Abstract
Synopsis
The enantiomerically pure (S-enantiomer) amide local anaesthetic drug ropivacaine blocked nerve fibres responsible for transmission of pain (Aδ and fibres) more completely than those that control motor function (Aβ fibres) in in vitro studies. The drug shares the biphasic vascular effects common to the amide local anaesthetic drug class. In vitro studies indicate that ropivacaine is less cardiotoxic than equimolar concentrations of bupivacaine.
Apart from one trial in women undergoing hysterectomy, clinical studies that compared the efficacy of different doses of epidurally administered ropivacaine in patients undergoing various surgical procedures did not reveal any consistent dose-related differences with respect to sensory blockade. However, motor blockade did become more intense as the dose of ropivacaine increased.
Overall, direct comparisons show that epidural ropivacaine is less potent than epidural bupivacaine when the 2 drugs are administered at the same concentration. However, this difference is less marked in terms of sensory blockade than motor blockade. The greater degree of separation between motor and sensory blockade seen with ropivacaine relative to bupivacaine is more apparent at the lower end of the dosage scale. Nevertheless, higher doses of ropivacaine than bupivacaine are generally required to elicit equivalent anaesthetic effects.
Ropivacaine has been shown to induce successful brachial plexus anaesthesia when given at a concentration of 5 mg/ml, but not 2.5 mg/ml, and was as effective as bupivacaine in comparative studies in this indication.
Limited data indicate that continuous epidural infusion of ropivacaine post-operatively reduces postsurgical pain in a dose-related manner. Morphine consumption was also reduced. Higher doses of ropivacaine were significantly more effective than placebo. Similarly, ropivacaine controlled postsurgical pain when infiltrated directly into surgical wound sites (i.e. wound infiltration) and was as effective as bupivacaine, and more effective than placebo, in this regard.
Adverse events associated with epidurally administered ropivacaine include hypotension, nausea, bradycardia, transient paraesthesia, back pain, urinary retention and fever. The drug appears to have an adverse event profile similar to that of bupivacaine.
In animal studies, overdoses of ropivacaine were better tolerated than overdoses of bupivacaine but not lidocaine (lignocaine). Human volunteers tolerated a higher intravenous dosage of ropivacaine than bupivacaine before developing initial signs of toxicity.
Thus, ropivacaine, according to animal data, is less cardiotoxic than bupivacaine. Based on available clinical data, ropivacaine appears to be as effective and well tolerated as bupivacaine when equianalgesic doses are compared. The greater degree of separation between motor and sensory blockade seen with ropivacaine relative to bupivacaine at lower concentrations (≈5 mg/ml) will be advantageous in certain applications.
Pharmacodynamic Properties
Ropivacaine is an enantiomerically pure (S-enantiomer) amide local anaesthetic drug. In in vitro preparations of animal nerves ropivacaine was more selective for nerve fibres responsible for transmission of pain (AS and C fibres) than those that control motor function (Aβ fibres). The drug also induced profound blockade of other animal nerves in vitro and appeared to be more potent than equimolar concentrations of bupivacaine in this regard.
Small volumes of ropivacaine injected intradermally have a vasoconstrictive effect. Similarly, in human tissues in vitro, low concentrations of ropivacaine induced vasoconstriction; however, in keeping with the biphasic vascular effects of amide local anaesthetic drugs, this was reversed at higher concentrations.
In anaesthetised pigs, a high intra-arterial dose of ropivacaine (5.33mg) significantly decreased mean arterial pressure and left ventricular dP/dT, and increased left ventricular end-diastolic pressure.
In guinea-pig cardiac muscle in vitro, ropivacaine-induced blockade of sodium channels was less potent than that induced by bupivacaine. In rabbit Purkinje fibres, ropivacaine depressed cardiac excitability and conduction to a lesser extent than bupivacaine but more so than lidocaine (lignocaine). Ropivacaine was less cardiotoxic than equivalent concentrations of bupivacaine in isolated perfused rabbit hearts. In vivo studies in pigs and dogs indicate that ropivacaine has less effect on cardiac rhythm than equianalgesic doses of bupivacaine but affects cardiac rhythm more than lidocaine.
