Drugs

, Volume 65, Issue 18, pp 2675–2717

Ropivacaine

A Review of its Use in Regional Anaesthesia and Acute Pain Management

Authors

    • Adis International Limited
  • Monique P. Curran
    • Adis International Limited
  • Vicki Oldfield
    • Adis International Limited
  • Gillian M. Keating
    • Adis International Limited
Adis Drug Evaluation

DOI: 10.2165/00003495-200565180-00013

Cite this article as:
Simpson, D., Curran, M.P., Oldfield, V. et al. Drugs (2005) 65: 2675. doi:10.2165/00003495-200565180-00013

Summary

Abstract

Ropivacaine (Naropin®) is the pure S(−)-enantiomer of propivacaine, and is a long-acting amide local anaesthetic agent, eliciting nerve block via reversible inhibition of sodium ion influx in nerve fibres.

Ropivacaine is a well tolerated regional anaesthetic effective for surgical anaesthesia as well as the relief of postoperative and labour pain. The efficacy of ropivacaine is similar to that of bupivacaine and levobupivacaine for peripheral nerve blocks and, although it may be slightly less potent than bupivacaine when administered epidurally or intrathecally, equi-effective doses have been established. Clinically adequate doses of ropivacaine appear to be associated with a lower incidence or grade of motor block than bupivacaine. Thus ropivacaine, with its efficacy, lower propensity for motor block and reduced potential for CNS toxicity and cardiotoxicity, appears to be an important option for regional anaesthesia and for the management of postoperative and labour pain.

Pharmacological Properties

Like other local anaesthetics, ropivacaine elicits nerve block via reversible inhibition of sodium ion influx in nerve fibres. The pKa of ropivacaine is similar to that of bupivacaine and levobupivacaine (≈8.2) but, unlike racemic bupivacaine, ropivacaine is the pure S(−)-enantiomer of propivacaine. It has lower lipid solubility and is less likely than bupivacaine to penetrate large, myelinated motor fibres. The degree of ropivacaine-induced sensory and motor block are dose- and age-dependent.

Despite the lower potency (based on minimum local anaesthetic concentrations) of ropivacaine than bupivacaine or levobupivacaine at lower doses, such as those used for epidural or intrathecal analgesia, ropivacaine has similar efficacy to these agents at higher doses such as those used for peripheral nerve block.

As with other local anaesthetics, ropivacaine has the potential to induce cardiovascular toxicity (e.g. arrhythmias and reduced myocardial conductivity and contractility) and CNS toxicity (e.g. seizures) at high plasma concentrations such as those occurring after large doses or inadvertent intravascular administration. It has a significantly higher threshold for cardiovascular and CNS toxicity than bupivacaine in animals and healthy volunteers.

Ropivacaine displays linear and dose-proportional pharmacokinetics up to 80mg (when administered intravenously). Absorption from the epidural space is complete and biphasic; the first phase (half-life [t;] 14 minutes) is followed by a slower second phase (t; 4.2 hours). Ropivacaine is extensively protein bound and crosses the placenta during epidural administration for Caesarean section. It is metabolised in the liver and excreted in the urine.

Therapeutic Efficacy

Randomised, double-blind, comparative clinical trials in adults have demonstrated the efficacy of ropivacaine in providing a profound sensory and motor block suitable for anaesthesia and a sensory/motor block profile suitable for postoperative or labour pain when administered by various routes (principally epidural or intrathecal administration and peripheral nerve block).

For epidurally administered surgical anaesthesia, ropivacaine and bupivacaine have similar efficacy, whereas with epidural administration for postoperative or labour analgesia, where doses required are lower than those needed for anaesthesia, ropivacaine has a shorter-lasting sensory block as well as a lower incidence/ degree of motor block than bupivacaine; equipotent doses have been established.

The duration of analgesia was less with ropivacaine than bupivacaine when administered intrathecally for anaesthesia or labour pain relief, but the duration of sensory block is still adequate for anaesthesia and the quicker regression of the motor block encourages mobilisation and recovery.

Peripheral nerve block for anaesthesia in orthopaedic surgery and for postoperative pain relief requires the use of relatively high doses of regional anaesthetic agents and the potency differences between ropivacaine and bupivacaine that were evident with epidural or intrathecal administration were not observed with this route of administration.

Ropivacaine and levobupivacaine are generally similarly effective for the above indications and routes of administration.

In children aged <12 years, ropivacaine provided effective postoperative pain relief when administered as a caudal or lumbar epidural injection, as a continuous epidural infusion or as a peripheral nerve block. The analgesic efficacy of ropivacaine was similar to that of bupivacaine and levobupivacaine; however, postoperative motor blockade was significantly less in ropivacaine than in bupivacaine recipients.

Tolerability

Ropivacaine is generally well tolerated regardless of the route of administration. Adverse events that occurred in ≥5% of patients in clinical trials who received ropivacaine 0.125–1% via various routes of administration for surgery, labour, Caesarean section, postoperative pain management, peripheral nerve block or local infiltration were hypotension (32%), nausea (17%), vomiting (7%), brady-cardia (6%) and headache (5%). Epidural administration of ropivacaine for surgery produced dose-dependent adverse events similar to those observed with equal doses of bupivacaine. Ropivacaine is generally well tolerated in the fetus or neonate following maternal epidural administration. The incidence of cardiovascular and CNS toxicity as a result of inadvertent intravascular injection of ropivacaine appears to be low.

The tolerability of ropivacaine in children (aged from 1 month to 15 years) appears to be at least similar to that of bupivacaine or levobupivacaine and is generally good, regardless of the route of administration. The most frequently occurring adverse events were nausea and vomiting.

1. Introduction

The reversible inhibition of nerve impulses produced by long-acting regional anaesthetic agents provide a prolonged sensory and motor block appropriate for anaesthesia in different types of surgery.[13] At lower doses, the sensory block is suitable for relief of postoperative, labour and other forms of acute pain, but the accompanying motor blockade serves no purpose and is generally undesirable.

Bupivacaine is a well established, long-acting regional anaesthetic that, like all amide-type anaesthetics, has been associated with cardiotoxicity when used in high concentrations or if accidentally administered intravascularly. Ropivacaine (Naropin®)1 is a long-acting regional anaesthetic that is structurally related to bupivacaine; unlike bupivacaine, which is a racemate, ropivacaine is a pure S(−)-enantiomer (of propivacaine) developed for the purposes of reducing the potential toxicity and improving the relative sensory and motor block profiles.

This review focuses on the use of ropivacaine in regional anaesthesia and acute pain management.

2. Pharmacodynamic Properties

Ropivacaine is a long-acting amide local anaesthetic agent belonging to the pipecoloxylidide group.[2] The pharmacodynamic properties of ropivacaine are similar to those of other amide local anaesthetics.[1,2] This section provides an overview of the mechanism of action and pharmacodynamic effects of ropivacaine, which are summarised in table I.
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Table I

Overview of the pharmacodynamic properties of ropivacaine (ROP)

2.1 Mechanism of Action

Like other local anaesthetics, ropivacaine elicits nerve block via reversible inhibition of sodium ion influx in nerve fibres (table I).[1,2] This action is potentiated by dose-dependent inhibition of potassium channels.[6]

The pKa of ropivacaine is similar to that of bupivacaine and levobupivacaine (≈8.2) but, unlike racemic bupivacaine, ropivacaine is the pure S(−)-enantiomer of propivacaine. Ropivacaine has a propyl group, whereas bupivacaine has a butyl group, on the amine portion of pipecoloxylidide, and ropivacaine is less lipophilic than bupivacaine and is less likely to penetrate large, myelinated motor fibres.[1] In isolated animal nerve studies, ropivacaine was more selective for Aδ and C (pain) than Aβ (motor) nerve fibres[4] and produced significantly less depression at motor fibres than bupivacaine (table I).[5]

The degree of ropivacaine-induced sensory and motor block is dose-[2527] and age-dependent.[28] With spinal anaesthesia, the upper level of sensory block increased significantly with age in patients aged 18–40, 41–60 and ≥61 years (T8, T6 and T4; p < 0.05 for all inter-group comparisons) and the maximum degree of motor block was significantly greater in patients aged ≥61 years than in patients aged 18–40 years (p = 0.001).[28] In paediatric patients aged 1–5 years, the minimum local anaesthetic concentration (MLAC) necessary for effective caudal analgesia was 0.11% (volume 1 mL/kg).[29] Time to onset and duration of sensory block are independent of ropivacaine dose.[25,30] The median effective dose (ED50) of ropivacaine for epidural labour analgesia in 66 parturients was 18.4mg (95% CI 13.4, 25.4), established using 0.1–0.5% solutions of ropivacaine.[25]

2.2 Relative Potency

MLAC (which is also defined as the median effective analgesic concentration or dose [EC50 or ED50, the concentration or dose required for efficacy in 50% of patients]) was originally developed to assess the potency of local anaesthetic agents during the first stage of labour and used the up-down sequential allocation technique.[31] The concentration/dose for administration to each patient is determined according to the response of the previous patient to a higher or lower concentration/dose, and the ED50 or EC50 can then be determined. Efficacy is assessed using 100mm visual analogue scale (VAS) pain scores, with a score of <10mm within 1 hour defined as effective.[31]

This concept has since been extended to assess local anaesthetic potency in other clinical settings. Full dose-response curves have not been determined for ropivacaine, levobupivacaine or bupivacaine, and there are inconsistencies in potency determinations when different doses, for example, the ED95 (a more clinically relevant dose), or the higher doses required for peripheral nerve block, are estimated.[13,31]

Although ropivacaine has similar potency to bupivacaine at doses higher than the ED50 for labour pain relief, such as clinically relevant doses for this application or those used for peripheral nerve block in patients undergoing knee or hip surgery,[14] ropivacaine has lower potency than bupivacaine[710] or levobupivacaine[9,1113] at lower doses, such as the ED50 for labour pain analgesia or other epidural or intrathecal administration[31] (table I).

In parturients who received intrathecal analgesia, MLAC (doses) were 3.64, 2.94 and 2.37mg for ropivacaine, levobupivacaine and bupivacaine, respectively, and a significantly greater number of bupivacaine and levobupivacaine recipients experienced motor block compared with ropivacaine recipients in this study (p ≤ 0.032).[9] Motor block responses to intrathecal local anaesthetics appear to parallel those of the analgesic responses; the ED50 for any degree of motor block within 5 minutes after intrathecal administration was also higher with ropivacaine than with levobupivacaine or bupivacaine (5.79 vs 4.83 and 3.44mg; p = 0.04).[13,32] However, despite its lower potency, ropivacaine has similar efficacy to bupivacaine and levobupivacaine at clinically relevant doses in surgical anesthesia (section 4.1).

