Levobupivacaine: a review of its pharmacology and use as a local anaesthetic

Based on findings that the cardiotoxicity infrequently observed with racemic bupivacaine shows enantioselectivity, i.e. it is more pronounced with the R(+)-enantiomer, the S(-)-enantiomer (levobupivacaine) has been developed for clinical use as a long acting local anaesthetic. The majority of in vitro, in vivo and human pharmacodynamic studies of nerve block indicate that levobupivacaine has similar potency to bupivacaine. However, levobupivacaine had a lower risk of cardiovascular and CNS toxicity than bupivacaine in animal studies. In human volunteers, levobupivacaine had less of a negative inotropic effect and, at intravenous doses >75 mg, produced less prolongation of the QTc interval than bupivacaine. Fewer changes indicative of CNS depression on EEG were evident with levobupivacaine. Levobupivacaine is long acting with a dose-dependent duration of anaesthesia. The onset of action is < or = 15 minutes with various anaesthetic techniques. In studies of surgical anaesthesia in adults, levobupivacaine provided sensory block for up to 9 hours after epidural administration of < or = 202.5 mg, 6.5 hours after intrathecal 15 mg, and 17 hours after brachial plexus block with 2 mg/kg. Randomised, double-blind clinical studies established that the anaesthetic and/or analgesic effects of levobupivacaine were largely similar to those of bupivacaine at the same dose. Sensory block tended to be longer with levobupivacaine than bupivacaine, amounting to a difference of 23 to 45 minutes with epidural administration and approximately 2 hours with peripheral nerve block. With epidural administration, levobupivacaine produced less prolonged motor block than sensory block. This differential was not seen with peripheral nerve block. Conditions satisfactory for surgery and good pain management were achieved by use of local infiltration or peribulbar administration of levobupivacaine. Levobupivacaine was generally as effective as bupivacaine for pain management during labour, and was effective for the management of postoperative pain, especially when combined with clonidine, morphine or fentanyl. The tolerability profiles of levobupivacaine and bupivacaine were very similar in clinical trials. No clinically significant ECG abnormalities or serious CNS events occurred with the doses used. The most common adverse event associated with levobupivacaine treatment was hypotension (31%). Conclusions: Levobupivacaine is a long acting local anaesthetic with a clinical profile closely resembling that of bupivacaine. However, current preclinical safety and toxicity data show an advantage for levobupivacaine over bupivacaine. Clinical data comparing levobupivacaine with ropivacaine are needed before the role of the drug can be fully established. Excluding pharmacoeconomic considerations, levobupivacaine is an appropriate choice for use in place of bupivacaine.     

Cardiotoxicity with modern local anaesthetics: is there a safer choice?

The recognition that long-acting local anaesthetics, particularly bupivacaine the de facto standard long-acting local anaesthetic, were disproportionately more cardiotoxic than their shorter-acting counterparts stimulated the development of the bupivacaine congeners, ropivacaine and levobupivacaine. These agents, like all local anaesthetics, can produce cardiotoxic sequelae by direct and indirect mechanisms that derive from their mode of local anaesthetic actions, i.e. inhibition of voltage-gated ion channels. While all local anaesthetics can cause direct negative inotropic effects, ropivacaine and levobupivacaine are less cardiotoxic than bupivacaine judging by the larger doses tolerated in laboratory animal preparations before the onset of serious cardiotoxicity (particularly electro-mechanical dissociation or malignant ventricular arrhythmias). Additionally, they are less toxic to the CNS than bupivacaine judging by the larger doses tolerated before the onset of seizures. This may be clinically important because CNS effects may be involved in the production of serious cardiotoxicity. Preclinical studies in humans are a 'blunt instrument' in their ability to distinguish significant differences between these drugs because of the relatively small doses that can be used. Nevertheless, available evidence from human studies corroborates the preclinical laboratory animal studies. Because clinically significant differences between these drugs are more quantitative than qualitative, i.e. toleration of a larger dose before manifestation of toxicity, we have concluded that these newer agents have a lower risk of causing serious cardiotoxicity than bupivacaine. Thus, compared with bupivacaine, the newer agents may be seen as 'safer', but they must not be regarded as 'safe'.     

