British Journal of Anaesthesia, 123 (3): 335e349 (2019)

doi: 10.1016/j.bja.2019.06.014
Advance Access Publication Date: 11 July 2019
Review Article

Molecular mechanisms of action of systemic lidocaine in acute and

chronic pain: a narrative review
Henning Hermanns1, Markus W. Hollmann1, Markus F. Stevens1,*, Philipp Lirk2,
Timo Brandenburger3, Tobias Piegeler4 and Robert Werdehausen4
1
Department of Anaesthesiology, Amsterdam UMC, University of Amsterdam, Amsterdam, the
Netherlands, 2Department of Anaesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA, USA, 3Department of Anaesthesiology, University Hospital Düsseldorf, Düsseldorf,
Germany and 4Department of Anaesthesiology and Intensive Care Medicine, University of Leipzig, Leipzig, Germany

*Corresponding author. E-mail: m.f.stevens@amc.nl

Summary
Systemic administration of the local anaesthetic lidocaine is antinociceptive in both acute and chronic pain states,
especially in acute postoperative and chronic neuropathic pain. These effects cannot be explained by its voltage-gated
sodium channel blocking properties alone, but the responsible mechanisms are still elusive. This narrative review fo-
cuses on available experimental evidence of the molecular mechanisms by which systemic lidocaine exerts its clinically
documented analgesic effects. These include effects on the peripheral nervous system and CNS, where lidocaine acts via
silencing ectopic discharges, suppression of inflammatory processes, and modulation of inhibitory and excitatory
neurotransmission. We highlight promising objectives for future research to further unravel these antinociceptive
mechanisms, which subsequently may facilitate the development of new analgesic strategies and therapies for acute
and chronic pain.

Keywords: acute pain; analgesia; inflammation; lidocaine; local anaesthetics; neurotransmitter; neuropathic pain

Lidocaine was first synthesised under the name Xylocaine® by
€ fgren in 19421 and marketed in 1948. In addition to its
Nils Lo
use as a local anaesthetic and anti-arrhythmic drug, i.v.
lidocaine was soon reported to exhibit analgesic properties
in various pain conditions. The first reports were published
in the 1950s and 1960s.2e4 The antinociceptive effects of
parenteral lidocaine were subsequently confirmed in various
acute and chronic pain states.5e8 There is now convincing
preclinical and clinical evidence that i.v. lidocaine has anti-
hyperalgesic effects. Numerous studies in healthy volunteers
have shown that lidocaine infusion reverses hyperalgesia. In
most studies, an initial bolus of 1e2 mg kg
1 was
administered, followed by continuous infusion of 2e4 mg
kg
1 h
1, resulting in plasma concentrations of 1e3 mg ml
1
(z4e13 mM).9e16 Furthermore, clinical studies have shown
the efficacy of lidocaine in patients suffering from chronic
neuropathic pain. In many neuropathic pain states, i.v.
lidocaine reduced spontaneous pain, allodynia, or
hyperalgesia17e29 (Table 1) at plasma lidocaine
concentrations of 1e3 mg ml
1 (z4e13 mM).17e29
Numerous meta-analyses have demonstrated the anal-
gesic benefit of systemic lidocaine in the perioperative setting,
especially during laparoscopic abdominal surgery30e35
(Table 2). In most cases, lidocaine was administered with an
initial bolus of 1.5e2 mg kg
1 followed by infusion of 1.5e3 mg
kg
1 h
1 or 2e3 mg min
1. Plasma lidocaine concentrations,
when measured, were in the range of 0.5e5 mg ml
1 (z2e21
mM), which are comparable with concentrations after epidural
administration.30e35 Positive effects on other outcome vari-
ables have also been shown, such as improved rehabilitation,
shorter hospital stay,36,37 and earlier bowel movement, and
also reduced chronic post-surgical pain32,36,38,39 (Table 2).

Editorial decision: 03 June 2019; Accepted: 3 June 2019

© 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
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335
 336 - Hermanns et al.

Table 1 Effects of systemic lidocaine on different chronic pain modalities.

Effects on chronic pain Spontaneous pain Hyperalgesia Allodynia

25,27
Neuropathic pain Reduced
Diabetic neuropathy Reduced28
Peripheral nerve injury Reduced19,23 Reduced19,23
Post-herpetic neuralgia Reduced17,23 Reduced23 Reduced17,23
Chronic regional pain Reduced at high (3 mg ml
1) plasma Reduced for cold Reduced for cold and mechanical
syndrome concentration20 threshold only20 threshold20
Central pain Reduced21,24 Reduced21 Reduced21