The potency of ropivacaine may be altered by coadministration with other anaesthetics or analgesics. In parturients who received epidural analgesia for labour, the MLAC decreased from 0.097% with 20mL of plain ropivacaine to 0.035% with 20mL of ropivacaine plus clonidine 60μg (p < 0.02)[33] and from 0.13% with 20mL of plain ropivacaine to 0.09% with the addition of sufentanil 0.75 μg/mL (p < 0.00001).[34]

2.3 CNS and Cardiovascular Effects

As with other local anaesthetics, ropivacaine has the potential to induce CNS and cardiovascular toxicity at high plasma concentrations such as those occurring after large doses or inadvertent intravascular administration.[1,2] As well as blocking fast voltage-gated sodium and other ion channels on peripheral neural axons, local anaesthetics block those in the CNS and cardiovascular system.[35] CNS toxicity is associated with a two-stage process; an excitatory stage at lower concentrations (dizziness, visual and hearing disturbances, paraesthesia and generalised seizures) followed by CNS depression at higher concentrations. Cardiotoxicity results from both indirect cerebral effects (which, like CNS effects, are initially stimulatory then depressive) and direct effects on the myocardium (e.g. arrhythmias, reduced ventricular function and widening of the QRS interval during sinus rhythm).[35]

Ropivacaine is less lipophilic than bupivacaine (see section 2.1), and that, together with its stereoselective properties,[36] contributes to ropivacaine having a significantly higher threshold for cardiovascular and CNS toxicity than bupivacaine in animals[19,20,36,37] and healthy volunteers (table I).[15,16]

The lower lipophilicity of ropivacaine versus bupivacaine correlated with the lesser cardiodepressant effects of both ropivacaine isomers than of the bupivacaine isomers in animal studies.[36] Atrioventricular conduction time was longer with bupivacaine (and longer for the S[−]-isomer than for the R[+]-isomer even at the lowest concentration studied [0.5 μmol/L]) than with ropivacaine (no difference between isomers except at concentrations >30 μmol/L).[36] Ropivacaine (both isomers) had significantly smaller ionotropic effects than either isomer of bupivacaine at 5 and 10 μmol/L (p < 0.001 and p < 0.05), and similar depressant effects at 20–40 μmol/L to those of bupivacaine at 10 μmol/L.[36] The lower lipophilicity of ropivacaine also correlated with less depression of mitochondrial adenosine triphosphate (ATP) synthesis in fast metabolising cells. Intracellular ATP level may, according to in vitro and in vivo data, be involved with contractility and resuscitation of cardiomyocytes.[35] Resuscitation of dogs after induced ventricular dysrhythmias was possible in three of four animals that received ropivacaine and none that received bupivacaine.[35]

In healthy volunteers, the onset of CNS symptoms with intravenously administered ropivacaine occurred at a dose of 39.2mg[17] and the mean maximum tolerated dose of ropivacaine for CNS toxicity was 124mg (table I).[15,16] The majority of cardiovascular and CNS symptoms occurred at a plasma concentration of 1–2 μg/mL in one study in healthy volunteers.[16] In this study, the mean maximum tolerated dose for CNS and cardiovascular toxicity was significantly higher with ropivacaine than bupivacaine (124 vs 99mg; p < 0.01)[16] and the mean maximum tolerated unbound arterial plasma concentration was ≈2-fold higher with ropivacaine than bupivacaine (0.56 vs 0.30 mg/L; p < 0.001) [table I].[15] In healthy volunteers, the onset of CNS symptoms occurred with similar volumes of ropivacaine 0.5% and levobupivacaine 0.5% (equivalent to doses of 39.2 and 36.9mg; table I).[17]

CNS effects occurred sooner than cardiotoxic symptoms during an intravenous infusion of local anaesthetic (10 mg/min of ropivacaine or bupivacaine) in human volunteers and the infusion was stopped at this point. Significant changes in cardiac function (contractility, conduction time and QRS width) were already evident, and the increase in QRS width was significantly smaller with ropivacaine than with bupivacaine.[35] The effect of ropivacaine on peripheral vasculature is biphasic; it causes vasoconstriction at concentrations ≤0.5% and vasodilation at concentrations ≥1%.[38]

Although both ropivacaine and levobupivacaine were developed as less cardiotoxic alternatives to bupivacaine, it was levobupivacaine that resulted in the greatest inhibition (≈2-fold) of the human ether-à-go-go related gene (HERG) potassium channel compared with ropivacaine or bupivacaine;[39] excessive HERG channel block is responsible for acquired long QT syndrome, which can be associated with ventricular arrythmias.[39]

Following administration of ropivacaine 1.0% (15mL), the ropivacaine-induced decrease in mean arterial pressure was significantly greater (p = 0.0009) in patients aged ≥61 years than in patients aged 18–40 and 41–60 years, suggesting that cardiovascular symptoms may be related to age[28] (see also section 5.1). Pregnancy may affect the CNS toxicity potential of ropivacaine; the cumulative dose of ropivacaine required to produce convulsions was lower in pregnant than in nonpregnant ewes (0.019 vs 0.021 mmol/kg; p < 0.001).[37]

2.4 Other Effects

Ropivacaine has been shown to inhibit platelet aggregation in plasma at concentrations of 3.75 and 1.88 mg/mL (0.375% and 0.188%), which correspond to those which could occur in the epidural space during infusion.[40]

Ropivacaine appears to modulate the post-surgical acquired immune response; postoperative epidural ropivacaine 0.125% produced a smaller decrease in the number of circulating B and T cells than intravenous morphine (p < 0.05).[41] It also dose-dependently inhibited neutrophil production of reactive oxygen species (hydrogen peroxide, superoxide anion and hydroxyl radicals) in human neutrophils in vitro (p < 0.05 vs control) suggesting that, like lidocaine, ropivacaine may modify ischaemia-reperfusion injury.[42] Bupivacaine had no effect on neutrophil function in this study.[42]

Like other anaesthetics, ropivacaine has antibacterial activity in vitro, inhibiting the growth of Staphylococcus aureus,[43,44] Escherichia coli[43] and Pseudomonas aeruginosa.[44]

2.5 Neonatal Outcome

Ropivacaine does not appear to reduce uteroplacental blood flow in healthy pregnant women[1] and epidural ropivacaine has no effect on fetal oxygen saturation (table I).[24,45] Mean fetal pulse oxygen saturation values before and after administration of epidural ropivacaine 0.1% and sufentanil 10μg were 46% and 45%.[24] There was no association between the umbilical venous concentration of ropivacaine at delivery (mean 0.09 mg/L) and the neurological and adaptive capacity (NAC) score within the concentration range achieved in this study.[45]

3. Pharmacokinetic Properties

3.1 Absorption and Distribution

The plasma concentration of ropivacaine depends on the total dose administered and the route of administration (see table II), as well as the haemodynamic/circulatory condition of the patient and the vascularity of the administration site.[47]
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Table II

Summary of the pharmacokinetic properties of ropivacaine (ROP) in adults. Mean values presented unless stated otherwise

When ropivacaine was administered intravenously, its pharmacokinetics were linear and dose-proportional up to 80mg.[47] The absorption of ropivacaine 150mg from the epidural space is complete and biphasic; the mean half-life (t½) of the initial phase is approximately 14 minutes, followed by a slower phase with a mean absorption t½ of approximately 4.2 hours.[49]

Ropivacaine is extensively (94%) bound to plasma proteins, mainly α1-acid glycoprotein;[47] systemic toxicity (see section 2.3) is considered to be related to the unbound drug concentration. The total plasma concentration increase during continuous epidural infusion of ropivacaine[47,50] is caused by an increase in the degree of protein binding and subsequent decrease in clearance of ropivacaine (section 3.2).[50]

The change in protein binding is related to the increase in plasma α1-acid glycoprotein that accompanies the stress response to surgery.[47] During a 72-hour epidural infusion (10 mL/h) of ropivacaine 0.2% or 0.3% in patients undergoing hip or knee arthroplasty, total plasma concentrations of ropivacaine and its metabolite 2′, 6′-pipecoloxylidide increased markedly with time, but unbound plasma concentrations of ropivacaine became relatively stable after ≈24 hours (mean free plasma concentrations at steady state with infusion of 0.2% or 0.3% ropivacaine of 0.06 and 0.07 mg/mL).[50] Unbound concentrations of 2′, 6′-pipecoloxylidide increased less than total plasma concentrations of the metabolite.[50]

After intravascular administration, the volume of distribution of ropivacaine at steady state was 41L.[47]

Ropivacaine rapidly crosses the placenta during epidural administration for Caesarean section, resulting in near complete equilibrium of the free fraction of ropivicaine in the maternal and fetal circulation.[51] However, the total plasma concentration of ropivacaine was lower in the the fetal circulation than in the maternal circulation, reflecting the binding of ropivacaine to α1-acid glycoprotein which is more concentrated in maternal than in fetal plasma.

The administration of epinephrine with ropivacaine may improve analgesia by reducing vascular uptake of the local anaesthetic and by a direct agonist effect on spinal α2 receptors. The addition of epinephrine 5 μg/mL to epidural ropivacaine (initial dose 30mg followed by an infusion of 10 mg/h) resulted in reduced mean plasma ropivacaine concentrations (0.31 vs 0.17 mg/mL; p < 0.05) after 1 hour of infusion, but not at delivery, in women during labour (randomised study, n = 21) [see also section 4.3.1].[52]

3.2 Metabolism and Elimination

Ropivacaine is metabolised extensively in the liver, predominantly by aromatic hydroxylation to 3′-hydroxy-ropivacaine by cytochrome P450 (CYP) 1A2 and N-dealkylation to 2′, 6′-pipecoloxylidide by CYP3A4.[53] Other metabolites include 4′-hydroxy-ropivacaine and 2′-hydroxy-methyl-ropivacaine.[53]

After administration of a single intravenous dose of radiolabelled ropivacaine, 86% of the dose was excreted in the urine, mainly as 3′-hydroxy-ropivacaine (37% of the dose); the unchanged parent drug accounted for only 1% of the radioactivity.[54]

Following epidural administration, the rate-limiting step in the elimination of ropivacaine (section 3.1) is its slow absorption; the terminal elimination t½ was ≈4.2 hours.[49] The mean terminal elimination t½ of ropivacaine of 2.3 hours after bilateral intercostal blockade was probably a reflection of the more rapid absorption of ropivacaine from that site.[55]

In vivo, there is no evidence of metabolic racemisation of ropivacaine.[56]

3.3 In Children

The pharmacokinetics of ropivacaine have been studied in children and infants when the agent was administered as a single caudal[5761] or lumbar[62] epidural injection, a continuous epidural infusion[63] or an ilioinguinal-iliohypogastric nerve block[64] (see table III for dosages).
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Table III

Pharmacokinetic parameters in paediatric patients administered ropivacaine. Mean values presented unless otherwise stated

In children aged 1–12 years who were administered a single caudal injection, the pharmacokinetics of ropivacaine were similar to those in adults (table II).[5761] Peak plasma concentrations (Cmax) of total (table III) or free ropivacaine (0.024 mg/L[59]), after caudal or epidural injection or peripheral nerve block, were well below those associated with CNS toxicity in adults (section 2.3).[15]

The clearance of ropivacaine in neonates aged 0–3 months[65] was significantly reduced compared with that in infants aged 3–12 months[65] , and that in infants aged 3–11 months was significantly reduced compared with older infants and children (age 11–48 months)[62] in studies in which ropivacaine was administered as a caudal[65] or lumbar[62] epidural injection (table III). Moreover, the protein-binding capacity was reduced in neonates administered a single caudal injection of ropivacaine 2 mg/kg;[65] median free ropivacaine Cmax values (0.099 vs 0.038 mg/L; p = 0.0002) and median free fractions of ropivacaine (10% vs 5%; p = 0.01) were significantly higher in infants aged 0–3 months than in those aged 3–12 months.

The addition of epinephrine to caudal blocks with regional anesthetic agents is sometimes recommended to detect accidental intravascular injection.[66] The addition of epinephrine 5 μg/mL to a caudal block with 0.2% ropivacaine (1 mL/kg) in a randomised study in boys aged ≤4 years (n = 18) resulted in a lower Cmax (0.93 mg/L with plain ropivacaine vs 0.61 mg/L for ropivacaine with epinephrine; p = 0.05) and significantly delayed the time to Cmax (47 minutes with plain ropivacaine vs 124 minutes for ropivacaine with epinephrine; p = 0.003).[66]

3.4 Drug Interactions

When coadministered with ropivacaine, the CYP1A2 inhibitors fluvoxamine[67] and ciprofloxacin[68] significantly reduced the plasma clearance of ropivacaine by 77% (p < 0.001)[67] and 31% (p < 0.05).[68] This occurred via the inhibition of the CYP1A2-mediated formation of 3′-hydroxy-ropivacaine. The combination of erythromycin and fluvoxamine, compared with fluvoxamine alone, further reduced ropivacaine plasma clearance from 95 to 59 mL/min, although the difference was not statistically significant.[67] The CYP3A4 inhibitor ketoconazole reduced the in vivo clearance of ropivacaine by 15%;[69] however, this effect was not statistically or clinically significant. The CYP3A4 inhibitors clarithromycin and itraconazole had no significant effect on the pharmacokinetics of ropivacaine, although the formation of 2′, 6′ -pipecoloxylidide was significantly reduced.[70] Rifampicin (rifampin) [an inducer of CYP3A4] increased the plasma clearance of ropivacaine by 93% in healthy volunteers (p < 0.001).[71]

4. Therapeutic Efficacy

Numerous clinical trials have evaluated the efficacy of ropivacaine for surgical anaesthesia and postoperative and labour pain (in adults), and for postoperative pain (in children). Ropivacaine has been compared primarily with bupivacaine or levobupivacaine. The effect of the addition of opioids (sufentanil or fentanyl) or clonidine has also been investigated.