Effects of levobupivacaine,ropivacaine and bupivacaine on HERG channels: stereoselective bupivacaine block

1 Levobupivacaine and ropivacaine are the pure S(-) enantiomers of N-butyl- and N-propyl-2',6'-pipecoloxylidide, developed as less cardiotoxic alternatives to bupivacaine. In the present study, we have analysed the effects of levobupivacaine, ropivacaine and bupivacaine on HERG channels stably expressed in CHO cells. 2 The three drugs blocked HERG channels in a concentration-, time- and state-dependent manner. Block measured at the end of 5 s pulses to -10 mV induced by 20 microM bupivacaine (52.7+/-2.0%, n=15) and ropivacaine (55.5+/-2.7%, n=13) was similar (P>0.05) and both lower than that induced by levobupivacaine (67.5+/-4.2%, n=11) (P<0.05). 3 Dextrobupivacaine (20 microM) was less potent (47.2+/-5.2%, n=10) than levobupivacaine (P<0.05), indicating stereoselective HERG channel block. 4. Block induced by the three local anaesthetics exhibited a steep voltage dependence in the range of channel activation. In all cases, block measured at the maximum peak current at a test potential of 0 mV after promoting recovery from inactivation (I-->O) was lower than that observed at the end of 5-s pulses (I+O). 5. Levobupivacaine, ropivacaine and bupivacaine accelerated HERG inactivation kinetics, slowed the recovery from inactivation and shifted the inactivation curve towards more negative membrane potentials. The three local anaesthetics induced a rapid time-dependent decline after using a protocol that quickly activates HERG channels. 6. All these results suggest that: (1) these drugs bind to the open and the inactivated states of HERG channels, (2) they stabilize HERG channels in the inactivated state, and (3) block induced by bupivacaine enantiomers is stereoselective.     

Effects of bupivacaine and ropivacaine on hemodynamic parameters in rabbits

In the present study the toxic effects of ropivacaine and bupivacaine on the cardiovascular and respiratory systems of rabbits were studied. Both drugs were administered intravenously at doses of 0.5, 1, 2.5, 5 and 10 mumol/kg. The effects of the two drugs on blood pressure, ECG and respiration rate were evaluated by considering the changes occurring 30 sec after intravenous bolus injection. High doses (5 and 10 mumol/kg) of bupivacaine and ropivacaine significantly reduced the heart rate and systolic pressure (p < 0.05). Five and 10 mumol/kg of bupivacaine significantly reduced diastolic pressure (p < 0.05), but only the 10 mumol/kg dose of ropivacaine had the same effect. Low doses of bupivacaine and high doses of ropivacaine significantly increased the PR interval, QRS duration and QT interval (p < 0.05). The 5 mumol/kg dose of bupivacaine caused ventricular tachycardia in 3 of 6 rabbits, whereas ropivacaine caused tachycardia in 1 of 5 rabbits. Neither drug had a significant effect on respiration rate or blood gas values (p > 0.05). The results indicate that ropivacaine is less cardiodepressive and arrhythmogenic than bupivacaine.     

Ropivacaine: a review of its use in regional anaesthesia and acute pain management

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.     

