1Musgrave Park Hospital, Belfast, UK. 2AstraZeneca R & D, Södertälje, Sweden.*Corresponding author: Department of Anaesthetics, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, UK**Present address, Belfast City Hospital, Belfast, UK
Accepted for publication: June 12, 2001
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Abstract |
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Br J Anaesth 2001; 87: 5706
Keywords: anaesthetics local, bupivacaine; anaesthetics local, ropivacaine; anaesthetic techniques, regional, intra-articular; equipment, arthroscope
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Introduction |
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Ropivacaine is an aminoamide local anaesthetic with similar clinical efficacy to12 and lower cardiotoxicity than racemic bupivacaine.11 13 It is a long-acting local anaesthetic that is chemically homologous to bupivacaine and mepivacaine. Ropivacaine is in the form of the S-enantiomer, making it the first enantiomerically pure local anesthetic.12 In contrast to bupivacaine, it has shown fewer inherent vasodilator properties after intradermal administration.14 The purpose of this study was to compare the analgesic efficacy and systemic uptake of three different doses of ropivacaine administered as single intra-articular injections after arthroscopic knee surgery, with bupivacaine as a control.
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Methods |
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Patients were unpremedicated and on arrival in the operating theatre all received a standardized general anaesthetic. This consisted of a sleep dose of propofol and alfentanil 10 µg kg1, after which a laryngeal mask was inserted. Anaesthesia was maintained using isoflurane (12%) with nitrous oxide (66%) in oxygen. Non-invasive monitoring was undertaken, consisting of ECG, arterial blood pressure, peripheral oxygen saturation, FE'CO2 and FIO2.
Patients were allocated to one of four groups of 18 patients in a double-blind, randomized manner using randomly selected sealed envelopes. They received ropivacaine 100 mg (5 mg ml1, group R100), ropivacaine 150 mg (7.5 mg ml1, group R150), ropivacaine 200 mg (10 mg ml1, group R200) or bupivacaine 100 mg (5 mg ml1, group B100) in a 20 ml intra-articular injection at the end of surgery. A syringe of the corresponding local anaesthetic was prepared by an assistant who took no further part in the study. The anaesthetist, surgeon, observer and patient were all unaware of the nature of the contents of each syringe. These drugs were administered by intra-articular injection by the surgeon on completion of surgery, 5 min before deflation of the tourniquet, which had been inflated to a pressure of 300 mm Hg. All patients had 2% lidocaine 2 ml with epinephrine infiltrated into each skin wound at the end of surgery. In eight patients in each group, blood (5 ml) was drawn from a dedicated, unheparinized cannula sited in the non-injection antecubital fossa before (time 0) and 10, 20, 30, 45, 60, 90, 120 and 180 min after completion of the local anaesthetic injection. These samples were centrifuged as soon as possible after collection and the separated plasma was frozen at 80°C until assay. The total plasma concentrations of ropivacaine and bupivacaine base were determined by high-performance liquid chromatography with ultraviolet detection at 210 nm using bupivacaine as the internal standard. The limit of quantitation of the method was 50 ng ml1. The unbound (free) plasma concentration of ropivacaine base was determined by coupled column liquid chromatography with ultraviolet detection at 210 nm after ultrafiltration of the plasma samples.15 The limit of quantitation was 3 ng ml1. The unbound concentration was determined in peak plasma samples of ropivacaine or in samples taken at an adjacent sampling time.
Postoperative pain scores (VAS, 0100 mm) on active flexion of the knee were recorded by a blinded observer 1, 2 and 4 h after the intra-articular injection. Postoperative pain was treated by the ward nursing staff with paracetamol 1 g + codeine phosphate 60 mg (Kapake) and, if this did not provide adequate analgesia, as judged by recovery nursing staff, morphine 0.15 mg kg1 was administered i.v. Patients were discharged 4 h after surgery if comfortable, with analgesic packs and instructions to take the above dose of Kapake up to every 4 h if needed. The time to the first request for analgesia and the total analgesic requirements were recorded. Patients were telephoned at home on the second postoperative day and their post-discharge analgesic use and a subjective verbal rating of overall pain severity were recorded. Ratings were no pain, mild pain, moderate pain and severe pain and were identified as such for reference purposes on the record chart given to the patient on discharge from hospital.
Physical characteristics, operation type and duration were analysed by analysis of variance (ANOVA) and the 2 test when appropriate, and their relationships to pain scores tested with Spearmans rank correlation. Pain scores were analysed by ANOVA and time to first analgesia by survival analysis. Analgesic tablet consumption and verbal rating scale scores were analysed with the MannWhitney U-test. Results were considered statistically significant when P<0.05. To achieve an 80% power of detecting a 15 mm difference in VAS score, the study required 18 patients in each group if the common standard deviation of pain scores in all groups is 5 mm.