Results reported in this section are from larger, well designed, randomised, double-blind, multicentre trials where possible, but where data are lacking, reports of smaller, single-blind or open-label and/or single-centre trials are included. All subsections, other than section 4.2.4, describe trials in adult patients.

Enrolled patients belonged to the American Society of Anesthesiologists (ASA) classification I–III (but the status of women in labour or undergoing elective Caesarean section was generally I–II), and treatment groups were well matched for the demographic criteria appropriate for the procedure or indication. Endpoints were generally associated with the characteristics of the sensory or motor block, but specific outcomes are discussed in each section. Quality of anaesthesia was generally related to the adequacy of the analgesia (as assessed by the requirement for further analgesic administration) and muscle relaxation (as estimated clinically), or the measure of satisfaction with the block as provided by the patient or investigator. The sensory block for surgical anaesthesia was assessed by regional pinprick or temperature testing, and that for postoperative pain was generally assessed by patient-reported scores reflected on a 10 or 100mm VAS, 0 = no pain to 10 or 100 = worst pain imaginable). The degree of motor block was generally assessed according to the modified Bromage scale (0 = no motor block to 3 = complete block), unless otherwise stated.

4.1 Surgical Anaesthesia

Clinical trials indicate that ropivacaine is an effective regional anaesthetic when administered via a variety of routes (sections 4.1.1 to 4.1.5). Endpoints in trials in this indication included time to onset, and duration, of sensory and motor blocks, and quality of anaesthesia (represented by the patient- and/or surgeon/anaesthesiologist’s assessment of satisfaction with the block and/or the incidence of the perioperative requirement for fentanyl).

4.1.1 Epidural Administration

Epidural ropivacaine, administered primarily in the lumbar region, has efficacy as an anaesthetic for a variety of surgical procedures. The majority of studies of epidural ropivacaine are in Caesarean section and although the drug has also been investigated as an anaesthetic agent for other abdominal or gynaecological procedures, as well as orthopaedic and vascular surgery, the main use of epidural ropivacaine in these latter procedures is for postoperative pain relief (section 4.2). All trials reviewed in this section are randomised, double-blind (except for one trial which was single-blind[72]) and multicentre. Where stated, the primary efficacy endpoint was the onset time of sensory block.[73,74]

Caesarean Section
Clinical trials of epidural anaesthesia for elective Caesarean section indicate that ropivacaine (0.5%[75] or 0.75%[76]) provides a clinically similar onset of sensory and motor block to that of bupivacaine 0.5% (table IV).[75,76]
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Table IV

Efficacy of epidural ropivacaine (ROP) versus bupivacaine (BUP) or levobupivacaine (LEV), or with the addition of sufentanil (SUF), for surgical anaesthesia. Patients were undergoing elective Caesarean section, or hip or lower limb surgery in randomised, double-blind (except for one trial which was single-blind[72]), multicentre trials

The median duration of analgesia within dermatomes relevant for surgery (T6–S3) was 1.7–4.2 hours for ropivacaine and 1.8–4.4 hours for bupivacaine but the median duration of complete motor block was significantly longer with bupivacaine than with ropivacaine (2.5 vs 0.9 hours, p < 0.05).[75] Similar proportions of ropivacaine and bupivacaine recipients in two studies had complete motor block (17% and 13%,[75] and 55% and 41%[76]). Supplementary analgesia was required by similar proportions of ropivacaine or bupivacaine recipients (21% and 28%,[76] and 30% and 23%[75]).

In further trials, the addition of sufentanil 20μg improved the anaesthesia achieved with 13mL ropivacaine 0.75%,[74] but not that of 12mL ropivacaine 1%.[73] The addition of sufentanil 10 or 20μg to 13mL of ropivacaine 0.75% significantly reduced the time to onset of sensory block (primary endpoint; p < 0.001) [table IV]and the proportion of patients requiring supplementary analgesia (5% and 10% vs 45%; p = 0.005 and 0.015), but pain relief at delivery was significantly better only in the sufentanil 20μg plus ropivacaine group compared with the sufentanil 10μg plus ropivacaine group (VAS score 9 vs 32mm; p = 0.028).[74] In terms of these endpoints, the addition of sufentanil 10 or 20μg to 12mL ropivacaine 1% made no significant difference to the anaesthesia achieved; although VAS scores at delivery were 18mm for ropivacaine alone, 1mm for ropivacaine plus sufentanil 10μg and 6mm for ropivacaine plus sufentanil 20μg, there were no significant differences between groups.[73] This may reflect the fact that the addition of an opioid improves the anesthetic block quality only when the dose of local anesthetic is suboptimal.

In these trials,[7376] neonatal outcomes, as assessed by Apgar and NAC scores, were similar among ropivacaine and bupivacaine groups (see also section 5.3).

Hip or Lower Limb Surgery

In patients undergoing lumbar epidural anaesthesia for lower limb surgery, ropivacaine provided a similar anaesthetic profile (with regard to onset of analgesia or anaesthesia and onset of motor block) to those of levobupivacaine[72] or bupivacaine[77] (table IV). A 20mL dose of ropivacaine 0.5% or bupivacaine 0.5% also resulted in a median duration of T10 sensory block of 3.5 versus 3.4 hours, and 15% versus 18% of patients with complete motor block.[77] The incidence of satisfactory sensory and motor blocks was considered relatively low in both groups (78% and 78% satisfactory blocks with ropivacaine vs 62% and 71% with bupivacaine).[77] As expected, the use of a greater concentration of ropivacaine (1%) than of bupivacaine (0.5%) in patients undergoing hip surgery, resulted in a significantly longer duration of T10 sensory block (5.9 vs 4.3 hours; p = 0.02), a significantly higher proportion of patients with investigator-related satisfactory analgesia (86% vs 68%; p = 0.002) and a significantly longer mean duration of complete motor block (3.4 vs 2.1 hours; p < 0.05 [table IV]) with ropivacaine than with bupivacaine.[78]

The maximum spread of motor block with ropivacaine or bupivacaine was T4 vs T3,[76] T5 vs T4[75] and T6 for both.[77]

No significant differences in results emerged for patients receiving 15mL of ropivacaine 0.75% or levobupivacaine 0.5%; the mean time to readiness for surgery was 25 versus 29 minutes (table IV), and time to complete resolution of sensory and motor block was 3.4 vs 3.1 hours and 1.6 vs 1.8 hours (table IV).[72]

4.1.2 Intrathecal Administration

Intrathecal anaesthesia is useful for ‘ambulatory anaesthesia’, requirements of which are a sensory and motor block of adequate duration for the procedure and a fast regression of the motor block to assist mobilisation. The majority of data relating to the efficacy of intrathecal ropivacaine for regional anaesthesia to date are derived from studies of patients undergoing Caesarean section or orthopaedic surgery. Ropivacaine has also shown efficacy in several trials (n = 40–72) in other types of surgery (perineal surgery,[79] inguinal herniorrhaphy,[80] other lower abdominal or gynaecological procedures[81] and anorectal surgery[82]), but not all of these trials are discussed further. All trials included in this section are randomised, double-blind studies. Primary endpoints were generally not defined, but where stated included recovery from motor block[83,84] and success rate of anaesthesia (based on the requirement for rescue analgesia during surgery).[85]

Single doses of 2–4mL of 0.5%–2% solutions of ropivacaine were generally used; intrathecal ropivacaine has been shown to be less potent than bupivacaine (section 2.2) and is, therefore, generally administered at higher doses than bupivacaine.

Hyperbaric (i.e. relative to cerebrospinal fluid) solutions of ropivacaine (i.e. with the addition of glucose 5–8.3%) have been compared with isobaric solutions of the drug for intrathecal anaesthesia for a variety of procedures[79,83,86] and generally resulted in improved anaesthesia (faster onset of anaesthesia and faster recovery from the blocks) [table V]. Although hyperbaric solutions of ropivacaine appear to provide a more predictable block, the spread and duration of the block still varies markedly.[79] Hyperbaric ropivacaine solutions are not commercially available.
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Table V

Efficacy of hyperbaric (with glucose [GLU]) versus plain solutions of ropivacaine (ROP). Data are from randomised, double-blind trials in patients (pts) undergoing intrathecal anaesthesia for Caesarean section,[86] lower limb[83] or perineal[79] surgery. Mean[86] or median[79,83] values reported. Note that hyperbaric ROP solutions are not commercially available

Caesarean Section
In comparative clinical trials in patients undergoing elective Caesarean section, doses of intrathecal ropivacaine ranged from 12 to 20mg (table VI),[85,87,88] and the anaesthesia provided compared favourably with that of other similarly administered local anaesthetics. Ropivacaine 12mg, bupivacaine 8mg and levobupivacaine 8mg (all with sufentanil 2.5μg) were effective (sensory block to at least T4 and no supplemental epidural analgesia required) in 87%, 97% and 80% of parturients, respectively.[85] Times to onset of analgesia were generally similar among agents,[85,87,88] and the time to recovery from sensory and motor blocks with ropivacaine was similar to that with levobupivacaine,[85] but significantly shorter than that with bupivacaine[85,88] (table VI).
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Table VI

Comparative efficacy of intrathecal ropivacaine (ROP). Randomised, double-blind, single-centre trials of ROP, bupivacaine (BUP) and levobupivacaine (LEV) in patients (pts) undergoing anaesthesia for elective Caesarean section or lower limb surgery. Where stated, mean[85,87,88] or median[84,89] values reported

It is well documented that the coadministration of opioids reduces the total dose of local anaesthetic agent required for anaesthesia. In women undergoing elective Caesarean section (n = 59), the administration of fentanyl 10μg with 18mg of ropivacaine (as a hyperbaric solution) significantly prolonged the duration of complete (2.4 vs 1.7 hours; p < 0.001) and effective (3.45 vs 2.3 hours; p < 0.001) analgesia compared with patients receiving no fentanyl, but did not prolong the duration of the motor block.[91]

Lower Limb Surgery

For anaesthesia in knee arthroscopy, the durations of both sensory and motor blocks with ropivacaine 8 or 10mg were significantly shorter than that with bupivacaine 8mg or the other doses of ropivacaine (12 or 14mg) [table VI].[90] In addition, the quality of the intra-operative anaesthesia was significantly lower (p < 0.05) with ropivacaine 8mg versus comparators (with respect to the surgeon’s assessment of motor blockade) and for ropivacaine 8 and 10mg versus comparators (with respect to the patient’s assessment of intraoperative analgesia).[90] Moreover, in another trial (in which patients underwent lower limb orthopaedic surgery or varicotomy),[84] because the duration of sensory block with ropivacaine 15mg was similar to that with bupivacaine 10mg, and the motor block was significantly shorter, it was suggested that on a mg-for-mg basis the potency of ropivacaine relative to bupivacaine is two-thirds with regard to the sensory block and half with regard to the motor block (table VI). In knee arthrospcopy, ropivacaine 7.5mg provided a similar time to onset of anaesthesia to that of levobupivacaine 7.5mg, but the ropivacaine group had significantly faster recovery times from the blocks than the levobupivacaine group[89] (table VI).