Update on ropivacaine

Long-acting local anaesthetics are primarily used in the practice of anaesthesia, particularly in regional anaesthesia and analgesia. Ropivacaine is a new long-acting local anaesthetic that has been the focus of interest because of its increased cardiovascular safety compared with bupivacaine. Other advantages of ropivacaine over bupivacaine include a greater sensorimotor differential block and shorter elimination half-life (t(1/2)), with a lower potential for accumulation. The most important attribute of ropivacaine, however, is its increased margin of safety compared with bupivacaine when given in equal doses. Many post-marketing studies have focused on the comparisons of efficacy in blocks and toxicity profiles of bupivacaine versus ropivacaine. Recent animal toxicity studies confirm the results of original studies showing that ropivacaine has less cardiovascular toxicity than bupivacaine with respect to direct myocardial depression, success of resuscitation and arrhythmogenic potential when given in equal doses. Reduced cardiotoxicity may be a distinct characteristic of ropivacaine. A review of current literature suggests that, at clinically relevant doses, ropivacaine provides the lowest potential risk of cardiotoxicity for inadvertent intravascular injection. Studies are currently under way comparing ropivacaine with levobupivacaine, the latest addition to the group of long-acting local anaesthetics.     

异丙酚抑制长效酰胺类局麻药致大鼠中毒惊厥作用的比较

目的:比较异丙酚抑制左旋布比卡因、罗哌卡因和布比卡因所致惊厥的作用。方法:64只Wistar大鼠随机分为对照组(C组)、左旋布比卡因组(L组)、罗哌卡因组(R组)和布比卡因组(B组),4组内再分为实验(EG)和异丙酚处理(PG)2个亚组(n=8)。L组、R组和B组分别经尾静脉泵入0.75%相应局麻药,速度均为2mg·kg-1·min-1,PG各亚组在出现惊厥反应后静脉注射2mg/kg异丙酚。C(EG)组泵入生理盐水,C(PG)组泵入生理盐水后静脉注射异丙酚。惊厥2h后,测定海马CA1区c-fos阳性细胞数、NO水平和一氧化氮合酶(NOS)活性表达。结果:除C组外各组均有惊厥发生。异丙酚处理组在给予异丙酚后很快抑制惊厥。与C(EG)组比较,L(EG)、R(EG)及B(EG)组海马CA1区c-fos阳性细胞数、NO含量以及NOS活性表达均显著增加(P<0.01)。L(PG)、R(PG)和B(PG)组海马CA1区c-fos阳性细胞数、NO含量以及NOS活性表达较对应的L(EG)、R(EG)及B(EG)组均明显减少(P<0.01)。L组与R组较B组c-fos阳性细胞数、NO水平和NOS活性表达的K值明显减小(P<0.01)。结论:异丙酚能在一定程度上抑制左旋布比卡因、罗哌卡因和布比卡因引起的惊厥,且对布比卡因致惊厥的抑制作用强于左旋布比卡因和罗哌卡因。     

Update on ropivacaine

Long-acting local anaesthetics are primarily used in the practice of anaesthesia, particularly in regional anaesthesia and analgesia. Ropivacaine is a new longacting local anaesthetic that has been the focus of interest because of its increased cardiovascular safety compared with bupivacaine. Other advantages of ropivacaine over bupivacaine include a greater sensorimotor differential block and shorter elimination half-life (t_1/2), with a lower potential for accumulation. The most important attribute of ropivacaine, however, is its increased margin of safety compared with bupivacaine when given in equal doses. Many post-marketing studies have focused on the comparisons of efficacy in blocks and toxicity profiles of bupivacaine versus ropivacaine. Recent animal toxicity studies confirm the results of original studies showing that ropivacaine has less cardiovascular toxicity than bupivacaine with respect to direct myocardial depression, success of resuscitation and arrhythmogenic potential when given in equal doses. Reduced cardiotoxicity may be a distinct characteristic of ropivacaine. A review of current literature suggests that, at clinically relevant doses, ropivacaine provides the lowest potential risk of cardiotoxicity for inadvertent intravascular injection. Studies are currently under way comparing ropivacaine with levobupivacaine, the latest addition to the group of long-acting local anaesthetics.     

Cardiac and CNS toxicity of levobupivacaine: strengths of evidence for advantage over bupivacaine.

