Eur J Anaesthesiol 2014; 31:575–585

REVIEW

Local anaesthetics: 10 essentials Philipp Lirk, Susanne Picardi and Markus W. Hollmann This review seeks to address 10 essential questions regarding the clinical use of local anaesthetics. Each local anaesthetic has distinctive physicochemical properties but with the same mode of action; they block voltage-gated sodium channels in the axon. Sodium channel block is brought about by a conformational change and the creation of a positive charge in the channel pore. Different local anaesthetics can reach the local anaesthetic binding site in the axon from the cytoplasmic compartment (classic hydrophilic pathway), or directly via its lipid membrane (hydrophobic pathway), or can enter via large-pore channels (alternative hydrophilic pathway). Beyond the nervous system, local anaesthetics exert beneficial effects on pain and can affect the inflammatory response and the haemostatic system. There are problems with the efficacy of local anaesthetics in the presence of local inflammation, and with significant intravascular toxicity, which can be fatal. But when preventive measures are taken, the incidence of cardiac arrest is low. Intralipid has been proposed to treat systemic local anaesthetic overdose and has

Local anaesthetics are widely used both independently for regional anaesthesia and in combination with general anaesthesia. They play a major role in the management of acute and chronic pain. This review seeks to address 10 essential topics regarding the use of local anaesthetics in daily practice.

General physicochemical properties Local anaesthetics are a heterogeneous group of compounds that block voltage-gated sodium channels (VGSCs). Their molecular structure shares common features, with a hydrophobic aromatic group, an amide group and the connecting intermediary chain. This gives the molecule both hydrophobic and hydrophilic properties. Local anaesthetics are often categorised into ester-linked and amide-linked compounds according to the type of the intermediary chain. They can also be divided into shortacting (e.g. chloroprocaine), intermediate-acting (e.g.

been enthusiastically adopted worldwide, even though the mechanism of action is incompletely understood. Intralipid is an aid to the management of local anaesthetic toxicity rather than an antidote and meticulous conduct of regional anaesthesia remains paramount. All local anaesthetics are toxic, in a dose- and time-dependent manner, on virtually all tissues, including nerves and muscles. The question of whether local anaesthetics protect against perioperative tumour progression cannot be answered at this moment, and results from clinical (retrospective) studies are equivocal. Future areas of interest will be the design of new subtype-specific sodium channel blockers, but as we look forward, older local anaesthetics such as 2-chloroprocaine are being reintroduced into the clinical setting. Multimodal perineural analgesia and liposomal bupivacaine may replace catheter techniques for some indications.

Published online 4 September 2014

mepivacaine, lidocaine) and long-acting (e.g. bupivacaine, ropivacaine) compounds. Ester-linked local anaesthetics are metabolised by plasma cholinesterases and tissue esterases, whereas amide-linked local anaesthetics are primarily metabolised in the liver through the mixedfunction oxidase system.1 A defect at any stage of metabolism has the potential to increase systemic concentrations. All local anaesthetics are hypoallergenic and are widely considered to be among the safest perioperative drugs in this regard.2 The pipecolyl xylidide family of local anaesthetics, featuring bupivacaine and ropivacaine, is chiral, which means that they feature an asymmetrical carbon atom and one or other of two spatial molecular configurations, called enantiomers (optical isomers). Lidocaine is achiral and has a single molecular presentation.3 An optical isomer rotates polarised light either to the left (levo) or

From the Department of Anaesthesiology, Academic Medical Centre, University of Amsterdam, the Netherlands (PL, MWH), and the Department of Anaesthesiology, University Hospital Heidelberg, Germany (SP) Correspondence to Dr Philipp Lirk, Department of Anaesthesiology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands Tel: +31 20 566 4032; fax: +31 20 697 9441; e-mail: [email protected] 0265-0215 ß 2014 Copyright European Society of Anaesthesiology

DOI:10.1097/EJA.0000000000000137

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576 Lirk et al.