The addition of clonidine 15μg to ropivacaine 8mg for intrathecal anaesthesia for knee arthroscopy (n = 120) significantly (p < 0.05) improved the subjectively assessed quality of anaesthesia (surgeon-assessed intraoperative motor blockade and patient-assessed intraoperative analgesia) compared with ropivacaine alone, without affecting early postoperative mobilisation (times to recovery from the blocks).[92]

4.1.3 Peripheral Nerve Block for Upper Limb Anaesthesia

Peripheral nerve block is employed principally for anaesthesia for orthopaedic surgery, and onset and spread of local anaesthetic is influenced by the site of injection.[93] Design details of trials in patients undergoing peripheral nerve block with ropivacaine for upper limb surgery are summarised in table VII. Primary endpoints were not specified; outcomes were generally associated with the onset and duration of blocks, and, in some trials, the quality of anaesthesia. Quality was determined by patient- or surgeon/anaesthesiologist/investigator-assessed satisfaction with anaesthesia[9498] and/or the need for supplemental analgesia[98] or a general anaesthetic.[98]
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Table VII

Comparative efficacy of ropivacaine (ROP), bupivacaine (BUP) and levobupivacaine (LEV) for brachial plexus anaesthesia in patients (pts) undergoing upper limb surgery. Results of randomised, double-blind, single-[93,95,98100] or multicentre[94,96,97,101] trials. Mean values reported unless otherwise stated

Axillary Brachial Plexus Block

The long-acting sensory and motor block provided by ropivacaine 0.5% or 0.75% for axillary brachial plexus blocks for hand or arm surgery compared favourably with bupivacaine 0.5%[97,98,101] or levobupivacaine 0.5%[95,98] (32–45mL bolus doses) [table VII], and the quality of regional anaesthesia was at least similar to that of bupivacaine 0.5% or levobupivacaine 0.5%.

The onset of anaesthesia with ropivacaine was generally similar to that with bupivacaine,[97,98,101] but in one trial,[97,98,100,101] patients receiving ropivacaine were considered ready for surgery (based on sensory and motor blockade) before those receiving bupivacaine (table VII). In the study comparing the axillary brachial plexus block characteristics of ropivacaine, bupivacaine and levobupivacaine,[98] complete anaesthesia at 45 minutes was significantly (p < 0.01) more frequent in ropivacaine recipients than in levobupivacaine or bupivacaine recipients. The duration of analgesia was generally similar for ropivacaine and bupivacaine[97] and was also similar for ropivacaine and levobupivacaine in one study,[98] but significantly shorter with ropivacaine in another (table VII).[95]

The duration of motor block with ropivacaine (0.5% or 0.75%) was generally similar to that with bupivacaine,[97,98,101] although significantly shorter in one study[99] (table VII). The duration of motor block was also significantly shorter with ropivacaine than with levobupivacaine,[95] although the block (which included both sensory and motor blocks) was similar for ropivacaine, bupivacaine and levobupivacaine in one study[98] (table VII).

Patients and/or the surgeon/anaesthesiologst reported their satisfaction with the blocks with ropivacaine, bupivacaine and levobupivacaine to be similar in these trials.[95,97,98,100,101]

In a randomised, double-blind, placebo-controlled study in 50 patients undergoing axillary brachial plexus block, the addition of clonidine 150μg to 40mL of ropivacaine 0.75% provided an additional 4 hours of analgesia, as well as a further 2.4 hours of anaesthesia and 2.8 hours of motor block (all p < 0.01 vs ropivacaine alone).[102] Another randomised, double-blind trial of these doses of ropivacaine and clonidine (n = 20 per treatment group) did not demonstrate any difference in onset of sensory block or duration of motor block (11.7 hours with ropivacaine and 11.9 hours with ropivacaine plus clonidine) when clonidine was coadministered with ropivacaine.[103]

Interscalenic and Subclavian Perivascular Brachial Plexus Block

Ropivacaine 0.5% or 0.75%, bupivacaine 0.5% or levobupivacaine 0.5% administered as an interscalenic or subclavian perivascular brachial plexus block (volume 30mL) provided similar anaesthetic profiles with respect to one or more features that included onset, duration and quality of the surgical block[93,94,96,99] (table VII).

The onset of the sensory block or anaesthesia and the duration of analgesia was similar for ropivacaine 0.5% or 0.75% and bupivacaine 0.5%, when each was administered as an interscalenic block (table VII).[93,99] Overall, in the study comparing ropivacaine 0.75% with bupivacaine 0.5%, 84% of blocks in each group were successful.[93]

Compared with levobupivacaine 0.5%, ropivacaine 0.5% provided a similar onset (table VII) and quality of anaesthesia (as assessed by patient satisfaction or proportion of patients requiring perioperative fentanyl).[94]

Ropivacaine and bupivacaine had similar anaesthetic profiles when administered as subclavian perivascular blocks for upper limb surgery (table VII). In addition, the quality of anaesthesia was deemed similar among groups; 65–76% of patients in treatment groups had satisfactory or excellent investigator-assessed pain relief or muscle relaxation during surgery.[96]

4.1.4 Peripheral Nerve Block for Lower Limb Anaesthesia

Ropivacaine has been compared with mepivacaine, bupivacaine and levobupivacaine in randomised, double-blind trials of sciatic and combined femoral and sciatic nerve block for knee, ankle and/or foot surgery (trial design details and results summarised in table VIII). Primary endpoints were not specifically defined, but endpoints related to the onset and regression of the sensory and motor blocks provided, and the quality of the block.
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Table VIII

Comparative efficacy of ropivacaine (ROP), bupivacaine (BUP), levobupivacaine (LEV) and mepivacaine (MEP) for sciatic or combined femoral and sciatic[104,105] nerve block in patients (pts) undergoing lower limb surgery. Results of randomised, double-blind, single-[104] or multicentre[105,106] trials. Mean values reported unless otherwise stated

Ropivacaine 0.75% or 1% (dose 225mg) had a similar onset of analgesia but a significantly longer duration of sensory or motor block than 25mL mepivacaine 2%[104,105] and 20mL ropivacaine 0.5% had similar onset and duration of sensory and motor blocks to that with 20mL levobupivacaine 0.5%[106] (table VIII).

Ropivacaine 0.75% (25mL) had a significantly shorter onset of sensory and motor block than 25mL bupivacaine 0.5%, and although ropivacaine had a significantly shorter duration of sensory block, the two agents showed a similar duration of motor block (table VIII).[104]

The quality of the block was similar for ropivacaine and mepivacaine (the block was considered adequate in 85–91% of patients in each treatment group).[105] For ropivacaine and levobupivacaine, two patients in each group required supplementary ankle block before surgery, as well as supplementation with intravenous fentanyl; of these patients, one in the ropivacaine group and two in the levobupivacaine group required general anaesthesia to complete surgery.[106] In the trial comparing ropivacaine with bupivacaine and mepivacaine, two patients receiving bupivacaine and one receiving mepivacaine demonstrated unsatisfactory blocks (required supplemental intravenous analgesia and sedation) compared to no patients in the ropivacaine group; no general anaesthesia was required and there was no significant difference between groups.[104]

4.1.5 Dental and Peribulbar Anaesthesia

Dental Anaesthesia

The potential of ropivacaine as a dental anaesthetic was examined in two small (n = 30[107] and 40[108]), randomised, double-blind studies in healthy volunteers. Subjects received maxillary infiltration with 0.5 or 1mL of ropivacaine 0.2%, 0.5% or 0.75%,[107] or 1.8mL of ropivacaine 0.5% with or without epinephrine 1 : 200 000 or 1.8mL of bupivacaine 0.5% with epinephrine 1 : 200 000.[108] In the smaller study, all subjects received mandibular nerve block with 1.8mL of ropivacaine 0.2%, 0.5% or 0.75% subsequent to the maxillary infiltration.[107]

Maxillary infiltration with ropivacaine 0.5% was considered successful in one study (68% of plain ropivacaine 0.5% recipients had no response when tested with the maximum output of the electric pulp tester [for tooth vitality] on two consecutive occasions)[108] but ropivacaine 0.2–0.75% did not provide adequate dental anaesthesia in the other study (17% of subjects achieved onset of pulpal anaesthesia within 10 minutes of administration).[107] Maxillary infiltration with plain ropivacaine was associated with a significantly shorter onset (1.73 vs 3.0 minutes; p < 0.05) and duration (13 vs 33 minutes; p < 0.05) of pulpal anaesthesia than ropivacaine plus epinephrine; the duration of pulpal anaesthesia with bupivacaine plus epinephrine was also 33 minutes.[108] Successful anaesthesia was achieved in a similar proportion of patients receiving maxillary infiltration with ropivacaine plus epinephrine (75%) and bupivacaine plus epinephrine (80%).[108]

Mandibular nerve block with ropivacaine 0.75% was effective for dental anaesthesia, providing pinprick and pulpal anaesthesia in 8 and 7 out of 10 subjects.[107] Median anaesthesia onset times for pin prick and pulpal anaesthesia were 6 and 8 minutes, and anaesthesia durations were 5.9 and 8 hours.[107]

Ocular Anaesthesia
The efficacy of ropivacaine for ocular anaesthesia (peribulbar block) was compared with bupivacaine in several trials in patients undergoing cataract or intraocular surgery (see table IX for study design details).[109116] Hyaluronidase was administered with the local anaesthetic to promote the spread of anaesthesia and reduce intraocular pressure[109,114,115] and lidocaine 2% was administered with ropivacaine and/or bupivacaine in some trials.[110113,115,116] Supplementary anaesthetic doses (≤5mL) were administered after 5–12 minutes if sensory anaesthesia or akinesia was considered to be insufficient for surgery. Where specified, primary endpoints included the rate of onset of globe and lid akinesia[109,112] and the quality of ocular akinesia (the proportion of patients with a successful block, which was defined as an ocular mobility score ≤4).[112]
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Table IX

Comparative efficacy of ropivacaine (ROP) and bupivacaine (BUP) for peribulbar anaesthesia. Randomised, double-blind trials in patients (pts) undergoing cataract or intraocular surgery.

Peribulbar injection with 5–10mL of ropivacaine 0.5–1% (alone or with lidocaine 2%) appears to provide sensory anaesthesia that is at least similar in quality to that achieved with 5–10mL of bupivacaine 0.5% or 0.75% (alone or with lidocaine 2%) [table IX].[109,111,115] In general, numerically fewer ropivacaine than bupivacaine recipients seemed to require a supplementary dose of anaesthetic at 10 minutes after the initial dose because of insufficient sensory anaesthesia or akinesia,[109,113116] although the between-group difference was significant in only one study (table IX).[111] Perioperative pain was reported by similarly few patients in each treatment group (table IX).[109111]

Ropivacaine and bupivacaine generally appear to have similar effects on ocular and eyelid movement, although a trend is difficult to establish since the studies summarised in table IX used different scoring systems to measure ocular and eyelid akinesia.[110112,114,115] Compared with bupivacaine recipients, a greater number of ropivacaine recipients achieved eyelid akinesia at 2, 6 and 8 minutes after injection in one study (p ≤ 0.047)[116] and at 2, 8, 10 and 20 minutes after injection in another study (p ≤ 0.044).[109] In the same trial, significantly more ropivacaine than bupivacaine recipients had complete ocular akinesia at 2 minutes after injection (52% vs 39%; p = 0.039).[109] Eyelid akinesia at 2, 4, 6, 8 and 10 minutes after injection was significantly better with ropivacaine plus lidocaine than with plain ropivacaine in one study (p ≤ 0.027).[113] However, there were no between-group differences in the rate of onset or degree of akinesia achieved with ropivacaine and bupivacaine plus lidocaine in another study.[112] Similar proportions of patients had akinesia scores ≤4 at 6 minutes in this study (60% with ropivacaine vs 55% with bupivacaine plus lidocaine).[112]

Ropivacaine provided significantly lower ocular akinesia scores than lidocaine plus epinephrine at 6, 8 and 10 minutes after peribulbar injection in a randomised, double-blind study in 50 patients undergoing cataract surgery who received 7–10mL of ropivacaine 1% or 7–10mL of lidocaine 2% plus epinephrine 1 : 200 000 (p ≤ 0.026).[117] The duration of motor block was significantly longer with ropivacaine than with lidocaine plus epinephrine in this study (294 vs 143 minutes; p < 0.001).[117]

4.2 Management of Postoperative Pain

Lower doses of local anaesthetic are generally required for postoperative pain relief than for anaesthesia. Major efficacy outcomes in clinical trials assessing the efficacy of ropivacaine-containing regimens for the management of postoperative pain included those associated with pain relief (VAS scores, consumption of supplementary analgesia, total dose of local anaesthetic administered) and the incidence of and recovery from motor block.