The total (Cmax) and unbound (Cu,max) peak plasma concentrations were estimated from the observed values. The area under the plasma concentration-time curve during the 3 h of observation (AUC03) was calculated using the trapezoidal rule. The fraction of unbound drug in plasma (fu) was calculated as the unbound divided by the total plasma concentration. Dose proportionality for Cmax, Cu,max and AUC03 were analysed with the power model y=doseß, where
depends on subject, period and error.16 This model assumes a linear relationship between log y and log dose. Dose proportionality requires that ß=1 for dose-dependent parameters. In terms of this model, a doubling of the dose is reflected in the ratio R=2ß of corresponding effects, i.e. (y2/y1)=2ß. If dose proportionality holds, the effect ratio R equals 2. A simple linear regression was also used to study the relationships of dose with Cmax, Cu,max and AUC03. Ninety per cent confidence intervals for the intercepts were calculated.
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Results |
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Discussion |
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In this study pain scores demonstrated similar variability to that in work reported previously.19 As a result, there were non-significant consistent differences between groups in VAS pain scores in the first 4 h after surgery and in analgesic consumption in the first 48 h after surgery. However, for the verbal rating pain score, a significant improvement was seen with ropivacaine 150 mg compared with bupivacaine. In ethical clinical trials, pain scores should tend towards convergence with the free availability of analgesics, and serve to emphasize the adequacy of the rescue analgesic in placebo or control groups. In situations such as this, it may well be that analgesic consumption and overall patient satisfaction would be more reliable and appropriate measures than pain scores.
All patients had their skin entry wounds (two or three wounds) injected with a uniform dose of lidocaine and epinephrine in an attempt to standardize the effect of postoperative pain from these sites for at least the early VAS pain scores. This may have had the effect of removing a large component of the early postoperative pain, perhaps reducing early differences between the groups. Postoperative pain may have been further reduced across all groups by the interval of 5 min between injection and tourniquet deflation and the consequent increase in tissue uptake of the local anaesthetics.11 Furthermore, ropivacaine has anti-inflammatory effects in human mucosal cells,20 which may contribute to the observed difference in analgesic effect on the second postoperative day.
The systemic uptake of the two local anaesthetics from the knee joint appears similar, as reflected by their corresponding Cmax and tmax values. The similarity of these times in this study suggests that there was little difference in the vasomotor activities of the agents at the studied doses at this site. Cmax was considerably higher than previously described for intra-articular bupivacaine, probably as a result of the extended tourniquet inflation time and the hyperaemia resulting from post-ischaemic reperfusion.11 Plasma drug concentrations were still slowly rising in five patients (two receiving bupivacaine and three receiving ropivacaine) in the 180 min sample, although the curves were similarly shaped across the groups. The sustained plasma drug concentrations observed over the sampling period may be consistent with prolonged absorption exceeding the true elimination rate (i.e. the absorbtion/elimination rate that would be seen after i.v. administration of ropivacaine or bupivacaine, which have terminal half-lives of 1.9 and 2.7 h respectively).21 This may be at least partially technique-specific in this case, because of the delay between injection and tourniquet deflation and the fact that the uptake of both drugs was considerably slower than reported previously for bupivacaine.11 Prolonged uptake of drug from the joint might also reasonably be expected to extend the analgesic effect. Limitation of elimination by the absorption rate has been reported for ropivacaine after epidural administration.22 Prolonged systemic absorption has also been described after infiltration of the hernia wound with ropivacaine, the plasma concentration being elevated for the entire 2 h sampling period.23
In this study, the peak concentrations of both total and unbound ropivacaine were proportional to the dose administered, which is important in allowing predictability in analgesia and in the risk of systemic effects in clinical practice. Intersubject variability, however, is the largest unpredictable factor in this regard, and our curves appear to confirm this. Nevertheless, all total and unbound individual peak plasma concentrations for each drug and dose were well below the recognized toxic threshold.13 Bupivacaine administered intra-articularly to the knee has been associated with cardiovascular toxicity despite the use of accepted doses.24 This was probably as a result of an accidental intravascular injection in this relatively vascular joint, and in such a situation the lower cardiotoxicity of ropivacaine12 13would be beneficial.
In conclusion, we have demonstrated that ropivacaine and bupivacaine 100 mg provide similar and effective post-arthroscopy analgesia and that ropivacaine at the higher dose of 150 mg appears to further reduce patients pain ratings in the 48 h period after surgery. A higher ropivacaine dose does not seem to improve efficacy. Plasma concentrations for all patients and all doses fell below the estimated toxic thresholds, and therefore it seems that these drugs can be safely administered by intra-articular injection.