Table 1

Physicochemical properties of local anaesthetics

Substance

pKa

LAb (%)

O/B coeff

PB (%)

MW (Da)

EAC

Lidocaine Mepivacaine Bupivacaine Ropivacaine Prilocaine Procaine Articaine

7.9 7.6 8.1 8.1 7.9 8.9 7.8

25 39 15 15 24 3 28

2.4 21 346 115 25 1.7 17

64 77 95 94 55 6 70

234 246 288 274 220 236 321

1 1 0.25 0.5 1 2 1

Physicochemical properties pKa value, ionised fraction of LA (LAb) at pH 7.4 (in %), oil/buffer coefficient (O/B) with h-octanol/buffer at pH 7.4 and 258C, protein binding (PB, in %), molecular weight (MW, in Dalton) and relative effective anaesthetic concentrations at rat sciatic nerve (EAC). Adapted with permission from 7.

the right (dextro). Chiral local anaesthetics may exist as pure levo or dextro, or as a 50–50 mixture of each (racemate). The clinical relevance of chirality is that some pure enantiomers may offer pharmacological advantages over racemic mixtures, such as enhanced blockade and decreased toxicity.4 However, the differences in clinical use when comparing equipotent doses are modest, such that both conventional drugs such as bupivacaine, as well as the newer enantiomers, levobupivacaine and ropivacaine, continue to be in widespread use.5 Claims of differences between the three drugs concerning toxicity and differential blockade have been extensively studied, but many studies have failed to take into account the 40 to 50% potency difference between bupivacaine and ropivacaine.6 The reader is referred to the excellent review by Casati and Putzu6 on the differential pharmacology of long-acting local anaesthetics. Local anaesthetics have distinct physicochemical properties that determine their mode of action, most notably the pKa value, and the degrees of lipophilicity, protein binding and intrinsic vasoactivity. The main characteristics of drugs in clinical use are summarised in Table 1.7 The principal determinant of adverse systemic effects is the free fraction of local anaesthetic that is not bound by plasma proteins. The rate of absorption into the systemic circulation depends upon the site of injection. For example, equal plasma concentrations of lidocaine are attained when 300 mg is given intercostally, or 500 mg epidurally, or 1000 mg subcutaneously.8 A multifactorial approach to choosing well tolerated doses on an individual basis has been advocated, for which the reader is referred to the comprehensive review by Rosenberg et al.8 In plasma, local anaesthetics are bound to albumin, an abundant protein with weak affinity for local anaesthetic, and, more importantly, alpha-1-acidic glycoprotein (AAG), which is less abundant but is a potent binder of local anaesthetic.9 As AAG is an acute phase protein, synthesis increases postoperatively and after trauma, decreasing free local anaesthetic, and protecting against systemic toxicity. This was shown by Veering et al.,10 who found that a continuous postoperative infusion of epidural bupivacaine led to increasing levels of total local anaesthetic in the systemic circulation, but at the same

time, increasing postoperative AAG levels bound with bupivacaine resulting in stable systemic levels of free drug. Because synthesis of AAG does not mature before 1 year of age, neonates are theoretically at a higher risk of elevated free local anaesthetic plasma levels.9 Experimental evidence suggests that in pregnancy, protein binding of the more lipophilic bupivacaine is decreased, similarly increasing risk of systemic toxicity.11 Local anaesthetics are a heterogeneous group of compounds that block VGSCs. Each drug is characterised by distinctive physicochemical properties. The concentration of free local anaesthetic in the plasma determines systemic toxicity.

The primary target: voltage-gated sodium channels Local anaesthetics are primarily characterised by their ability to block VGSCs. The latter are protein-based structures that sit within the axon cell membrane. Crystallographic images have become available revealing that they consist of one main a-subunit, linked to one or more b-subunits.12,13 The a-subunit of the VGSC is the functional ion channel and harbours the binding site for local anaesthetics.14 This subunit consists of four domains numbered DI-DIV, each consisting of six segments numbered S1-S6 (Fig. 1).15–17 In contrast, the b-subunits of the VGSC modulate the kinetics and voltage dependence of activation and inactivation.14 The S1-S4 segments are considered the ‘voltage sensor’, and specific amino acid sequences between segments S5 and S6 mediate the channel’s specificity for sodium.18 The binding sites of local anaesthetic are the S6 segments of domains I, III and IV.14 Figure 2 gives a diagrammatic view of the VGSC in cross-section, with (from the outside) the extracellular pore, the selectivity filter, the central cavity and the innermost activation gate. Local anaesthetics preferably bind to open and inactivated channels, because in these states, the activation gate is open, a property described as use-dependent block.14 Under experimental conditions, binding of local anaesthetic to the receptor leads to a reversible and concentration-dependent reduction in the peak sodium current.12 This is achieved by modulation of the dynamic conformation of the voltage-sensing segments S4 across the domains of the VGSC,19 and by the creation of a positive charge within the channel’s pore, directly impeding sodium flux.20 There are at least 10 different subtypes of VGSC depending on the gene for the a-subunit. Dysfunction or mutation has been linked to several pathophysiological states, such as inherited erythromelalgia (syndrome of pain and erythema),15 paroxysmal extreme pain disorder,16 congenital insensitivity to pain,16 cardiac arrhythmias21 and epilepsy.22 Lastly, drugs other than local anaesthetics can effectively block the neuronal sodium channel. Of these, two