4.2.1 Epidural Administration

Ropivacaine is administered epidurally (via the lumbar or thoracic route) for postoperative pain following abdominal (upper or lower, including gynaecological surgery), orthopaedic and other surgery. Primary endpoints, where specifically stated, included pain on coughing,[120] VAS AUC[123] and consumption of rescue medication;[124] other endpoints included pain scores at rest or on coughing or mobilisation, duration of analgesia and/or motor block and degree of motor block.

Following Abdominal Surgery
The efficacy of epidural ropivacaine has been compared with intravenous morphine, epidural bupivacaine, and ropivacaine in combination with fentanyl; design details of the trials reviewed in this section are included in table X. In comparative studies reviewed in this section, treatment with ropivacaine with or without opioids was initiated or continued after surgery for a period of up to 96 hours as a continuous infusion (generally 8–10 mL/h)[119,121] or via a patient-controlled device (for patient-controlled epidural anaesthesia [PCEA]), with[118,120] or without[122] background infusions.
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Table X

Efficacy of epidural ropivacaine (ROP) for postoperative pain following major abdominal surgery (with thoracic epidural anaesthesia)

Ropivacaine, with or without morphine, was more effective at relieving postoperative pain than intravenous morphine alone.[119] Although the range of pain scores was similar among groups (table X), the area under the pain-time curve was significantly less for the ropivacaine groups (p < 0.02), and ropivacaine and ropivacaine plus morphine recipients consumed a significantly lower median total dose of morphine than patients receiving morphine alone (p < 0.01 and p < 0.05).[119]

Epidural ropivacaine administered by PCEA in combination with sufentanil[118,120] or morphine[122] generally provided similar postoperative pain relief to bupivacaine administered in combination with these opioids, as assessed by VAS pain scores, although in one study, VAS pain scores during coughing were significantly higher in recipients of ropivacaine with or without sufentanil than in recipients of bupivacaine plus sufentanil in the first three postoperative days[120] (table X).

The number of patients requiring rescue analgesia (one to three doses of tramadol) was similar among recipients of ropivacaine or bupivacaine (plus morphine),[122] but the consumption of ketoprofen on the first postoperative day was significantly more in ropivacaine plus sufentanil recipients than in bupivacaine plus sufentanil recipients, and (predictably) more in patients receiving ropivacaine alone compared with ropivacaine or bupivacaine with sufentanil (p < 0.05 for all comparisons).[120]

Local anaesthetic consumption was significantly lower in patients receiving bupivacaine 0.125% plus sufentanil than in those receiving ropivacaine 0.125% plus sufentanil during the first 3 postoperative days (146–176 vs 232–243 mg/day; p < 0.05) [consumption ratio 0.61–0.75].[120] This is in agreement with studies showing that epidural ropivacaine is less potent than bupivacaine (section 2.1). However, consumption ratios were ≈1 for ropivacaine 0.1% : bupivacaine 0.1% and ≈1.3 for ropivacaine 0.2% : bupivacaine 0.2% for postoperative hours 36–60 in a study in which patients received concomitant morphine.[122] Increasing the ropivacaine concentration did not improve analgesic efficacy, as the total dose of local anaesthetic consumed was significantly higher with ropivacaine 0.2% than with ropivacaine 0.1% (645 vs 354mg; p < 0.05).[122]

Ropivacaine was associated with faster recovery from motor block than bupivacaine in one study[118] but not in two others[120,122] (table X).

The addition of fentanyl 4 μg/mL to ropivacaine 0.2% resulted in significantly better analgesia; VAS pain scores were significantly lower at rest and during coughing with the combination regimen (table X).[121] Ropivacaine 0.2% plus fentanyl 4 μg/mL was also superior to ropivacaine 0.2% plus fentanyl 1 μg/mL in terms of VAS pain scores at rest (table X). No motor block was seen in >90% of patients within 24 hours of infusion.

Following Orthopaedic Surgery
Most data relating to ropivacaine administered epidurally for postoperative pain management in this surgical discipline are derived from studies in patients undergoing hip[123,125127] or knee[124,128,129] arthroplasty and this section focuses on studies in >50 evaluable patients (see table XI for details of trial design).
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Table XI

Efficacy of epidural ropivacaine (ROP) for postoperative pain following hip[123,125127] or knee[124,128,129] arthroplasty

Patients who had undergone hip arthroplasty had significantly more effective pain relief with epidural ropivacaine than with intravenous morphine (primary endpoint) and supplementary analgesia was administered to numerically more patients in the morphine group than in the ropivacaine group (table XI).[123]

In patients who had undergone knee arthroplasty,[128] pain relief (as assessed by a summary measure of the AUC) with epidural ropivacaine 0.2% was not as effective as bupivacaine 0.2% (table XI), and although there were no significant differences between groups for the number of patients recording VAS scores >30mm at rest, more patients in the ropivacaine group than in the bupivacaine group reported VAS scores >30mm for pain on movement between 8 and 24 hours post surgery. However, in another study comparing ropivacaine with bupivacaine in patients who had undergone hip arthroplasty,[127] the significantly lower incidence of motor block in ropivacaine recipients was accompanied by similarly effective pain relief among treatment groups (table XI) and greater patient satisfaction.[127]

In the only study comparing epidural ropivacaine with levobupivacaine (for postoperative pain relief in patients who underwent hip arthroplasty; study published as an abstract),[125] both groups experienced a similar duration of motor blockade (table XI) and similar pain relief (as assessed by pain scores and consumption of morphine); however, at or higher than the T10 dermatome, the duration of sensory block was shorter in the ropivacaine group than in the levobupivacaine group (4 vs 7.2 hours; p < 0.05).[125]

The addition of sufentanil to epidural ropivacaine for postoperative pain in patients who had undergone knee arthroplasty improved pain relief as assessed by the proportion of patients recording VAS scores ≤30mm at 24 hours post-surgery (table XI).[129]

The addition of clonidine to an epidural infusion of ropivacaine for postoperative pain significantly reduced supplementary analgesic requirements compared with those of patients not receiving clonidine.[124,126] Clonidine coadministered with ropivacaine plus fentanyl significantly (p < 0.05) reduced the median total dose of intramuscular oxycodone administered on request compared to that administered in the group receiving ropivacaine and fentanyl alone (primary endpoint; table XI)[124] and, in another study, the ropivacaine plus clonidine groups (two groups distinguished by intra-operative anaesthetic agent used) required a significantly lower cumulative 24-hour dose of intravenous morphine than the ropivacaine-only group (secondary endpoint; table XI).[126]

4.2.2 Peripheral Nerve Block

Following Upper Limb Surgery
Design details of clinical trials of patient-controlled interscalene analgesia for postoperative pain relief initiated 4–6 hours after an interscalenic brachial plexus block for shoulder surgery, as well as assessments of pain relief (usual endpoint) are presented in table XII. Primary endpoints were generally not specifically stated, although hand strength (on the operated side) after major open shoulder surgery was the primary endpoint in one trial.[130]
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Table XII

Efficacy of interscalenic brachial plexus block with ropivacaine (ROP) vs other local anaesthetics or intravenous (IV) nicomorphine (NIC) for postoperative pain following upper limb surgery. Study drugs administered as infusions with bolus doses on demand

Ropivacaine provided significantly more effective pain relief than nicomorphine, as assessed by VAS scores (table XII).[131]

There was similar pain relief with ropivacaine and bupivacaine (table XII),[130,132] although hand strength returned more quickly and there was less paraesthesia of the fingers in patients receiving ropivacaine than those receiving bupivacaine.[130] At 24 hours after the block, hand strength (primary endpoint) was reduced by 48% in ropivacaine recipients and 66% in bupivacaine recipients (p < 0.05), and at 6 hours after discontinuation of the infusion, hand strength was fully restored in the ropivacaine group but was still decreased by 25% in the bupivacaine group (p < 0.05).[130]

Compared with levobupivacaine recipients,[94] ropivacaine recipients required a significantly greater volume of local anaesthetic solution for the control of postoperative pain (table XII) and the ratio of bolus doses requested to doses received was 0.7 with ropivacaine and 0.8 with levobupivacaine (p = 0.004). No difference in the overall profile of the motor block for the two groups was detected.[94]

Although the addition of clonidine has been shown to prolong analgesia provided by a single-dose sciatic-femoral nerve block for postoperative pain (section 4.2.2)[133] or by an epidural infusion for labour pain relief (section 4.3.1),[134] clonidine 1 or 2 μg/kg added to a continuous interscalene (n = 20)[135] or infraclavicular (n = 34)[136] perineural infusion of 0.2% ropivacaine did not appear to improve or prolong analgesia in two small randomised, double-blind studies in patients undergoing shoulder surgery.

Following Lower Limb Surgery
Design details of trials in patients receiving peripheral nerve block with ropivacaine for anaesthesia for lower limb surgery are summarised in section 4.1.4 and table XIII. Primary endpoints were not specified.
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Table XIII

Efficacy of sciatic or combined femoral-sciatic nerve block with ropivacaine (ROP) for postoperative pain following lower limb (knee arthroplasty[137] or foot/ankle[104106,138]) surgery. Study drugs administered as bolus doses (or infusion[137])

Patients who received a sciatic or combined femoral and sciatic nerve block (bolus[104106] or continuous infusion[138]) with ropivacaine to facilitate foot/ankle[104106,138] surgery had similar[104] or better[105] postoperative pain relief than recipients of mepivacaine (and a longer duration of analgesia, section 4.1.4) and had similar pain relief to recipients of levobupivacaine[106,138] (table XIII).

For patients undergoing knee arthroplasty who received similar concentrations and bolus doses of ropivacaine or bupivacaine (2 mg/kg of 0.75% as a combined femoral-sciatic block) there was significantly greater pain relief (as assessed by VAS scores) in bupivacaine recipients than in ropivacaine recipients.[137] There was similar pain relief among groups when the dose of ropivacaine was greater than that of bupivacaine (25mL of ropivacaine 0.75% or 25mL of bupivacaine 0.5%)[104] [table XIII].

A small, randomised, double-blind trial (n = 30)[133] in patients undergoing femoral-sciatic nerve block for foot surgery showed that clonidine 1 μg/kg added to 30mL ropivacaine 0.75% resulted in a 3-hour delay in the first postoperative request for analgesia.