Bupivacaine is currently the most widely used long-acting local anaesthetic. Its uses include surgery and obstetrics; however, it has been associated with potentially fatal cardiotoxicity, particularly when given intravascularly by accident. Levobupivacaine, a single enantiomer of bupivacaine, has recently been introduced as a new long-acting local anaesthetic with a potentially reduced toxicity compared with bupivacaine. Numerous preclinical and clinical studies have compared levobupivacaine with bupivacaine and in most but not all studies there is evidence that levobupivacaine is less toxic. Advantages for levobupivacaine are seen on cardiac sodium and potassium channels, on isolated animal hearts and in whole animals, anaesthetised or awake. In particular the intravascular dose of levobupivacaine required to cause lethality in animals is consistently higher compared with bupivacaine. In awake sheep, for example, almost 78% more levobupivacaine was required to cause death. In contrast, in anaesthetised dogs no differences were seen in the incidence of spontaneous or electrical stimulation- induced ventricular tachycardia and fibrillations among animals exposed to levobupivacaine or bupivacaine. The reversibility of levobupivacaine-induced cardiotoxicity has also been assessed. Some data point to an advantage of levobupivacaine over bupivacaine but this potential advantage was not confirmed in a recent study in anaesthetised dogs. Three clinical studies have been conducted using surrogate markers of both cardiac and CNS toxicity. In these studies levobupivacaine or bupivacaine were given by intravascular injection to healthy volunteers. Levobupivacaine was found to cause smaller changes in indices of cardiac contractility and the QTc interval of the electrocardiogram and also to have less depressant effect on the electroencephalogram. Assuming that levobupivacaine has the same local anaesthetic potency as bupivacaine, then, all things being equal, it is difficult to argue that levobupivacaine should not displace bupivacaine as the long-acting local anaesthetic of choice. It would appear, however, that levobupivacaine has not yet significantly displaced bupivacaine from the markets in which it is sold. This may be due to a lack of perceived safety benefit and/or consideration of the additional costs that are associated with switching to levobupivacaine, which is approximately 57% more expensive than bupivacaine. If the price of levobupivacaine were closer to bupivacaine then the argument to switch to levobupivacaine would undoubtedly be much stronger. With the continued clinical use of levobupivacaine the database available to make comparisons will increase and this may allow cost-benefit arguments to be made more forcefully for levobupivacaine in the future.     

Levobupivacaine: a new safer long acting local anaesthetic agent

The choice of local anaesthetic is influenced by several factors; it must provide effective anaesthesia and analgesia for the duration of the procedure and meet the expectations for post-operative pain management. Of primary concern is patient safety. Bupivacaine, currently the most widely used long acting local anaesthetic agent in both surgery and obstetrics, generally has a good safety record but its use has resulted in fatal cardiotoxicity, usually after accidental intravascular injection. Hence, for several years there has been a need for a long acting local anaesthetic, similar to bupivacaine, but with an improved cardiovascular safety profile. Levobupivacaine, the single enantiomer version of bupivacaine, offers a new long acting local anaesthetic, clinically equivalent in anaesthetic potency to bupivacaine, but with a reduced toxicity profile. Preclinical studies, from in vitro in single ion channels to whole large animal models, have unquestionably demonstrated that levobupivacaine is significantly less CNS toxic and cardiotoxic than bupivacaine. Cardiotoxicity is less easy to study in man, as the clinical signs are not usually seen until the CNS toxicity is marked, and well beyond that which is tolerable to volunteers or patients. Nevertheless, levobupivacaine has been shown to have less effect on myocardial contractility and QTc prolongation, early signs of cardiotoxicity, than bupivacaine in healthy subjects. In clinical use levobupivacaine has been shown to be equally efficacious as bupivacaine at comparable doses and concentrations, and has been found to produce similar anaesthetic characteristics (onset, duration and density of block). As levobupivacaine now becomes commercially available, the database available with which to make efficacy and safety comparisons with other local anaesthetics will increase, and the true value of this new long acting local anaesthetic should become even more apparent.     