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Local anaesthetics

577

Fig. 1

DI

N

D II

L1

D III

L2

D IV

L3

C

Inactivation peptide Homozygous Compound heterozygous Inherited erythromelalgia I136V F216S S241T N395K I848T L858H

L858F A863P F1449V

Paroxysmal extreme pain disorder R996C T1464I V1298F M1627K V1298D V1299F I1461T F1462V

Nav 1.7-related Congenital indifference to pain R277X W897X Y328X F1200LfsX33 S459X ∆11bpl1235LfsX2/K1659X E693X/I2 ∆GTTT I767X R830X

R1488X W1689X

Spatial configuration of the alpha subunit of the voltage-gated sodium channel. The most frequent mutations related to inherited erythromelalgia,16 paroxysmal extreme pain disorder,17 congenital insensitivity to pain17 are given. Reproduced with permission from 17.

members of the opiate family, pethidine and buprenorphine, have clinically relevant local anaesthetic properties.23,24 Sodium channel block is caused by a conformational change and the creation of a positive charge in the channel lumen.

The three ways for local anaesthetics to block the primary target To block the VGSC, classic local anaesthetics in contemporary use need to attach to a specific binding site on the inner surface of the channel, which they cannot access from outside the axon through the sodium-specific channel itself. Following the ‘classic hydrophilic’ pathway, local anaesthetics need to traverse the cell membrane as uncharged molecules first, and then conjugate with hydrogen ions and reach the binding site from the cytoplasm (Fig. 2). Another pathway, described as ‘hydrophobic’, is seen with benzocaine, a permanently uncharged local anaesthetic, characterised by its low pKa value, and primarily used for topical anaesthesia.25 It reaches the sodium channel directly through the nerve membrane and then lateral fenestrations in the channel, a concept supported by recent crystallographic investigations.13

There is an alternative hydrophilic pathway seen with the permanently charged lidocaine derivative, QX-314. Because it is charged, QX-314 will only very slowly cross nerve cell membranes. However, artificial activation of the transient receptor potential vanilloid-1 (TRPV-1) channel creates a pore large enough to allow for the influx of QX-314.26 Conduction block by local anaesthetics begins with the non or thinly myelinated fibres (those responsible for the sympathetic nervous system and nociception), whereas fibres with the thickest myelin sheaths (motor fibres) are blocked last. However, this effect cannot be explained solely on the basis of different myelin sheath diameters. For example, Huang et al.27 demonstrated that C-type fibres were more resistant to blockade than Ad and Ab-type fibres, which have a larger myelin sheath. Rather, it is increasingly appreciated that different neuronal populations differ not only by myelin thickness and size but also by different patterns of electrophysiological properties and ion channel composition.28 Local anaesthetics in common use act via the classic hydrophilic pathway, reaching the local anaesthetic binding site from the cytoplasmic compartment. Others may act directly via the lipid membrane (’hydrophobic pathway’), or can enter via large-pore channels (’alternative hydrophilic pathway’).

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578 Lirk et al.

Fig. 2

B ó ΒΗ+

(a)

(b) Top view

Side view

F203

Pore portal

B ó ΒΗ+ Crystallographic structure of the sodium channel. (a) Side view of the sodium channel, with (from top) extracellular pore, the selectivity filter, the central cavity and the innermost activation gate, and (b) Top view of the same structure. Local anaesthetics exist in an equilibrium between the uncharged form B and the charged form BHþ, where B can cross the membrane but BHþ is required to bind to the channel. Hþ denotes hydrogen ions. Adapted with permission from 13.