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Acknowledgements |
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References |
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2 Smith I, Hemelrijck JV, White PF, Shively R. Effects of local anaesthesia on recovery after outpatient arthroscopy. Anesth Analg 1991; 73: 5369[Abstract]
3 Heard SO, Edwards WT, Ferrari D, et al. Analgesic effect of intra-articular bupivacaine or morphine after arthroscopic knee surgery: a randomized prospective double-blind study. Anesth Analg 1992; 74: 8226[Abstract]
4 Geutens G, Hambridge JE. Analgesic effects of intra-articular bupivacaine after day-case arthroscopy. Arthroscopy 1994; 10: 299300[ISI][Medline]
5 Morrow BC, Milligan KR, Murthy BV. Analgesia following day-case knee arthroscopythe effect of piroxicam with or without bupivacaine infiltration. Anaesthesia 1995; 50: 4613[ISI][Medline]
6 Henderson RC, Campion ER, DeMasi RA, Taft TN. Post arthroscopy analgesia with bupivacaine: a prospective, randomized, blinded evaluation. Am J Sports Med 1990; 18: 6147[Abstract]
7 Osborne D, Keene G. Pain relief after arthroscopic surgery of the knee: a prospective, randomized and blinded assessment of bupivacaine and bupivacaine with adrenaline. Arthroscopy 1993; 9: 17780[ISI][Medline]
8 Aasbo V, Raeder JC, Grogaard B, Roise O. No additional analgesic effect of intra-articular morphine or bupivacaine compared with placebo after elective knee arthroscopy. Acta Anaesthesiol Scand 1996; 40: 5858[ISI][Medline]
9 Moiniche S, Mikkelsen S, Wetterslev J, Dahl JB. A systematic review of intra-articular local anesthesia for postoperative pain relief after arthroscopic knee surgery. Reg Anesth Pain Med 1999; 24: 4307[ISI]
10 Wasudev G, Smith BE, Limbird TJ. Blood levels of bupivacaine after arthroscopy of the knee joint. Arthroscopy 1990; 6: 402[Medline]
11 Katz JA, Heading CS, Hill JR, Henthorn TK. The pharmacokinetics of bupivacaine when injected intra-articularly after knee arthroscopy. Anesth Analg 1988; 67: 8715
12 McClure JH. Ropivacaine. Br J Anaesth 1996; 76: 3007
13 Knudsen K, Beckman Suurküla M, Blomberg S, Sjövall J, Edvardsson N. Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth 1997; 78: 50714
14 Cederholm J, Evers H, Lofstrom JB. Skin blood flow after intradermal injection of ropivavacine in various concentrations with and without epinephrine evaluated by laser-Doppler flowmetry. Reg Anesth 1992; 17: 3228[ISI][Medline]
15 Arvidsson T, Eklund E. Determination of free concentration of ropivacaine and bupivacaine in blood plasma by ultrafiltration and coupled-column liquid chromatography. J Chromatogr 1995; 668: 918
16 Gough K, Hutchison M, Keene O, et al. Assessment of dose proportionality: report from the statisticians in the pharmaceutical industry/pharmacokinetics UK joint working party. Drug Inf J 1995; 29: 103948
17 Smith I, Hemelrijk J van, White PF. Effects of local anesthesia on recovery after outpatient arthroscopy. Anesth Analg 1991; 73: 5369[Abstract]
18 Cook TM, Tuckey JP, Nolan JP. Analgesia after day-case knee arthroscopy: double-blind study of intra-articular tenoxicam, intra-articular bupivacaine and placebo. Br J Anaesth 1997; 78: 1638
19 Convery PN, Milligan KR, Quinn P, Scott K, Clarke RCN. Low dose intra-articular ketorolac for pain relief following arthroscopy of the knee joint. Anaesthesia 1998; 53: 11259[ISI][Medline]
20 Martinsson T, Haegerstrand A, Dalsgaard CJ. Effects of ropivacaine on eicosanoid release from human granulocytes and endothelial cells in vitro. Inflamm Res 1997; 46: 398403[ISI][Medline]
21 Tucker GT, Mather LE. Properties, absorption, and disposition of local anesthetic agents. In: Cousins MJ, Bridenbaugh PO, eds. Neural Blockade in Clinical Anesthesia and Management of Pain. Philadelphia: Lippincott-Raven, 1998; 5595.
22 Emanuelsson B-M, Persson J, Alm C, Heller A, Gustafsson LL. Systemic absorption and block after epidural injection of ropivacaine in healthy volunteers. Anesthesiology 1997; 87: 130917[ISI][Medline]
23 Mulroy M, Burgess F, Emanuelsson BM. Ropivacaine 0.25% and 0.5%, but not 0.125% provide effective wound infiltration analgesia after outpatient hernia repair, but with sustained plasma drug levels. Reg Anesth Pain Med 1999; 24: 13641[ISI]
24 Garret Sullivan S, Abbott PJ. Cardiovascular toxicity associated with intra-articular bupivacaine. Anesth Analg 1994; 79: 5913[ISI][Medline]