Clinical application of ropivacaine in obstetrics

Ropivacaine is a new long-acting local anesthetic which is a pure (S)-(-)-enantiomer, with an efficacy profile similar to that of bupivacaine. Compared in equal doses, ropivacaine shows more separation between sensory and motor blockade than bupivacaine. Moreover, ropivacaine has a lower systemic toxicity than bupivacaine. In obstetrics, ropivacaine and bupivacaine have been compared for Cesarean section and for epidural pain relief during labor and delivery. For Cesarean section, both drugs provide similar analgesia when given in equal doses, but motor block is less pronounced with ropivacaine. Neonatal outcome as determined by Apgar scores and Neurological Adaptive Capacity Scores (NACS) is also similar. For epidural pain relief during labor and delivery, both drugs are equally effective, either when given alone or in combination with opioids; a meta-analysis of six studies showed that compared to bupivacaine, the use of ropivacaine is associated with significantly less motor block and instrumental deliveries.     

Comparative effects of levobupivacaine and racemic bupivacaine on excitotoxic neuronal death in culture and N-methyl-D-aspartate-induced seizures in mice

We compared the neurotoxic profile of racemic bupivacaine and levobupivacaine in: (i) a mouse model of N-methyl-D-aspartate (NMDA)-induced seizures and (ii) in an in vitro model of excitotoxic cell death. When used at high doses (36 mg/kg) both bupivacaine and levobupivacaine reduced the latency to NMDA-induced seizures and increased seizure severity. However, levobupivacaine-treated animals underwent less severe seizures as compared with bupivacaine-treated animals. Lower doses of levobupivacaine and bupivacaine had opposite effects on NMDA-induced seizures. At doses of 5 mg/kg, levobupivacaine increased the latency to partial seizures and prevented the occurrence of generalized seizures, whereas bupivacaine decreased the latency to partial seizures and did not influence the development of generalized seizures. In in vitro experiments, we exposed primary cultures of mouse cortical cells, containing both neurons and astrocytes, to 100 microM NMDA for 10 min for the induction of excitotoxic neuronal death. This treatment killed 70-80% of the neuronal population, as assessed 24 h after the excitotoxic pulse. In this particular model, both levobupivacaine and bupivacaine were neuroprotective against NMDA toxicity. However, neuroprotection by levobupivacaine was seen at lower concentrations (with respect to bupivacaine) and was maintained at concentrations of 3 mM, which are much higher than the plasma security threshold for the drug in vivo. In contrast, no protection against NMDA toxicity was detected when 3 mM concentrations of bupivacaine were applied to the cultures. Our data show a better neurotoxic profile of levobupivacaine as compared to racemic bupivacaine, and are indicative of a safer profile of levobupivacaine in clinical practice.     

Benefit and risks of local anesthetics in infants and children

Regional anesthesia has become a routine part of the practice of anesthesiology in infants and children. Local anesthetic toxicity is extremely rare in infants and children; however, seizures, dysrhythmias, cardiovascular collapse, and transient neuropathic symptoms have been reported. Infants and children may be at increased risk from local anesthetics compared with adults. Larger volumes of local anesthetics are used for epidural anesthesia in infants and children than in adults. Metabolism and elimination of local anesthetics can be delayed in neonates, who also have decreased plasma concentrations of alpha(1)-acid glycoprotein, leading to increased concentrations of unbound bupivacaine. Most regional anesthetic procedures in infants and children are performed with the patient heavily sedated or anesthetized; because of this, and because a test dose is not a particularly sensitive marker of intravenous injection in the anesthetized patient, detection of intravascular local anesthetic injection is extremely difficult. The same local anesthetics used in adult anesthetic practice are also used in infants and children. Because of its extremely short duration of action, chloroprocaine has been used primarily for continuous epidural techniques in infants and children. The use of tetracaine has generally been limited to spinal and topical anesthesia. Lidocaine (lignocaine) has been used extensively in infants and children for topical, regional, plexus, epidural and spinal anesthesia. The association between prilocaine and methemoglobinemia has generally restricted prilocaine use in infants and children to the eutectic mixture of local anesthetics (EMLA). Because of its greater degree of motor block compared with other long-acting local anesthetics, etidocaine has generally been limited to plexus blocks in infants and children. Mepivacaine has been used for both plexus and epidural anesthesia in infants and children. Because postoperative analgesia is often the primary justification for regional anesthesia in infants and children, bupivacaine, a long-acting local anesthetic, is the most commonly reported local anesthetic for pediatric regional anesthesia. Given the lower toxic threshold of bupivacaine compared with other local anesthetics, the risk-benefit ratio of bupivacaine may be greater than that of other local anesthetics. Two new enantiomerically pure local anesthetics, ropivacaine and levobupivacaine, offer clinical profiles comparable to that of bupivacaine but without its lower toxic threshold. The extreme rarity of major toxicity from local anesthetics suggests that widespread replacement of bupivacaine with ropivacaine or levobupivacaine is probably not necessary. However, there are clinical situations, including prolonged local anesthetic infusions, use in neonates, impaired hepatic metabolic function, and anesthetic techniques requiring a large mass of local anesthetic, where replacement of bupivacaine with ropivacaine, levobupivacaine or (for continuous techniques) chloroprocaine appears prudent.     