The secondary targets: from ion channels to G-protein coupled receptors In addition to sodium channel blockade, local anaesthetics also interact with a wide array of alternative target structures, for example tetrodotoxin-resistant sodium channels, potassium channels, calcium channels, N-methyl-D-aspartate (NMDA) receptors and G-protein coupled receptors.1 Their wide range of activity has seen them well established in therapeutic roles requiring systemic rather than local application. Specific areas of use include administration of lidocaine as a class Ib antiarrhythmic acting on cardiac sodium channels to treat ventricular tachycardia/fibrillation/extrasystole, although recent guidelines limit its use.29 Other reserve uses have been described for status epilepticus and tinnitus.30,31 When therapeutic systemic doses are exceeded, tinnitus, seizure and arrhythmia are also hallmarks of systemic toxicity. Systemic local anaesthetics have a positive stabilising effect on some physiological systems. Firstly, some studies have described an antinociceptive effect of local anaesthetics,32 while others found no clinically relevant analgesic effect.33,34 The latter is potentially caused by lidocaine metabolites modulating glycinergic pathways,35 while antihyperalgesic effects may, at least in part, be explained by antagonism at the NMDA receptor.36 Secondly, lidocaine has for decades been used as a coanaesthetic, and recent evidence confirms an anaesthetic-sparing effect of lidocaine.37 Thirdly, local anaesthetics have a pronounced anti-inflammatory effect, as they modulate several steps of the inflammatory cascade, including leucocyte adhesion to the endothelium, shape change, transendothelial migration, phagocytosis, and priming and release of inflammatory mediators.38 In-vivo studies have shown that local anaesthetics attenuate inflammatory disorders, such as reperfusion injury in

the heart, lung and brain as well as endotoxin or hyperoxia-induced pulmonary injury.38 Mortality was significantly decreased in rats with septic peritonitis after continuous intravenous (i.v.) infusion of lidocaine.39 In patients undergoing colorectal surgery, perioperative systemic lidocaine improved gastrointestinal motility in addition to postoperative pain levels and shortened length of hospital stay significantly, possibly due to an attenuated stress response.34 Remarkably, as they tend to prevent excessive stimulation of the inflammatory system and do not impair host defence or suppress inflammation per se, local anaesthetics neither delay wound healing nor increase the rate of infection.40–42 Similarly, systemic local anaesthetics were thought to mediate perioperative hypercoagulability without affecting homeostasis.43 One potential mechanism underlying the anti-inflammatory effects of local anaesthetics may be the modulation of G-protein-coupled receptor signalling, in particular interference with G-proteins of the Gq/11 family, which predominantly mediate haemostatic and inflammatory signalling, such as the lysophosphatidic acid (LPA), thromboxane (TXA) 2 or platelet-activating factor (PAF)-receptors.44 However, the complete mechanisms of local anaesthetic action on these receptors and certain G-protein families remain undetermined. Amide-linked local anaesthetics can block potassium channels, contributing to a more intense nerve fibre block,45 and explaining symptoms of central nervous system (CNS) excitation such as tinnitus and seizures through depolarisation of thalamocortical neurones.46 Well recognised syndromes such as some forms of long QT syndrome (LQTS) due to potassium channel mutation share important pathogenic features with systemic toxicity of local anaesthetics.47 Another site of local anaesthetic blockade is the nicotinic acetylcholine receptor, a nonselective cation channel. This mechanism

