unbound venous plasmaropivacaine concentration estimated to be 1.5 mg/L,which is 10-fold higher than the venous plasmathreshold for CNS toxicity reported by Knudsen etal (0.15 mg/L).[19] The patient recovered fully.[154]

6. Dosage and Administration

Ropivacaine is indicated for the production ofanaesthesia during surgery (e.g. epidural block,major nerve block or local infiltration) and for re-lief of postoperative or labour pain (e.g. epiduralcontinuous infusion or intermittent bolus, or localinfiltration).[158] Generally, higher concentrationsand dosages are required for surgical anaesthesiathan for analgesia. The dose range of ropivacaineconsidered appropriate for successful block inadults is presented in table X. Ropivacaine is notyet indicated for paracervical block anaesthesia,retrobulbar block or spinal anaesthesia because ofinsufficient data.Careful aspiration for blood or cerebrospinal

fluid (where applicable) is recommended beforeinjecting ropivacaine to avoid intravascular or sub-

arachnoid injection. A test dose (3 to 5ml of lido-caine with epinephrine) is then recommended beforeinduction of complete epidural block to further re-duce the risk of inadvertent intravascular adminis-tration. This needs to be repeated if the patient ismoved to such an extent that the epidural cathetermay have been displaced.Fractional (incremental) doses are to be admin-

istered whenever possible, thereby avoiding therapid injection of a large volume of ropivacaine.The patient needs to be closely observed duringadministration and the injection stopped immedi-ately if signs of toxicity develop.The risk of reaching a toxic plasma concentra-

tion must be considered whenever prolonged blocksare used (achieved with either continuous infusionor repeated bolus doses). However, cumulativedoses of up to 800mg over 24 hours for surgery andpostoperative pain were well tolerated in adults inclinical studies,[158] as were postoperative contin-

Table X. Dosage recommendations for ropivacaine[158]

Indication andprocedure

Conc.(%)

Volume Dose

Labour analgesiaLumbar epiduralbolus

0.2 10-20ml 20-40mg

Continuous infusion 0.2 6-14 ml/h 12-28 mg/hTop-ups(if necessary)

0.2 10-15 ml/h 20-30 mg/h

Postoperative analgesiaLumbar epiduralcontinuous infusion

0.2 6-14 ml/h 12-28 mg/h

Thoracic epiduralcontinuous infusion

0.2 6-14 ml/h 12-28 mg/h

Field block (minornerve block andinfiltration)

0.2 1-100ml 2-200mg

Surgical anaesthesiaLumbar epidural forcaesarean section

0.75 15-20ml 113-150mg

Lumbar epiduralfor surgery

0.75 15-25ml 113-188mg1.0 15-20ml 150-200mg

Major nerve block(e.g. brachial plexusblock)

0.75 10-40ml 75-300mg

Field block (minornerve block andinfiltration)

0.75 1-30ml 7.5-225mg

Conc. = concentration.



uous epidural infusions at rates up to 28 mg/h for72 hours.[92]Ropivacaine must be used with caution in pa-

tients receiving other local anaesthetics or structur-ally-similar drugs because the toxic effects of thesedrugs are additive. Other potential interactions in-volve drugs metabolised by CYP1A2 (section 3.5).The drug should be administered with caution

in patients with hepatic disease or impaired cardio-vascular function. Those with severe hepatic dis-ease are at higher risk of developing toxic plasmaconcentrations than healthy patients because oftheir inability to metabolise the drug normally. Pa-tients with impaired cardiovascular function areless able than healthy patients to compensate forcardiovascular changes (prolongation of A-V con-duction) associated with ropivacaine.Administration of ropivacaine to children youn-

ger than 12 years of age cannot be recommendeduntil further experience is gained in this group.

7. Place of Ropivacaine in Regional Anaesthesia

Ropivacaine has a similar chemical structure tothe long-acting local anaesthetic bupivacaine (bothagents are pipecoloxylidide derivatives) and hasdemonstrated a pronounced sensory motor blockdifferential at the low concentrations typically em-ployed for regional analgesia.Clinical studies have shown that epidural ad-

ministration of the drug for the initiation and main-tenance of labour analgesia provides a level of painrelief broadly similar to that achieved with thesame dose of bupivacaine. Importantly, ropivaca-ine does not significantly affect neonatal outcomeor mode of delivery when used for labour pain andcauses only mild motor blockade. This latter effectis an important issue for drugs used in the deliverysuite and represents a major therapeutic advantageover older agents such as lidocaine, chloroprocaineand mepivacaine which are associated with an un-desirable reduction in motor function.[159] More-over, clinical evidence suggests that ropivacainemight cause less motor block during labour thanbupivacaine at low concentrations.

Epidural ropivacaine also provides reasonablepain relief when administered after major abdomi-nal or orthopaedic surgery and its efficacy is en-hanced by coadministration of epidural opioids.The drug (either alone or with opioids) thereforerepresents a viable therapeutic alternative to intra-venous opioids alone, which are frequently em-ployed for postoperative pain but which can causeunwanted nausea and vomiting, sedation and respi-ratory depression.[1] Comparative data have shownthat postoperative ropivacaine causes less motorblock than equivalent doses of bupivacaine and as aresult may allow for earlier ambulation after surgery.As well as providing effective management of

labour or postoperative pain, ropivacaine has beenused for regional anaesthesia via epidural or pe-ripheral nerve block in a variety of surgical proce-dures including orthopaedic or genitourinary sur-gery, and caesarean section. The drug generallyprovides a pattern of anaesthesia similar to that ofequivalent concentrations of bupivacaine, althoughhigher doses of epidural ropivacaine were neededto provide the same pattern of sensory and motorblockade as bupivacaine during lower limb or genito-urinary surgery in clinical trials.Significantly, preclinical studies have shown

that ropivacaine is less cardiotoxic[11,15,17,29,160]and causes less CNS toxicity[30] than the sameconcentrations of bupivacaine. Furthermore, thethreshold for CNS toxicity was higher for ropi-vacaine than for bupivacaine in volunteers.[19] Thislower risk of CNS or cardiovascular toxicity is amajor benefit when large doses of local anaes-thetics are required, and at other times because ofthe ever-present risk of inadvertent intravascularadministration during regional anaesthesia.As is evident from the preceding discussion,

most comparative trials of ropivacaine for regionalanaesthesia and analgesia performed to date haveemployed bupivacaine as the comparator. However,levobupivacaine, the S-enantiomer of bupivacaine,has recently become available commercially. It tooseems to have a lower risk of cardiovascular andCNS toxicity than bupivacaine yet possesses sim-ilar efficacy.[161] Trials comparing the efficacy of



ropivacaine with that of levobupivacaine for localanaesthesia are therefore awaited with interest.In conclusion, ropivacaine is a well tolerated

regional anaesthetic with an efficacy broadly sim-ilar to that of bupivacaine. However, it may be apreferred option because of its reduced CNS andcardiotoxic potential and its lower propensity formotor block in the management of postoperativepain and labour pain.

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Correspondence: Karen J. McClellan, Adis InternationalLimited, 41 Centorian Drive, Private Bag 65901, MairangiBay, Auckland 10, New Zealand. E-mail: [email protected]



Ropivacaine: An Update of its Use in Regional Anaesthesia

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