4.2.3 Local Infiltration, Instillation and Intra-Articular Administration

Infiltration and Instillation

The efficacy of local infiltration with ropivacaine for postoperative analgesia was investigated in a number of randomised, double-blind trials in patients (n = 50–144) undergoing inguinal hernia repair,[139141] abdominal surgery,[142] laparoscopic cholecystectomy[143,144] or sterilisation,[145] tonsillectomy,[146] Caesarean delivery,[147] or breast surgery.[148] Several other smaller (n ≤ 40), randomised, double-blind studies have been conducted in patients undergoing shoulder[149,150] or hemorrhoidal[151] surgery, arthroscopic subacromial decompression[152] or otoplasty[153] but will not be discussed. The primary endpoint in one study was pain score for the first 8 hours after surgery;[145] primary endpoints were not specified for any of the other trials discussed in this section.[139144,146,148152]

Pre-[139] or postoperative[140] wound infiltration with ropivacaine provided short-term, dose-dependent relief of postoperative pain in patients who underwent inguinal hernia repair in two placebo-controlled, multicentre studies (n = 110[140] and 131[139]). The time to first request for analgesia was significantly longer with local infiltration of 30mL of ropivacaine 0.25% and 0.5% than with 30mL of ropivacaine 0.125% or placebo (2.2 and 2.5 vs 1.8 and 1.5 hours; p < 0.05 for all comparisons).[140] Compared with patients who received local infiltration with 40mL of ropivacaine 0.25% or placebo, patients who received 40mL of ropivacaine 0.5% had significantly less wound pain at rest at 3 hours after surgery and wound pain on mobilisation at 3 and 6 hours after surgery, according to VAS scale measurements (p ≤ 0.05 for all comparisons).[139]

Postoperative local infiltration with 40mL of ropivacaine 0.75% was associated with similar postoperative analgesia to that achieved with 40mL of bupivacaine 0.25%, according to VAS pain scores at rest, on mobilisation and on coughing in a study in 144 patients undergoing inguinal hernia repair.[141] During the 24 hours after hernia surgery, patients who received ropivacaine were able to walk with minor or no problems earlier than patients who received of bupivacaine (p < 0.03).[141]

Preoperative local infiltration with ropivacaine provided effective relief of postoperative pain in patients who underwent abdominal surgery,[142] laparoscopic cholecystectomy[143] or laparotomy for sterilisation[145] in three placebo-controlled trials (n = 58–84). VAS scores for wound pain on mobilisation at 6 hours after surgery were significantly lower in patients who received 70mL of ropivacaine 0.25% than in placebo recipients (p = 0.001).[148] Similarly, patients who received a total 286mg of ropivacaine had significantly lower total VAS pain scores at rest and on mobilisation over the 3 hours after surgery than placebo recipients (p < 0.01 for both comparisons).[143] In the other study,[142] mean VAS scores at 24–48 hours after surgery were significantly lower for patients who received 30mL of ropivacaine 0.5% than for placebo recipients (2.69 vs 4.26mm; p = 0.02) despite there being no significant between-group differences in VAS scores over the first 24 hours after surgery. Patients undergoing laparoscopic cholecystectomy (n = 57)[144] who received local infiltration with 20mL of ropivacaine 1% reported significantly higher (worse) VAS scores than patients who received 20mL of levobupivacaine 0.5% at 4 and 24 hours after surgery (3.4 vs 1.05mm and 2.45 vs 0.57mm; p < 0.001 for both comparisons).

Pain ratings during the first 5 minutes after tonsillectomy was significantly less in 77 patients who received preoperative local infiltration with 20–30mL of ropivacaine 0.2% plus epinephrine 1 : 100 000 than with 10–30mL of lidocaine 2% plus epinephrine 1 : 100 000 according to a numerical analogue scale (1.02 vs 2.62; p < 0.001).[146] There was no between-group difference in VAS scores for pain at rest over the first 6 hours after surgery in 60 women undergoing breast surgery who received preoperative local infiltration with 0.3 mL/kg ropivacaine 3.75 mg/mL in the breast followed by 0.3 mL/kg ropivacaine 3.75 mg/mL in the axilla or placebo.[148]

Instillation with ropivacaine provided more effective postoperative analgesia than placebo in two randomised, double-blind studies in patients undergoing laparoscopic sterilisation (n = 80)[145] or Caesarean delivery (n = 50).[108] Patients undergoing laparoscopic sterilisation who received 285mg ropivacaine by preincision infiltration and intraperitoneal instillation had significantly lower VAS pain scores at rest, on mobilisation and on coughing than placebo recipients during the first 8 hours after surgery (p < 0.0001 for all comparisons).[145] Women who self-administered ropivacaine during the first 24 hours after Caesarean delivery received a mean dose of 67mL ropivacaine 0.2% and significantly fewer ropivacaine than placebo recipients required morphine (48% vs 92%; p < 0.01).[147]

Intra-Articular Administration

In a randomised, double-blind study in 45 patients undergoing arthroscopic knee surgery,[154] intra-articular injection with 30mL of ropivacaine 0.75% or 30mL of bupivacaine 0.5% provided similar postoperative analgesia.[154] VAS pain scores at rest and on mobilisation over the 24 hours following surgery were similar in ropivacaine and bupivacaine recipients. Compared with placebo recipients, patients who received ropivacaine in this study had significantly lower VAS scores for pain at rest at 15 minutes after surgery (7 vs 19mm) and for pain on movement at 15 minutes (13 vs 26mm) and 2 hours (16 vs 23mm) after surgery (p < 0.05 for all comparisons).[154]

Intra-articular ropivacaine 75mg in 20mL of saline provided similar postoperative analgesia to intra-articular morphine 2mg in 20mL of saline according to VAS scores over the first 24 hours after arthroscopic knee surgery in a randomised, double-blind study (n = 90).[155] Patients who received ropivacaine 75mg had significantly lower VAS scores over the first 4 hours after surgery than placebo recipients (p < 0.001);[155] typically, time to onset of pain relief with intra-articular morphine is several hours.

4.2.4 In Children

This section focuses on randomised, double-blind studies in paediatric patients (aged <12 years) that investigated the efficacy of ropivacaine, administered as a postoperative analgesic, when administered as a single bolus injection via the caudal[156165] or lumbar[166] route (table XIV), or as a peripheral nerve block.[167169]
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Table XIV

The efficacy of ropivacaine (ROP) as a postoperative analgesic in children. ROP was administered as a single bolus injection (0.75[166] or 1[156163] mL/kg) by the caudal (or lumbar[166]) route in randomised, double-blind studies

Where stated, the primary endpoint was the analgesic effectiveness (according to a 6-point faces scale and a 4-point observer scale,[156] the Children’s Hospital of Eastern Ontario Pain Scale [CHEOPS][165] or the FLACC scoring system [five behavioural categories are scored from 0–2; Facial expression, Leg movement, Activity, Crying and Consolability]),[167] the depth and duration of motor block,[159] the proportion of children with effective caudal block,[163] the effect of ketamine on the duration of anaesthesia[164] and the onset time and duration of motor block.[166]

Administration of ropivacaine for postoperative pain by continuous epidural infusion in children is not a licensed indication and the efficacy of the drug investigated in randomised, open-label studies[170,171] will only be briefly discussed.

Bolus Caudal/Lumbar Injection

A single injection (1 mL/kg) of ropivacaine 0.1–0.375% administered via the caudal route achieved satisfactory analgesia for postoperative pain in children in well controlled trials (table XIV).

A dose-ranging study indicated that the analgesic efficacy of 1 mL/kg of ropivacaine 0.1% was significantly (p < 0.05) less than that with ropivacaine 0.2% and 0.3% (assessed according to the 4-point Observer scale).[156] The time to first treatment with rescue analgesic is shown in table XIV.

When administered as a single bolus injection via the caudal route, 1 mL/kg of ropivacaine 0.2–0.375% provided similar postoperative analgesia to bupivacaine 0.25%[159,161163] or 0.375%,[158] or levobupivacaine 0.2%[160] or 0.25%[157,163] (table XIV). Time to onset of analgesia (table XIV), the time to the administration of the first rescue medication (table XIV), the duration of pain relief and the quality of pain relief was similar with ropivacaine and its comparators. Postoperative motor blockade in ropivacaine recipients was generally significantly less than that in bupivacaine recipients,[158,159,163] but similar to that in levobupivacaine recipients[157,160,163] (table XIV).

In paediatric patients undergoing surgery, the addition of ketamine 0.25 mg/kg to a caudal epidural injection (1 mL/kg) of ropivacaine 0.2% increased the duration of postoperative analgesia four-fold in one study (n = 32),[164] but there was no between-group difference in the duration of analgesia in another (n = 99).[165] However, in the latter study,[165] the addition of tramadol to ropivacaine increased the duration of analgesia from 16.8 to 23.0 hours (p = 0.001). In ropivacaine recipients, the number of doses of supplemental postoperative analgesia in the first 24 hours was significantly less with the addition of ketamine in one study (1 vs 3; p < 0.0001)[164] and with the addition of tramadol in the other study (3 vs 14; p = 0.005).[165]

In a small study in infants,[166] a single bolus lumbar epidural injection of ropivacaine achieved similar postoperative analgesia to that with bupivacaine, with a similar onset of action (table XIV), duration of analgesia (table XIV) and proportion of patients requiring additional rescue analgesia (43% vs 57%).

Continuous Epidural Infusion

Continuous epidural infusion for the administration of ropivacaine for postoperative pain relief has been investigated in two studies in children,[11,170] but it is not an approved indication in this population.

Adequate postoperative analgesia was achieved in 48 children (aged 7–12 years) who had undergone lower extremity orthopaedic procedures and were treated with ropivacaine 0.2% as a continuous epidural infusion (0.4 mg/kg/h) or as PCEA (bolus 2mL doses of ropivacaine 0.2% with a lockout interval of 10 minutes and a background infusion rate of 1.6 mL/h).[170] The use of PCEA had an analgesic-sparing effect compared with continuous epidural infusion (0.2 vs 0.4 mg/kg/h; p < 0.001; 239 vs 576mg administered in 48 hours; p < 0.001). There was no between-group difference in VAS pain scores or supplemental analgesic requirements.

There was no between-group difference in the postoperative analgesic efficacy of a continuous epidural infusion (0.2 mg/kg/h) of ropivacaine 0.125% (n = 26), bupivacaine 0.125% (n = 28) or levobupivacaine 0.125% (n = 27) in children (aged 2–6 years) who had undergone hypospadias repair.[171] The Children’s and Infant’s Post-operative Pain Scale score was <4 during the first 48 hours, without any need for supplemental postoperative analgesia, in all treatment groups. Significantly more patients treated with bupivacaine displayed signs of motor blockade than those treated with ropivacaine or levobupivacaine (p < 0.03).

Peripheral Nerve Block or Infiltration

In 35 children aged 1–11 years undergoing hand surgery, axillary brachial plexus blocks with 0.5 mL/kg of ropivacaine 0.2% or bupivacaine 0.25% provided similar pain relief.[167] There was no between-group difference in the time to the first dose of codeine phosphate (median 7.25 vs 9.3 hours) or the requirement for supplemental analgesia in the first 24 hours.[167]

Peritonsillar injection of ropivacaine 1% (0.15 mL/kg) plus clonidine 1 μg/kg (0.01 mL/kg) or ropivacaine 1% (0.15 mL/kg) prior to tonsillectomy was significantly more effective than isotonic sodium chloride in reducing late post-tonsillectomy pain and medication use in 63 children aged 3–15 years.[168] The addition of clonidine to ropivacaine reduced the need for supplemental analgesia in the later postoperative period (days 3 and 5). Recovery to normal activity was shorter in those receiving ropivacaine plus clonidine than in those treated with isotonic saline (5.8 vs 8.1 days; p = 0.03).

In 130 children (aged 2–12 years) undergoing adenotonsillectomy, injections in the tonsillar fossae immediately following tonsillectomy of ropivacaine 0.5% (maximum 2 mg/kg) with epinephrine 1 : 200 000 did not reduce postoperative pain compared with isotonic saline.[169]

4.3 Management of Labour Pain

Studies of lumbar epidural or intrathecal ropivacaine for pain relief during active labour were conducted in women who generally had cervical dilation of <5cm (but up to 7cm in some studies). Following a test dose and an initial dose, pain relief was delivered as bolus doses by PCEA with or without a continuous infusion (see tables XV and XVI for study design details).
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Table XV

Efficacy of epidural ropivacaine (ROP) versus bupivacaine (BUP) [with or without fentanyl (FEN) or sufentanil (SUF)] in the management of labour pain. Data are from randomised, double-blind studies; two trials were multicentre.[172,185] Study drugs were administered as an initial bolus dose, followed by an infusion in most studies, and further bolus doses on demand

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Table XVI

Efficacy of intrathecal ropivacaine (ROP) in randomised, double-blind studies in the management of labour pain

Where stated, the primary endpoint was the incidence of operative delivery (instrumental plus Caesarean delivery)[172,173] or the duration of analgesia.[174] Other endpoints were typically related to analgesic efficacy, onset and duration of the sensory block and onset, duration and characteristics of the motor block. Sensory block was assessed by regional pinprick or temperature testing and motor block according to the modified Bromage scale. Analgesic efficacy was assessed by patient-reported VAS scores, total dose of local anaesthetic administered or the demand for supplemental analgesia.