Central Effects Index--a semiquantitative method for the assessment of CNS toxicity of local anaesthetic agents in sheep

Local anaesthetic agents can cause central nervous system (CNS) and cardiovascular system toxicity. Whereas most previous work has described their behavioural CNS effects qualitatively (i.e., absence or presence of convulsions), we wished to describe their CNS effects more quantitatively. We hypothesised that early CNS excitatory or disinhibitory effects leading to convulsions represent a prodrome to the onset of chaotic dynamics in the form of a bifurcation in the chaotic map. We therefore used a chaotic map with a continuous scale to model their CNS effects. A Central Effects Index (CEI) was developed from our observation of behaviours before and after intravenous (iv) administration of local anaesthetic agents in graded doses to conscious sheep. These behaviours were ranked in severity, and modelled according to a logistic population growth equation using the onset of convulsive behaviour and death as point attractors. The behaviours, scaled to the maximum and area under the curve (AUC) CEI units, were then compared for intravenous doses of (+/-)-RS-bupivacaine and (-)-(S)-bupivacaine (or levobupivacaine), which is being evaluated as a substitute for (+/-)-RS-bupivacaine. (-)-(S)-bupivacaine produced smaller maximum and AUC CEI values at 75 and 100 mg doses, but equivalent values at 150 and 200 mg when the doses exceeded the convulsant threshold. It was concluded that the CEI provides a useful quantitative tool for evaluating these agents in subconvulsant doses, and that the CNS stimulatory potency of (-)-(S)-bupivacaine is less than that of (+/-)-RS-bupivacaine.     

Pharmacological effects of the non-competitive NMDA antagonist CNS 1102 in normal volunteers.

1. Non-competitive antagonists at the glutamatergic N-methyl D-aspartate receptor significantly reduce the volume of ischaemic cerebral infarction in animals and are potential agents for the treatment of acute stroke in humans. 2. CNS 1102, a novel non-competitive NMDA antagonist, was administered as a 15 min intravenous infusion to healthy male volunteers in a double-blind, placebo-controlled, dose-ranging study. This was the first administration to man. 3. Clinically significant sedation, increased mean arterial pressure and pulse rate were seen at doses of 30 micrograms kg-1 and above. Symptoms of sedation and central nervous excitation became unacceptable for conscious individuals at doses of 45 micrograms kg-1 and above. 4. Rapid onset of central nervous system effects after administration is in keeping with rapid distribution of CNS 1102 to brain. Steady state volume of distribution was large (444 l) and terminal elimination half-life from plasma was approximately 4 h. 5. Pharmacokinetic properties are favourable for a potential neuroprotective therapy. The maximum tolerated dose for conscious individuals was 30 micrograms kg-1 given intravenously over 15 min. Further assessment of CNS 1102 should seek methods of drug administration which maximise administered dose with minimal side effects.     