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Local anaesthetics

of action is thought to contribute to the enhancement of neuromuscular blockade by local anesthetics,48 but the clinical importance seems minor.49 Alternative effects, however, depend on adequate systemic levels of local anaesthetic. Classic pharmacokinetic studies carried out on rodent sciatic nerves suggest that only a minor fraction of local anaesthetic actually participates in nerve block, the majority being absorbed into the systemic circulation.50 The use of ultrasound-guided regional anaesthesia has led to a reduction in the volumes administered.51 Renes et al.52 used approximately one-tenth of the dose of local anaesthetic that was proposed for interscalene block in the original description by Winnie.53 These smaller doses will invariably result in lower plasma levels of local anaesthetic, potentially decreasing the incidence and severity of systemic toxicity,54 and at the same time, resulting in the loss of the above-mentioned beneficial effects, which are only beginning to be fully appreciated and understood. In the view of the authors, the desire to benefit from systemic effects will need to be weighed against the challenge to find the minimum effective dose for daily clinical practice. Next to sodium channel blockade, local anaesthetics have additional effects when given or absorbed systemically. Specifically, systemic local anaesthetics have been shown to attenuate perioperative hyperalgesia, inflammation and hypercoagulability. They also block other ion channels (potassium, calcium, nicotinic acetylcholine). Systemic effects depend upon sufficient plasma levels.

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Neuronal excitability is a hypothesis that provides another explanation. Rood et al.61 suggested that peripheral sensitisation occurs following inflammation, with the potential to counteract nerve blockade. The hypothesis is underpinned by several pieces of experimental evidence. One is the observation that isolated rodent sciatic nerves immersed in inflammatory exudate showed a pro-excitatory shift and increases in compound motor action potentials, explaining the occurrence of nerve action potentials following the administration of local anaesthetic.55 A third hypothesis proposes that increased vascularity of the inflamed tissue leads to increased absorption.56 Supporting this hypothesis, Harris62 described improved efficacy in inflammatory conditions when local anaesthetic was injected together with a vasoconstrictor.63 This is in keeping with the observation by Rood59,60 that in dental anaesthesia for inflamed teeth, lidocaine 2% frequently failed to provide a satisfactory block, whereas the success rate of lidocaine 5% was excellent. This does not altogether solve the problem because the use of lidocaine 5% has largely been abandoned as a result of concerns over neurotoxicity, but it might point a way forward. It does indicate that the current viewpoint that inflammatory tissue renders local anaesthetic inactive should be replaced with ‘local anaesthetics may not function optimally in inflammatory tissue’. Inflamed tissue is harder, but not impossible, to anaesthetise. Increasing concentration or adding a vasoconstrictor can lead to successful blockade.

Systemic toxicity Local anaesthetics and inflamed tissue Local anaesthesia may not be successful when local anaesthetics are administered in the region of inflamed tissue.55,56 Three theories have been put forward to explain this: an acidic shift in tissue pH, increased excitability of nerves in inflamed tissues and increased vascularity leading to enhanced absorption. Any acidic shift will move the balance between ionised and unionised forms of local anaesthetic, resulting in less free base, and thus less free local anaesthetic to penetrate the cellular membrane. Reported pH values in inflamed tissue vary between 5 and 8.55,56 In experimental inflammation, after a short initial acidification, the pH returns to levels approximately 0.5 pH units lower than the norm of 7.4.56,57 However, even a small decrease of 0.5 pH units can shift the balance of charged and uncharged forms of local anaesthetic, lowering the available free base by up to 60%.58 Inflamed tissue appears to have a remarkable buffering capacity, allowing it to return to a near-physiological pH in a relatively short time.56 This may explain why simultaneous buffering when injecting the local anaesthetic into inflamed dental tissue made the drug no more effective than plain solution.59,60

Awareness of the dangers of local anaesthetic systemic toxicity (LAST) has led to the introduction of several safety measures, such as incremental administration of local anaesthetics, the use of test doses, repeated aspiration tests, compulsory monitoring of the patient and recommendations regarding maximum dosage. Recent large studies suggest a low incidence of important systemic toxicity. Barrington and Kluger,64 in a series of more than 20 000 patients, reported an overall incidence of mild signs of local anaesthetic systemic toxicity of approximately 1 : 1000, which fell to 1 : 1600 when ultrasound guidance was used. In the entire case series, only one incident progressed to cardiac arrest.64 Sites et al.65 in a case series of more than 12 000 patients did not report a single instance of cardiac arrest. In general, three forms of LAST can be differentiated. First, ‘instant’ LAST results from unintended i.v. injection of large amounts of local anaesthetic, typically resulting in cardiovascular collapse and seizures within a few circulation times. A second scenario leading to ‘instant’ LAST is accidental intra-arterial injection of local anaesthetic during blockades in the neck. This will result in immediate but short-lived seizures, which are rarely

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580 Lirk et al.