4.3.1 Epidural Administration

Numerous dose-finding studies (n = 77–133) have confirmed the efficacy of epidural ropivacaine for relief of labour pain[25,175177] and support the recommendation for the administration of a 10–20mL bolus of ropivacaine 0.2% (20–40mg) [with intermittent 20–30mg top-up injections], or a continuous epidural infusion of ropivacaine 0.2% (12–20 mg/h or 6–10 mL/h) for analgesia during labour.[3] This section reviews the efficacy of ropivacaine versus that of bupivacaine (table XV) or levobupivacaine, the effect of the addition of opioids,[178,179] clonidine[134] or epinephrine[52] to epidural ropivacaine and the effect of different regimens/methods of administration of epidural ropivacaine.[180,181]

In large (n > 180), randomised, double-blind trials (design details in table XV), the analgesic efficacy of ropivacaine was similar to or slightly less than that of bupivacaine. Although some studies show the incidence of motor block to be less with ropivacaine than bupivacaine, overall results for this parameter are not conclusive.

In the trials in which the incidence of operative delivery was the primary endpoint,[172,173] there was no significant difference between ropivacaine and bupivacaine (49% vs 54%[172] and 62% vs 58%[173]) and there was also no difference between the two agents for this parameter (tabulated as the incidence of spontaneous vaginal delivery) in the other trials reviewed (table XV and section 7).

Ropivacaine appeared to have similar efficacy to levobupivacaine in small, randomised, double-blind trials (n = 40[182] and 60[183]). The duration of analgesia was similar (1.7 vs 1.5 hours) for a 10mL bolus dose of ropivacaine 0.2% versus levobupivacaine 0.2%,[182] and the time between onset of analgesia provided by 15mL of ropivacaine 0.1% or levobupivacaine 0.1% (both with fentanyl 2 μg/mL) and the first 5mL bolus dose demand (PCEA) was 35 versus 34 minutes.[183] There was a similar incidence of motor block among groups in both studies (20–32%) and no patient developed motor block with a score >1.[182,183]

A randomised, observer-blinded study (n = 129)[184] concluded that equipotent doses of ropivacaine, levobupivacaine and bupivacaine (20mL each of 0.1%, 0.0625% and 0.0625%, respectively) in combination with sufentanil 10μg, had similar analgesic efficacy in labour pain (assessed on the 100mm VAS) and similar degrees of motor block (ability to walk unassisted), but the duration of analgesia was significantly longer with ropivacaine and levobupivacaine than with bupivacaine (119 and 114 vs 89 minutes) [p < 0.01].[184]

Randomised (double-blind[134,179] and blinding not reported[178]) trials in 58–80 patients have investigated the effects of the addition of opioids or clonidine to ropivacaine for epidural labour analgesia. The administration of a ropivacaine 0.1% epidural infusion with fentanyl 2 μg/mL (10 mL/h) significantly reduced local anaesthetic consumption (p < 0.01);[178,179] the quality of analgesia of the combined infusion was similar to that of a ropivacaine 0.2%-only infusion[179] or ropivacaine 0.2% plus fentanyl 2 μg/mL infused at a slower rate (8 mL/h).[178]

Clonidine 75μg in combination with a single 8mL dose of ropivacaine 0.1% or 0.2% resulted in a significantly longer duration of analgesia than 8mL of ropivacaine 0.2% alone (132 and 154 vs 91 minutes; p < 0.05).[134] The total local anaesthetic dose of ropivacaine in the ropivacaine 0.1% or 0.2% plus clonidine groups was also significantly less over the first 4 hours than that in the ropivacaine-only group (40.5 and 47 vs 72.5mg; p < 0.05).[134]

In a small (n = 21) randomised study of the addition of epinephrine 5 μg/mL to epidural ropivacaine (initial dose 30mg followed by an infusion of 10 μg/h) for labour pain relief,[52] patients in the ropivacaine plus epinephrine group experienced a greater degree of motor block than those in the ropivacaine alone group (Bromage score 2 vs 1; p < 0.05), but the groups were similar for onset and duration of sensory block, dose of ropivacaine or supplementary analgesia, and neonatal outcome (see also section 3.1).[52]

In a randomised, single-blind, multicentre trial (n = 80), ropivacaine 0.1% and sufentanil 0.5 μg/mL delivered as PCEA (4mL bolus doses with 20-minute lockout period) for labour analgesia was dose sparing compared with administration as a continuous epidural infusion (6 mL/h) [start dose for both groups was 8mL].[180] In a randomised, single-blind study (n = 66), PCEA with 4mL bolus doses (lockout period 20 minutes) and a continuous background infusion (4 mL/h) was more effective than PCEA (4mL bolus doses with lockout period 15 minutes) only.[181]

4.3.2 Intrathecal Administration

Intrathecal analgesia for the initial control of labour pain is generally administered in combination with epidural analgesia for maintenance of pain relief (combined spinal-epidural epidural [CSE] technique).

Randomised, double-blind studies of 36–60 women in labour (trial design details in table XVI) demonstrated that intrathecal ropivacaine, alone or with fentanyl or sufentanil, provided rapid and effective labour pain relief.[174,189191] The onset of analgesia was similar for ropivacaine and bupivacaine (both with fentanyl [mean 6.5 minutes for both]).[191]

The mean duration of analgesia was similar for ropivacaine and bupivacaine when each was combined with fentanyl[191] or sufentanil[189] but was significantly shorter with ropivacaine than with bupivacaine when each agent was administered alone[174] (table XVI). Patients receiving ropivacaine were significantly less likely to experience motor block than bupivacaine recipients (when each agent was administered alone[174] or in combination with fentanyl[191]) [table XVI].

Ropivacaine and levobupivacaine administered alone had similar mean durations of analgesia and a similar incidence of motor block (table XVI).[174]

The addition of sufentanil 10μg to ropivacaine[190] significantly improved 100mm VAS pain scores compared with ropivacaine alone (6.6 vs 37.4mm; p = 0.0005), and prolonged the duration of analgesia compared with ropivacaine alone, without affecting the incidence of motor block (table XVI).[190]

5. Tolerability

Ropivacaine was generally well tolerated in the clinical trials discussed in section 4; however, most studies were not primarily designed to investigate tolerability and report only a brief overview of adverse events. Therefore, this section includes information from reviews[1,2] and the manufacturer’s prescribing information,[3,47] which contains pooled analyses of adverse events reported in clinical studies.

5.1 In Adults

Ropivacaine is generally well tolerated regardless of the route of administration.[3,47,192] In a pooled analysis of data from controlled clinical trials, adverse events that occurred in ≥5% of patients who received ropivacaine 0.125–1% via various routes of administration for surgery, labour, Caesarean section, postoperative pain management, peripheral nerve block or local infiltration (n = 1661) were hypotension (32%), nausea (17%), vomiting (7%), bradycardia (6%) and headache (5%).[47] These events are a consequence of nerve block and occurred with similar incidence in patients (n = 1433) who received bupivacaine 0.25–0.75% for the same indications (29%, 14%, 6%, 5% and 5%, respectively).[47]

Epidural administration of ropivacaine for surgery generally produced dose-dependent adverse events similar to those observed with equal doses of bupivacaine (figure 1).[47] The incidence of hypotension (54% and 39%), nausea (29% and 7%), vomiting (15% and 2%), back pain (10% and 7%) and headache (8% and 5%) was numerically higher in females than males in this analysis (statistical analysis not reported).[47] The incidence of ropivacaine-induced cardiovascular symptoms may be age-related;[28] patients aged ≥61 years who received epidural ropivacaine 1% had a significantly higher incidence of bradycardia (11 of 19 [58%] vs 3 of 20 [15%] patients aged 41–60 years; p = 0.005) and hypotension (14 of 19 [74%] vs 3 of 15 [20%] patients aged 18–40 years; p = 0.002).[28] In the pooled analysis,[47] hypotension occurred more frequently in patients aged ≥65 years than in patients aged <65 years with all doses of ropivacaine (statistical analysis not reported).
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Fig. 1

Most common adverse events occurring in adults who received epidural ropivacaine (ROP) or bupivacaine (BUP) for surgery. Data are from a pooled analysis of results from clinical trials.[47] Zero incidence denoted by ø.

Large doses of ropivacaine may be used in peripheral nerve blocks in particular.[3] However, the incidence of cardiovascular and CNS toxicity as a result of inadvertent intravascular injection of ropivacaine appears to be low.[193] According to a pooled analysis of data from ≈3000 patients in 60 clinical studies, the incidence of probable accidental intravenous injection of ropivacaine was ≈0.2% (six patients) and only one patient experienced convulsions; no patients showed symptoms of cardiovascular toxicity.[193] In a patient who experienced a seizure followed by ventricular fibrillation due to suspected inadvertent intravenous ropivacaine administration during a sciatic nerve block, the unbound venous plasma ropivacaine concentration at 5 minutes after ropivacaine injection was 0.5 mg/L,[194] ≈3-fold higher than the threshold venous plasma concentration for CNS toxicity in healthy volunteers (0.15 mg/L [see also section 2.3].[15]

5.2 In Children

Ropivacaine was generally well tolerated in paediatric patients aged from 1 month to 15 years, regardless of the route of administration, according to results from studies discussed in section 4.2.4 (n = 28–245).[156,158163,165171] However, as with the trials conducted in adults, most studies were not primarily designed to investigate tolerability and report only a brief overview of adverse events.

The overall incidence of adverse events associated with ropivacaine appeared to be low,[156,158,161,162,166] with nausea and/or vomiting occurring most frequently.[156,163,168170] In several studies there were no adverse events reported in ropivacaine recipients.[158,161,162,166] However, in one study,[156] 30 of 110 (27%) paediatric patients who received 1 mL/kg of ropivacaine 0.1%, 0.2% or 0.3% via the caudal route experienced adverse events; the most common were nausea and vomiting (incidence not reported). The incidences of postoperative nausea and/or vomiting with 0.15 mL/kg of ropivacaine 0.1% and placebo were 30% and 60%, and those for headache were 32% and 40%, in a study in 64 children who underwent tonsillectomy; ear pain occurred in significantly fewer ropivacaine than placebo recipients in this study (63% vs 89%; p < 0.001).[168] In children undergoing adenotonsillectomy,[169] the incidence of postoperative retching was significantly higher in children who received up to 2 mg/kg ropivacaine plus 1 : 200 000 epinephrine compared with placebo (41% vs 19%; p = 0.006) although there were no between-group differences in the incidence of emesis or the requirement for rescue medication for retching or emesis in this study.

Few serious ropivacaine-related adverse events were reported. In the study in 130 children who underwent adenotonsillectomy,[169] two children who received ropivacaine plus epinephrine experienced airway obstruction that was resolved with oral suction and salbutamol (albuterol) treatment or positive airway pressure and one child complained of difficult breathing that was resolved with epinephrine treatment.[169] In another study in 100 children who received 1 mL/kg of caudal ropivacaine 0.1%, 0.2% or 0.3%, the one serious adverse event that occurred (iatrogenic perforation of the bladder) was considered to be unrelated to ropivacaine treatment.[156]

Ropivacaine appeared to be at least as well tolerated as levobupivacaine or bupivacaine in paediatric patients.[157,158,161163,166,167,171] In a study in 99 children aged <10 years,[163] two children who received 0.5–1 mL/kg of bupivacaine 0.25% via the caudal route experienced sinus bradycardia that was considered to be treatment-related; no ropivacaine recipients in this study experienced any haemodynamic adverse events.