Bupivacaine and ropivacaine: comparative effects on nerve conduction block

Unlike other drugs which act in the region of the synapse, local anesthetics are agents that reversibly block the generation and conduction of nerve impulses along a nerve fiber. This study aims to investigate the comparative inhibitions of bupivacaine and ropivacaine on the frog sciatic nerve. Isolated nerves were transferred to the nerve chamber which includes Ringer's solution. The nerves were stimulated by standard square wave pulse protocols and the responses were recorded with conventional systems. Bupivacaine (n = 8) and ropivacaine (n = 8) were administered in the nerve chamber bath with cumulative concentrations (10(-9) to 10(-3) M) and the effects were monitored for variable time periods (5, 10 and 15 min). Both bupivacaine and ropivacaine significantly depressed the compound action potential (CAP) parameters in a dose-dependent (p < 0.05) and reversible manner. Difference in the effects of these two drugs was detectable only when the dose (> or =10(-5) M) and exposure time (15 min) were increased. Percent inhibitions in maximum derivatives and latency-period measurements have shown that ropivacaine is not only fast but also much more powerful in conduction block for longer and higher doses. Bupivacaine, on the other hand, is effective in the group of fibers with relatively slower conduction velocity for all the measured doses and time periods. In conclusion, ropivacaine has a sensory specific side of action, when compared with the bupivacaine.     

Efficacy of levobupivacaine wound infiltration with and without intravenous lornoxicam for post-varicocoele analgesia: a randomized, double-blind study

BACKGROUND AND OBJECTIVE: The oxicam NSAID lornoxicam is a potent analgesic with excellent anti-inflammatory properties in a range of painful and/or inflammatory conditions, including postoperative pain. Levobupivacaine, the S-(-)-isomer of bupivacaine, is a long-acting local anaesthetic that can be infiltrated into wounds for management of postoperative pain. We assessed the analgesic efficacy of lornoxicam when administered as an adjuvant to levobupivacaine wound infiltration after varicocoele operation. METHODS: Sixty patients who underwent varicocoele surgery were randomly assigned to three different treatment groups. Before skin closure, patients received the following treatments: group I (n=20) patients received normal saline 20 mL wound infiltration and intravenous lornoxicam (Xefo, Nycomed Pharma AS, Roskilde, Denmark) 2 mL (8 mg); group II (n=20) patients received 0.25% levobupivacaine (Chirocaine, Abbott Scandinavia AB, Solna, Sweden) 10mL with normal saline 10 mL wound infiltration and intravenous normal saline 2 mL; group III (n=20) patients received 0.25% levobupivacaine 10 mL with normal saline 10 mL wound infiltration and intravenous lornoxicam 2 mL (8 mg). Pain scores and total pethidine (meperidine) consumption were measured at 1, 2, 4, 6, 12 and 24 hours postoperatively. Time to first analgesic requirement and patient satisfaction were also compared post-surgery. RESULTS: Pain scores during the first 6 hours postoperatively were significantly lower in group III than in group I and group II (p<0.01). Total pethidine consumption was significantly lower in group III (34.0+/-28.0 mg) than in group I (74.0+/-25 mg) and group II (76.0+/-29 mg) [p<0.01]. Time to first analgesic was also significantly longer in group III (14.8+/-8.4 hours) than in group I (6.2+/-5.2 hours) and group II (5.8+/-7.1 hours) [p<0.01]. The incidence of postoperative nausea and vomiting was significantly lower in group III than in group I and group II (p<0.05). More patients in group III described their analgesia as good or excellent than in group I or group II (p<0.01). CONCLUSION: In this study, levobupivacaine wound infiltration with adjuvant intravenous lornoxicam administration was associated with better postoperative analgesia during the early postoperative hours after varicocoele surgery than that induced by lornoxicam alone or levobupivacaine wound infiltration alone.     