Fig. 3

Intralipid: critical appraisal

bpm mmHg

Administration of block Phase I – CNS excitation Phase II – CV depression Phase III – CV collapse

Sequence of events during local anaesthetic induced systemic toxicity. Increasing systemic concentrations of free local anaesthetic lead to a cascade of central nervous system and cardiac symptoms. CNS, central nervous system; CV, Cardiovascular.

associated with cardiovascular events due to the small volume usually administered. Third, ‘slow’ LAST results from excessive plasma levels due to overdosing, excessive absorption, reduced metabolism or reduced plasma protein binding. Slow LAST may occur up to 30 min after injection.66 The initial presentation of slow systemic toxicity will vary depending on the plasma level of free local anaesthetic. The classic presentation of systemic toxicity is a cascade of events beginning with CNS symptoms increasing in severity from excitation to seizure to coma. CNS excitation first causes an initial tachycardia and hypertension, but subsequently, cardiac side-effects predominate and lead to progressive circulatory collapse (Fig. 3). The clinical reality is different. A recent study estimated that only 60% of LAST cases follow the classical cascade, and in general, there is substantial interindividual variability in presentation.67 It should be kept in mind that local anaesthetics have differential cardiotoxic effects. Substances such as lidocaine and mepivacaine predominantly affect contractility, whereas ropivacaine, levobupivacaine and bupivacaine are negatively inotropic and highly arrhythmogenic.68 Traditionally, bupivacaine has been considered to be the most cardiotoxic local anaesthetic, based on the smaller dose needed to elicit toxicity compared with other local anaesthetics. However, when comparing bupivacaine with ropivacaine, for example, it is imperative to consider the 40 to 50% potency difference. Comparisons must be based on clinically equivalent doses. In animal models of toxicity, ropivacaine and bupivacaine are near equipotent in eliciting CNS symptoms.5 Despite this, another consideration is that bupivacaine produces prolonged occupation of the sodium channel because of its slower kinetics (slow-in, slow-out).69 Systemic toxicity of local anaesthetics is potentially fatal. When preventive measures are taken, the incidence of cardiac arrest is low.

Treatment of local anaesthetic-induced systemic toxicity consists of supportive treatment to control seizures and maintain cardiocirculatory function. In addition, most contemporary guidelines advocate administration of Intralipid,70,71 which was first shown in 1998 to decrease the susceptibility of rodents to bupivacaine-induced systemic toxicity.72 The rapid and widespread adoption of Intralipid in LAST guidelines is surprising given that fundamental questions regarding its action remain unanswered.73 Specifically, the relative contributions of the three hypothetical mechanisms are unclear. First, according to the lipid sink hypothesis, Intralipid can bind free local anaesthetic. This mechanism may explain why Intralipid seems to work better when treating bupivacaine-induced LAST than when treating LAST induced by less lipophilic drugs such as mepivacaine.74,75 Second, experimental findings suggest that Intralipid interacts with the sodium channel, and third, the lipid emulsion may support mitochondrial metabolism.76 Interestingly, the efficacy of Intralipid to counteract bupivacaine toxicity seems to depend on the animal model used. Although it has generally worked well in rodent models, studies in porcine models, which are widely used in resuscitation research, generally show no beneficial effects, fuelling the debate as to which model is more relevant.77 There is only one human trial on the effects of Intralipid in this role. Litonius et al.78 infused bupivacaine i.v., followed by Intralipid. The authors found a reduced context-sensitive half-life of bupivacaine, potentially due to increased tissue distribution, but failed to detect a relevant lipid sink effect.78 Therefore, the evidence base for Intralipid treatment remains unclear, and prediction of clinically relevant benefit is not straightforward. Recent pharmacokinetic studies have suggested that Intralipid will decrease the cardiac bupivacaine concentration by 11% within 3 min of administration, and cerebral bupivacaine content by 18% within 15 min.79 Despite the theoretical nature of these findings, they are notable because they underline that Intralipid reduces rather than eliminates bupivacaine. Intralipid should not be considered an antidote with full antagonistic properties. It remains a valuable contribution to, but not a substitute for, careful and meticulous conduct of regional anaesthesia. Intralipid has been proposed for resuscitation from systemic local anaesthetic overdose, and enthusiastically adopted worldwide, even though the mechanism of action is incompletely understood, and the only human trial does not support its efficacy. Intralipid is not an antidote for systemic toxicity of local anaesthetics, and meticulous conduct of regional anaesthesia remains essential.

