Eur J Anaesthesiol 2014; 31:575585

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: p.lirk@amc.uva.nl
0265-0215 2014 Copyright European Society of Anaesthesiology

DOI:10.1097/EJA.0000000000000137

Copyright European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.

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 5050 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).1517 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 channels 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
channels 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

D II

L1

D III

L2

D IV

L3

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 +

(a)

(b)
Top
view

Side
view

F203

Pore
portal

B +
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 BH, where B can cross the membrane but BH is required to bind to the channel. H 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.4042 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.

579

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.

581

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, 96108
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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