Ropivacaine also appeared to be generally well tolerated when administered in conjunction with clonidine, ketamine or tramadol. Children who received 0.15 mL/kg of ropivacaine 0.1% plus clonidine 1 μg/kg had a similar incidence of nausea and/or vomiting (41%) and headache (25%) to those who received plain ropivacaine (30% and 32%).[168] In a study in 99 children who underwent inguinal hernia repair, the number of children who experienced nausea and vomiting was significantly lower with ropivacaine 2 mg/kg (1 of 32) than with of ropivacaine 1 mg/kg plus ketamine 0.25 mg/kg (7 of 33) or tramadol 1 mg/kg (8 of 34) [p = 0.032 for both comparisons].[165] No respiratory depression was reported in any treatment group in this study.[165]

5.3 In Exposed Fetuses and Neonates

Ropivacaine was generally well tolerated in the fetus or neonate following the use of regional anaesthesia in women undergoing Caesarean section or during labour.[47] The most common fetal or neonatal adverse events with ropivacaine (n = 639) were fetal bradycardia (12%), neonatal jaundice (8%) and unspecified neonatal complications (7%); these events occurred with similar frequency with bupivacaine (12%, 8% and 7%, respectively).[47] Other adverse events observed in ≥1% of fetuses or neonates after maternal ropivacaine administration were low Apgar scores (3%), neonatal respiratory disorder (3%), neonatal tachypnoea (2%), neonatal fever (2%), fetal tachycardia (2%), fetal distress (2%), neonatal infection (2%) and neonatal hypoglycaemia (1%).[47]

According to a meta-analysis of six double-blind trials, ropivacaine did not influence the neonatal NAC score at 2 hours after delivery and, at 24 hours after delivery, total NAC scores were significantly higher in neonates whose mothers had received ropivacaine rather than bupivacaine (p < 0.05).[195] Umbilical venous plasma concentrations of ropivacaine did not correlate with neonatal NAC scores at 30 minutes after delivery[45] (section 4.1.1).

6. Dosage and Administration

Ropivacaine is indicated in adults for: surgical anaesthesia via epidural administration, intrathecal administration, peripheral nerve block or cutaneous infiltration; postoperative pain relief via epidural administration, peripheral nerve block or wound instillation; and for labour or other acute pain relief via epidural administration.[3] Ropivacaine is indicated in children (aged 1–12 years) for epidural administration (continuous infusion currently not approved [see section 4.2.4]) and peripheral nerve block for postoperative or acute pain management.[3]

Dosages according to route and procedure are summarised in table XVII. Ropivacaine is available as a 0.2%, 0.5%, 0.75% and 1% solution in 10 and 20mL ampoules for injection, and as a 0.2% solution in 100 and 200mL infusion bags.[3]
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Table XVII

Dosage recommendations for ropivacaine in adults and children[3]

Higher doses of ropivacaine are required for surgical anaesthesia than for postoperative or labour analgesia (table XVII). Where prolonged blocks (as with continuous infusion or repeated bolus doses) or peripheral nerve blocks (which are often administered in close proximity to large blood vessels and there is an increased risk of intravascular administration) are used, the risk of reaching toxic plasma concentrations must be considered[3,47] (see section 2.3). As with the administration of any long-acting local anaesthetic, an initial test dose of a short-acting anaesthetic is recommended to test the injection technique. Incremental dosing of ropivacaine is recommended to reduce the risk of toxicity or overdose.[47]

As approved indications and dosage recommendations for ropivacaine vary between countries, the local prescribing information, which also includes relevant contraindications, warnings and precautions for the administration of the drug, should be consulted.

7. Place of Ropivacaine in Regional Anaesthesia and Acute Pain Management

Besides being well tolerated and safe, a regional anaesthetic agent ideal for anaesthesia should have a short time to onset of anaesthesia and result in profound sensory and motor blockade of a duration appropriate for the indication or procedure. Characteristics of an analgesic ideal for postoperative or labour pain relief would be fast onset of action, suitable duration of action, and quick regression of the motor block, which would promote mobilisation and hasten recovery and the patient’s discharge from hospital.[1,192,196]

Bupivacaine is a well established long-acting regional anaesthetic and is widely used in obstetric, orthopaedic and other surgery. Ropivacaine is structurally related to bupivacaine, but unlike bupivacaine, which is a racemate, ropivacaine has been developed and marketed as the pure S(−)-enantiomer of the parent drug. It also has a lower lipophilicity than bupivacaine; this reduced lipophilicity is associated with a decreased potential for CNS toxicity and cardiotoxicity[197] (section 2). The risk of these toxicities increases with the increased plasma drug concentrations that may occur with administration of large volumes or doses of local anaesthetic in certain blocks (e.g. peripheral nerve blocks) or continuous epidural infusions, or following accidental intravascular administration.[1,196,197] The lower toxicity potential of ropivacaine and levobupivacaine (the l-enantiomer of bupivacaine) compared with bupivacaine has not been proven in the clinical setting, but the current trend towards using low-dose epidural or intrathecal administration and incremental dose administration may in any case diffuse the issue of the toxicity risk/potential of regional anaesthetics.[1,12,198] However, there are inherent risks with regional anaesthetic administration, and the potential safety advantages of ropivacaine compared with bupivacaine when higher concentrations and volumes of the drug are required (e.g. in peripheral nerve block, continuous epidural infusion) or when the treatment group is more vulnerable (i.e. children) provides a rationale for the choice of ropivacaine in these treatment scenarios.[1,196,197]

Randomised, double-blind, comparative clinical trials have demonstrated the efficacy of ropivacaine in providing a profound sensory and motor block suitable for anaesthesia (section 4.1) and a sensory/motor block profile suitable for the management of postoperative (section 4.2) or labour (section 4.3) pain when administered by various routes (principally epidural or intrathecal administration and peripheral nerve block).

While ropivacaine and its two principal comparators, bupivacaine and levobupivacaine, all have efficacy for surgical anaesthesia and for acute pain relief, there has been intense debate about the relative potencies of these agents and the clinical similarities and/or differences of their sensory and motor blocks.[1,192,196199] Although ropivacaine has similar potency to bupivacaine at higher doses (e.g. those required for peripheral nerve blocks for surgical anaesthesia), ropivacaine is less potent (according to MLAC studies, which are based on effective analgesia in 50% of patients [section 2.2]) than bupivacaine and levobupivacaine at lower doses, such as those used for epidural or intrathecal analgesia. Providing anaesthesia or analgesia for the majority of patients is more clinically relevant than the MLAC and at the higher doses used in clinical practice, this potency difference is not always evident;[192] full dose-response curves would elucidate this issue.[1,31]

The lower lipophilicity of ropivacaine versus that of racemic bupivacaine also results in a relatively reduced motor nerve fibre penetration and block,[192] and ropivacaine therefore has a greater differential between its sensory and motor block profiles (reduced motor block compared with sensory block) [section 2] at lower doses, which could be useful when motor blockade is undesirable, as in postoperative or labour pain relief.[196,200] Although ropivacaine recipients generally experienced a lesser degree or lower incidence of motor block than bupivacaine, and sometimes levobupivacaine, results were not always consistent (section 4).

For epidurally administered surgical anaesthesia (section 4.1.1), ropivacaine and bupivacaine have essentially similar sensory and motor block profiles, whereas with epidural administration for postoperative (section 4.2.1) and labour (section 4.3.1) analgesia, where doses required are lower than those needed for anaesthesia, ropivacaine tends to have a shorter-lasting sensory block as well as a lower incidence and lesser degree of motor block than bupivacaine; equipotent doses have been established.

The use of intrathecal ropivacaine is now approved in some countries for surgical anaesthesia (section 4.1.2), including in Caesarean section. Ropivacaine provides rapid and effective intrathecal anaesthesia and analgesia, with a shorter duration of sensory and motor blocks than bupivacaine. However, the duration of sensory block provided by ropivacaine is still adequate for anaesthesia, and the quicker regression of the motor block encourages mobilisation and recovery.

Peripheral nerve block for anaesthesia in orthopaedic surgery (section 4.1.3), and particularly for postoperative pain relief (section 4.2.2), requires the use of relatively high doses of regional anaesthetic agents,[201] and the potency differences between ropivacaine and bupivacaine that were evident with their epidural or intrathecal administration were not observed with this route of administration. The reduced cardiotoxicity potential of ropivacaine could be an advantage for its use in peripheral nerve blockade because of the toxicity risk associated with the greater doses of anaesthetic agent required.[192,196,201] Continuous epidural infusions of ropivacaine or other regional anaesthetic agents via a perineural catheter and portable infusion pump is increasingly being used for postoperative pain relief at home in carefully selected patients who have undergone moderately painful procedures.[202] Because relatively large volumes of the drug solution are infused over an extended period of time, cardiotoxicity potential becomes an important criterion when selecting the anaesthetic agent administered using this technique.[202]

Ropivacaine and levobupivacaine generally have similar potencies and efficacies for the above indications and routes of administration (sections 2 and 4).

A meta-analysis of early studies of regional anaesthetic use for labour pain relief concluded that ropivacaine use was associated with more favourable obstetric outcomes (more spontaneous vaginal deliveries) compared with bupivacaine.[195] In a later review of studies, some of which were designed primarily to investigate this parameter, no differences were noted, although equivalent and not equipotent doses were compared (see section 4).[172,173] It appears that the advantage of ropivacaine exhibited in pre-1998 studies was lost in later studies that were specifically designed to investigate maternal and fetal outcomes, used more clinically relevant doses and included relevant statistical analyses and more accurate neonatal outcome measures.[200,203]

In a quest to find the minimum effective dose of ropivacaine, the coadministration of agents that facilitate the use of lower doses of the local anaesthetic have been evaluated.[204] The addition of clonidine to ropivacaine regimens may improve postoperative (sections 4.2.1. and 4.2.2) or labour (section 4.3.1) pain relief, but results were not consistent. However, the addition of opioids (fentanyl or sufentanil) to epidural or intrathecal ropivacaine has an anaesthetic-sparing effect; the combination results in a similar anaesthetic or analgesic block profile with the administration of a reduced total dose of the local anaesthetic (sections 4.1.1, 4.1.2, 4.2.1, 4.3.1 and 4.3.2). The dose of opioid must be optimised to minimise nausea, vomiting, pruritus and the possibility of a delayed discharge from hospital.[205] The administration of opioids (intravenous morphine) alone for postoperative pain relief is well established, but ropivacaine was more effective than intravenous morphine for postoperative (abdominal surgery) pain and the typical opioid-induced adverse events were avoided (section 4.2.1).

Ropivacaine is more costly than bupivacaine, but cost-effectiveness studies that include the potential clinical or tolerability benefits of ropivacaine have not been conducted.[192]

In conclusion, ropivacaine is a well tolerated regional anaesthetic effective for surgical anaesthesia as well as the relief of postoperative and labour pain. The efficacy of ropivacaine is similar to that of bupivacaine and levobupivacaine for peripheral nerve blocks and, although it may be slightly less potent than bupivacaine when administered epidurally or intrathecally, equi-effective doses have been established. Clinically adequate doses of ropivacaine appear to be associated with a lower incidence or grade of motor block than bupivacaine. Thus ropivacaine, with its efficacy, lower propensity for motor block and reduced potential for CNS toxicity- and cardiotoxicity, appears to be an important option for regional anaesthesia and for the management of postoperative and labour pain.

Footnotes
1

The use of trade names is for product identification purposes only and does not imply endorsement.

 

Acknowledgements

At the request of the journal, AstraZeneca provided a non-binding review of this article.

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