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Local anaesthetics

Table 2 Number of outcome studies analysing effects of regional anaesthesia on tumour recurrence, grouped according to patient outcome Type of malignancy Breast cancer Ovarian cancer Melanoma Intestinal cancer Prostate cancer ENT cancer

Positive effect

Subgroup effect

No effect

192 296,97 293,99 0 2104,105 1108

0 0 0

0 198 0 1103

3100– 102 0 0

2106,107 0

PubMed literature search ‘regional anaesthesia AND cancer’, access date 20 February 2014.

Local anaesthetic-induced neurotoxicity and myotoxicity In excessive doses, all local anaesthetics have the potential to produce toxicity in virtually any type of tissue. In the clinical setting, after cardiotoxicity, neurotoxicity and myotoxicity are the next causes for concern. On neuronal cells, local anaesthetics exhibit dose-dependent toxicity.7 The question of whether some local anaesthetics are more toxic than others has not been definitively answered and some experimental evidence suggests that equipotent doses of local anaesthetics exhibit the same degree of toxicity,7,80 whereas other investigations found that lidocaine was more toxic than bupivacaine, for example.81,82 In the classical observational study by Auroy et al.,83 spinal anaesthesia performed using lidocaine was associated with more neurological deficits than bupivacaine. Although short-term neurological dysfunction after peripheral nerve block is relatively frequent, permanent loss of function is rarely observed.84 Transient neurological syndrome (TNS) typically presents after resolution of spinal blockade, and is characterised by radicular segmental pain without motor deficit, and spontaneous recovery within 72 h.85 The cause is multifactorial, and both positioning (lithotomy) and drug (especially lidocaine) are important pathogenic factors.85,86 If TNS can be regarded as trivial, cauda equina syndrome is at the other end of the spectrum. It is a generalised destruction of lumbar and sacral nerve fibres, resulting in pain and both sensory and motor deficit, transcending segmental barriers. The incidence has been estimated close to 1 : 10 00083,87 and importantly, there are many causes other than local anaesthetic-induced neurotoxicity, including haematoma, abscess formation, tumours, epidural lipomatosis and ossification. Classically, this syndrome was associated with the pooling of hyperbaric lidocaine 5% in the dural sac when applied repeatedly via a spinal microcatheter,88 lending support to the concept of dose-dependent local anaesthetic-induced neurotoxicity. Myotoxicity of local anaesthetics has been recognised for a long time,89 but the clinical relevance is unclear.

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The regenerative potential of muscles and the functional redundancy mask myotoxic effects after the vast majority of peripheral nerve blocks. As a result, transient myotoxic effects are more likely to be observed after regional blockade for eye surgery, wherein a delicate balance between weak muscles is easily disturbed by myotoxicity.90 All local anaesthetics are toxic, dependent on dose. Neurotoxicity is rare, but disastrous for the patient when it happens. Myotoxicity is thought to occur frequently, but is only clinically apparent after ocular anaesthesia.

Local anaesthetics and tumour recurrence The perioperative period around tumour surgery has long been recognised as a vulnerable time in which tumour progression and metastasis are often accelerated.91 In small retrospective studies, it has been suggested that regional or local anaesthesia may improve patient survival and increase the disease-free interval after cancer surgery.92,93 Several experimental studies support this. In one, Deegan et al.94 found that serum taken from patients undergoing tumour surgery under regional anaesthesia halted growth in a tumour cell line in vitro. As a consequence, several large-scale, multicentre, randomised controlled trials are currently under way to assess the beneficial effects of regional anaesthesia in tumour surgery, but they are projected to last until the end of the decade because of long follow-up times.95 In the meantime, a number of retrospective analyses have been published, showing heterogeneous effects (Table 2).92,93, 96–108 The potential mechanisms of antimetastatic effects can be divided into direct and indirect effects of local anaesthetics. Direct effects include interference with tumourpromoting pathways,109 changes in the epigenetic signature of tumour cells110 and direct toxic effects when used for local infiltration.93 Indirect effects result from reduction of the perioperative stress response, and the preservation of the immune response.111 As many of these effects can be duplicated using i.v. local anaesthetics,34 another avenue of research may be the employment of systemic local anaesthetics in the perioperative period of tumour surgery. We forecast that even if large-scale outcome studies find positive effects, these will most likely not be universal, but limited to specific types of cancer, and possibly, the cancer stage. It will be imperative to integrate knowledge obtained in these trials into patient- and tumour-specific strategies to decrease tumour progression during the perioperative period. This will necessitate an overall patient care concept including, for well described indications, regional anaesthesia. The question of whether local anaesthetics protect against perioperative tumour progression cannot be