Ropivacaine: an update of its use in regional anaesthesia

Ropivacaine is a long-acting, enantiomerically pure (S-enantiomer) amide local anaesthetic with a high pKa and low lipid solubility which blocks nerve fibres involved in pain transmission (Adelta and C fibres) to a greater degree than those controlling motor function (Abeta fibres). The drug was less cardiotoxic than equal concentrations of racemic bupivacaine but more so than lidocaine (lignocaine) in vitro and had a significantly higher threshold for CNS toxicity than racemic bupivacaine in healthy volunteers (mean maximum tolerated unbound arterial plasma concentrations were 0.56 and 0.3 mg/L, respectively). Extensive clinical data have shown that epidural ropivacaine 0.2% is effective for the initiation and maintenance of labour analgesia, and provides pain relief after abdominal or orthopaedic surgery especially when given in conjunction with opioids (coadministration with opioids may also allow for lower concentrations of ropivacaine to be used). The drug had efficacy generally similar to that of the same dose of bupivacaine with regard to pain relief but caused less motor blockade at low concentrations. Lumbar epidural administration of 20 to 30ml ropivacaine 0.5% provided anaesthesia of a similar quality to that achieved with bupivacaine 0.5% in women undergoing caesarean section, but the duration of motor blockade was shorter with ropivacaine. For lumbar epidural anaesthesia for lower limb or genitourinary surgery, comparative data suggest that higher concentrations of ropivacaine (0.75 or 1.0%) may be needed to provide the same sensory and motor blockade as bupivacaine 0.5 and 0.75%. In patients about to undergo upper limb surgery, 30 to 40ml ropivacaine 0.5% produced brachial plexus anaesthesia broadly similar to that achieved with equivalent volumes of bupivacaine 0.5%, although the time to onset of sensory block tended to be faster and the duration of motor block shorter with ropivacaine. Ropivacaine had an adverse event profile similar to that of bupivacaine in clinical trials. Several cases of CNS toxicity have been reported after inadvertent intravascular administration of ropivacaine, but only 1 case of cardiovascular toxicity has been reported to date. The outcome of these inadvertent intravascular administrations was favourable. CONCLUSION: Ropivacaine is a well tolerated regional anaesthetic with an efficacy broadly similar to that of bupivacaine. However, it may be a preferred option because of its reduced CNS and cardiotoxic potential and its lower propensity for motor block.     

Actions of three local anaesthetics: lidocaine, bupivacaine and ropivacaine on guinea pig papillary muscle sodium channels (Vmax)

The new local anaesthetic ropivacaine (LEA 103) like lidocaine and bupivacaine used as references, blocked cardiac sodium channels in a use-dependent fashion. At equimolar concentrations lidocaine had the lowest efficacy and bupivacaine the highest. The action potential was shortened and the plateau was depressed at high concentrations of each drug. Pacing a papillary muscle at 3.3 Hz in the presence of all three drugs resulted in a marked use-dependent accumulation of block (P less than 0.01). The accumulated block slowly dissipated after rest. At -90 mV holding (= resting) potential, and at a concentration of 10 microM, the time constant for recovery from block was 186 msec. in lidocaine (n = 4), 1.4 sec. in ropivacaine (n = 7), and 2.1 sec. in bupivacaine (n = 7). Lidocaine decreased Vmax progressively at high rates of stimulation, but not significantly at rates below 2 Hz. Ropivacaine progressively decreased Vmax significantly at rates above 1 Hz, but to a lesser degree than bupivacaine. The use-dependent action of the drugs was increased at more depolarized (less negative) holding potentials, whereas at more hyperpolarized potentials the block was diminished. Lidocaine and ropivacaine could be readily dissociated from the receptors at more hyperpolarized membrane potentials (-100 to -120 mV), whereas bupivacaine bound much harder. All three drugs blocked sodium channels more effectively after a long single conditioning pulse. Bupivacaine had the most prominent effect, and lidocaine was least effective. Bupivacaine and ropivacaine seem to interact with the inactivated state of the sodium channels, whereas lidocaine acted on both the open and on the inactivated state of the channels.(ABSTRACT TRUNCATED AT 250 WORDS)