Studies evaluating the effects of epidural administration of ropivacaine to volunteers indicate that the duration of sensory anaesthesia is dose dependent. The effects of the drug on lower extremity motor function clearly increased as the dose increased.
Pharmacokinetic Properties
Intravenous infusion of ropivacaine 50mg over a 15-minute period produced a mean maximum plasma concentration (Cmax) of 1.5 mg/L. The mean volume of distribution of unbound drug (6%) was 742L, plasma clearance was 0.5 L/h and the terminal elimination half-life was 1.85 hours.
In patients undergoing orthopaedic surgery, epidural injection of ropivacaine 100, 150 or 200mg produced Cmax values of 0.53, 1.07 and 1.53 mg/L, respectively after 96 (100mg) or 40 (150 or 200mg) minutes (tmax). Mean residence time was inversely proportional to the dose but the area under the plasma concentration versus time curve was not dose-dependent. Similar trends were observed in patients undergoing other types of surgery including hysterectomy, hernia repair or varicose vein stripping. Compared with bupivacaine, ropivacaine has a signifi-cantly shorter elimination half-life (≈5 vs ≈10 hours) but is cleared at a similar rate (apparent plasma clearance ≈18 L/h). Continuous infusion of ropivacaine over a 21-hour period was associated with a continuous increase in plasma concentration. Compared with data from bolus dose studies, the apparent plasma clearance of the drug was higher and the half-life shorter.
Therapeutic Use
Most studies evaluating the efficacy of ropivacaine have involved epidural administration of the drug to patients undergoing surgery and, to a lesser extent, women in labour.
Apart from one study in women undergoing hysterectomy, ascending dose studies in patients undergoing a wide range of surgical procedures did not detect any dose-related trends in terms of the time taken to reach the maximum level of analgesia. However, the duration of anaesthesia and the degree of motor blockade increased as the dosage of ropivacaine increased.
Overall, double-blind comparisons in patients undergoing a variety of surgical procedures show that ropivacaine is less potent than bupivacaine in terms of motor blockade and, to a lesser extent, sensory blockade. Several studies in women undergoing caesarean section reported a significantly longer time to onset of motor blockade in ropivacaine recipients compared with bupivacaine recipients. Differences between the 2 drugs in terms of sensory blockade were less pronounced. All studies used equivalent dosages of each drug. In contrast, a study in patients undergoing urological surgery, which also compared equivalent dosages of ropivacaine and bupivacaine [150mg (7.5 mg/ml)], reported a similar time to onset of motor blockade with both drugs, but a significantly lower frequency of second and third degree motor block in ropivacaine recipients. Importantly, studies that compared ropivacaine and bupivacaine at a dose ratio of approximately 1.5 to 1 (for example ropivacaine 7.5 mg/ml vs bupivacaine 5 mg/ml) reported very similar patterns of motor and sensory blockade in both groups.
All of 3 noncomparative trials conducted to evaluate the anaesthetic efficacy of ropivacaine 150 or 165mg administered via the subclavian perivascular approach found the drug to induce satisfactory brachial plexus block in patients scheduled to undergo upper limb surgery. In all of these studies 50% of patients received epinephrine. Anaesthesia of brachial plexus dermatomes was achieved in between 86 and 100% of patients. In a randomised double-blind dosage comparison, the extent of brachial plexus nerve block achieved with ropivacaine 2.5 mg/ml (100mg dose) was significantly less useful than that provided by ropivacaine 5 mg/ml (200mg dose). The drug was as effective as bupivacaine in comparative studies in this indication.