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582 Lirk et al.

answered at this moment. Results from clinical (retrospective) studies are equivocal.

The future of local anaesthetics Currently, research efforts are being directed towards the generation of specifically configured sodium channel blockers, which will allow for the targeted treatment of problems such as neuropathic pain states.112 Although the combination of QX-314 and capsaicin does not lend itself to clinical application, the concept of targeting of local anaesthetics into nociceptors is of great potential interest.26 Substantial research is being directed at a comparison of the effects of i.v. administration of local anaesthetics with those of regional blockade. The success for these techniques will depend on careful selection of patient groups and refinement of appropriate procedures with suitable indications for regional anaesthesia, i.v. multimodal analgesia or a combination of both.113,114 At the same time, ‘old’ local anaesthetics are being rediscovered for new indications. For example, chloroprocaine, prilocaine and articaine have been proposed as suitable local anaesthetics for day-case surgery.115,116 In the same way that multimodal systemic analgesia has been adopted for perioperative pain treatment, multimodal perineural analgesia has been advocated. This technique uses a combination of several drugs for peripheral nerve blocks to avoid the need for catheter techniques.117 The liposomal slow-release formulation of bupivacaine, Exparel, has been put forward as an alternative to catheter techniques and adjuvants, and was recently granted U.S. Food and Drug Administration (FDA) approval for wound infiltration. When used in this role as part of a multimodal treatment regimen, encouraging results were obtained.118 However, when used for nerve blockade, there was substantial inter-individual variation in block characteristics,119 to the extent that before Exparel could be recommended, further studies would be needed. Regional anaesthesia is currently undergoing substantial changes. Many of the indications for peripheral and neuraxial techniques are under scrutiny because evidence of superior outcome is equivocal or missing for many interventions.120 Multimodal analgesia regimens, including the i.v. administration of local anaesthetics, have shown promise in replacing neuraxial techniques for some indications such as lower abdominal surgery.121 Other indications such as thoracotomy, upper abdominal surgery, major vascular surgery and analgesia for patients at a high risk of severe or chronic postoperative pain, such as chronic pain patients, remain current,121 and are even seeing increasing support.122 Peripheral regional anaesthesia techniques are unfortunately rarely investigated

for outcome beyond the immediate perioperative period.121 One point to note is that that virtually all findings reported above came from studies with large patient cohorts. Future studies might be smaller but with more standardised patient cohorts and specific regional anaesthesia interventions. Future areas of interest will be design of new subtypespecific sodium channel blockers, although older local anaesthetics such as 2-chloroprocaine are being reintroduced into the clinical setting. Multimodal perineural analgesia and liposomal bupivacaine may replace catheter techniques in some indications.

Conclusion The mechanisms of action and access pathways of local anaesthetics and their pharmacokinetics are increasingly understood and appreciated. Only very small amounts of local anaesthetic actually take part in sodium channel block, while most is absorbed into tissues or the systemic circulation. Systemic local anaesthetics seem to be responsible for a substantial share of beneficial effects of regional anesthesia. The dose of local anaesthetic administered should be tailored to block site and the individual patient. Local anaesthetics, administered systemically or locally, will remain of paramount importance in perioperative medicine.

Acknowledgements relating to this article Assistance with the manuscript: none. Financial support and sponsorship: none. Conflicts of interest: none. Presentation: this article is based upon the Refresher Course ‘Local anaesthetics’ held at Euroanesthesia, June 2014, Stockholm, Sweden.

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