Direct comparisons indicate that epidurally administered ropivacaine has generally similar efficacy to bupivacaine when given for pain relief during labour. In one study, a significantly shorter time to onset of analgesia was noted in bupivacaine than in ropivacaine recipients, and motor blockade was slightly less intense after ropivacaine in another. In all of these studies, neonatal outcome, assessed using Apgar scores, was not significantly affected and was similar with both drugs. A further trial, designed specifically to compare the effects of maternal epidural ropivacaine (mean dose 75mg) and bupivacaine (mean dose 85mg) on neonatal neurobehavioural status and outcome, reported no significant differences between the 2 groups. In contrast, a meta-analysis reported significantly higher neurological and adaptive capacity scores at 24 hours in infants born to mothers given epidural ropivacaine than in those born to mothers given bupivacaine.
The postsurgical analgesic efficacy of continuous epidural infusion of ropivacaine 10, 20 and 30 mg/h has been compared with that of placebo (saline) in patients undergoing upper or lower abdominal, or orthopaedic surgery. In all studies the drug was infused postoperatively. Pain became proportionally less severe and morphine consumption (when measured) decreased as the dosage of ropivacaine increased. Indeed, all studies reported a significant difference between higher doses of ropivacaine placebo. Motor blockade became more intense as the dosage of ropivacaine increased.
Two methods of wound infiltration have been investigated: preoperative subcutaneous infiltration along the line of the proposed incision and postoperative injection of the drug into the wound. In a dose-finding study, ropivacaine provided dose-related control of pain after hernia repair. Ropivacaine 100 to 175mg was significantly more effective than placebo (saline) when given just prior to chole-cystectomy and as effective as bupivacaine given immediately after herniotomy.
Tolerability
Most clinical trials evaluating the anaesthetic efficacy of ropivacaine included only an overview of adverse events data. In studies evaluating the efficacy of the drug administered epidurally, reported adverse events included hypotension, nausea, bradycardia, transient paraesthesia, back pain, urinary retention and fever. In direct comparisons between ropivacaine and bupivacaine the 2 drugs were associated with a similar incidence of adverse events.
Studies that compared the effects of overdoses of ropivacaine, bupivacaine and lidocaine in conscious animals reported a higher tolerance to ropivacaine than to bupivacaine, but not lidocaine. Similarly, human volunteers tolerated a significantly higher cumulative intravenous dosage of ropivacaine than bupivacaine before developing mild CNS toxicity (124 vs 99mg).
Dosage and Administration
Recommended epidural doses of ropivacaine for surgical anaesthesia range between 113 and 200mg. Different doses can be achieved by varying either the concentration or volume of solution injected. Epidural ropivacaine administered to control postsurgical pain can be given as a 20 to 40mg bolus with 20 to 30mg top-up doses at ≥30-minute intervals or as a 2 mg/ml continuous epidural infusion at a rate of 6 to 14 ml/h (lumbar) or 4 to 8 ml/h (thoracic).
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Various sections of the manuscript reviewed by: D.R. Ahernethy, Division of Clinical Pharmacology, Departments of Pharmacology and Medicine, Georgetown University Medical Center, Washington D.C., USA; I. Ceaerholm, Department of Cardiovascular and Thoracic Anaesthesia, University Hospital, Linköping, Sweden; H.S. Feldman, Department of Anesthesia Research Laboratories, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; B.T. Finucane, Department of Anaesthesia, University of Alberta, Edmonton, Alberta, Canada; S.P. Gatt, Department of Anaesthesia, Royal Hospital for Women, University of New South Wales Medical School, Sydney, New South Wales, Australia; R. Hickey, Department of Anesthesiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA; K. Nakamura, Department of Anesthesia, Kyoto University Hospital, Kyoto, Japan; G.T. Tucker, University Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield, England; J.A.W. Wildsmith, University Department of Anaesthesia, Ninewells Hospital and Medical School, Dundee, Scotland
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Markham, A., Faulds, D. Ropivacaine. Drugs 52, 429–449 (1996). https://doi.org/10.2165/00003495-199652030-00012
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DOI: https://doi.org/10.2165/00003495-199652030-00012