Whilst clinical data on the antinociceptive effects of i.v.
lidocaine are convincing, the precise molecular mechanisms
of action remain elusive. Results from numerous preclinical
investigations suggest that there might be multiple molecular
mechanisms of cellular, subcellular, regional, and systemic
effects that account for the analgesic properties of lidocaine.
This is related to the propensity of local anaesthetics to
interact with nearly all ion channels to at least some degree.
Furthermore, local anaesthetics tend to interact with many
intracellular second-messenger pathways. This makes it
difficult to identify specifically the mechanisms involved in
the antinociceptive action of lidocaine.
This review gives an overview of the current literature
regarding the effects of lidocaine and its major metabolites on
pathways involved in nociceptive neurotransmission. For the
sake of completeness, we also included possible targets that
are probably not clinically relevant. Unravelling those mech-
anisms might eventually lead to a more thorough under-
standing of the biology of chronic pain, and thus, to new
therapeutic approaches.
General pharmacology of lidocaine
Lidocaine is an amino-amide-type local anaesthetic. Given
intravenously, lidocaine is 60e80% protein bound, mostly to a-
1-acidic glycoprotein. Lidocaine crosses the bloodebrain bar-
rier through passive diffusion across membranes. It may exist
in ionised or un-ionised forms; given its pKa value of 7.9, 25% of
lidocaine is present in the un-ionised form at a physiological
pH of 7.4.
The major metabolism (~95%) of lidocaine in the liver is
through N-dealkylation, mainly by CYP3A4 to the pharmaco-
logically active metabolite, monoethylglycinexylidide (MEGX),
and then subsequently to glycinexylidide (GX), 2,6-xylidine,
and N-ethylglycine (EG), amongst others. MEGX is 80% as
potent as the parent drug, whilst GX is nearly ineffective
(Fig. 1). Lidocaine is excreted in the urine (90e95% as metab-
olites and 5e10% as unchanged drug). The elimination half-life
of lidocaine is between 90 and 120 min in most patients. This
may be prolonged in patients with hepatic insufficiency or
congestive heart failure.40,41
The principal mechanism of action of lidocaine as a local
anaesthetic is through blockade of voltage-gated sodium
channels (VGSCs) leading to a reversible block of action
potential propagation. Like with all local anaesthetics, only
the un-ionised form of the drug (i.e. the free base form) is
able to permeate the lipophilic cell membranes. Intracellu-
larly, the ionised form blocks sodium channels by binding to
Segment 6 of Domain 4 of the a-subunit of the ion channel.
When the local anaesthetic is bound to the sodium channel,
the influx of Naþ is interrupted and action potential gener-
ation and propagation are inhibited. Local anaesthetics bind
preferably to the open or inactivated state of VGSCs; thus,
the onset of local anaesthetic action is faster in rapidly firing
neurones.42
Effects on ion channels
Sodium channels
VGSCs enable electrical excitability and the generation and
propagation of action potentials in excitable membranes.
Hence, they form the molecular basis of nervous system
function, including sensory transmission, and thus, nocicep-
tive signalling. Many studies have shown the key role of VGSCs
in both neuropathic and inflammatory nociception.43 To date,
nine isoforms of VGSCs (Nav1.1eNav1.9) with distinct

Table 2 Effect of systemic lidocaine on acute and chronic post-surgical pain from recent meta-analyses. *This recently redone
Cochrane meta-analysis35 of an earlier meta-analysis32 found statistically significant differences in the reported variables, but
interpreted their clinical meaningfulness differently in the light of International Association for the Study of Pain definitions of
clinically meaningful differences. PONV, postoperative nausea and vomiting.

Perioperative antinociceptive effects Pain at rest (<24 h) Pain during activity Opioid requirement PONV

30e32,35,* 30e32 30e32,35,*

Abdominal surgery Reduced Reduced Reduced Reduced30,32,35,*

Chronic post-surgical pain33 (CPSP) Odds ratio for incidence of CPSP (4e6 Pain intensity (McGill Pain
months) Questionnaire score)

Overall Reduced Unchanged (P¼0.06)

Breast surgery Reduced
Non-breast surgery Reduced

Fig 1. Chemical structure of lidocaine, relevant metabolites, and similar molecules.
electrophysiological properties and expression patterns have
been identified. Six of the nine VGSCs are expressed in so-
matosensory primary afferent neurones, such as the dorsal
root ganglion (DRG), and are thus involved in propagation of
physiological and neuropathic and inflammatory pain.44
Several experimental studies have shown that i.v. lidocaine
suppresses ectopic discharges in injured DRG or peripheral
nerves. Ectopic firing could be diminished by a systemic dose
of lidocaine far below that required to inhibit nerve impulse
propagation along an uninjured axon.45e51 Of note, the Nav1.8
channel is about five times more sensitive to lidocaine than
the Nav1.7 channel or other channel subtypes.52,53 All local
anaesthetics show frequency-dependent block (i.e. block in-
tensity increases at higher action potential firing frequencies).
Thus, in isolated Nav1.8, the IC50 for low-frequency block is
319 mM, whereas the IC50 for high-frequency block is 50 mM
(Fig. 2). This may explain why systemic lidocaine blocks
ectopic activity in injured nerves, whilst normal nociception
remains unchanged at the same concentration.53 Of note,
Nav1.8 channels accumulate in painful neuromas and can be a
source of pathological spontaneous discharge.54,55
In the spinal cord, lidocaine at concentrations of 43e64 mM
decreased the response to dorsal root C-fibre stimulation and
suppressed the prolonged ventral root potentials.56,57 In vivo,
i.v. lidocaine suppressed the noxious-stimulus-evoked activity
in dorsal-horn wide-dynamic-range neurones, whilst sponta-
neous potentials and activity induced by non-noxious stimuli
remained unaltered.58,59 Comparing the doses required to
halve ectopic firing in a neuropathic pain model, dorsal-horn
neurones were more sensitive than cells in DRG or
Mechanisms of action of systemic lidocaine - 337
neuroma.60,61 Interestingly, silencing of the dorsal horn and
DRG could be achieved with i.v. lidocaine doses corresponding
to loading doses used clinically. In conclusion, there is fair
experimental evidence to support the hypothesis that sys-
temic lidocaine suppresses ectopic firing in injured peripheral
nerves, DRG, and dorsal-horn cells, representing a possible
mechanism to explain beneficial effects on chronic pain in the
clinic. However, ectopic discharges are more likely to underlie
the clinical phenomenon of spontaneous pain, and inhibition
of spontaneous pain cannot explain the effect of lidocaine on
allodynia and hyperalgesia. This is in line with findings that
experimental allodynia results from multiple factors, not all of
which are sensitive to lidocaine treatment.62 Furthermore,
findings that the clinical effects of lidocaine in chronic pain
patients far outlast plasma concentrations63,64 point to a
supra-spinal mechanism, involving other targets than sodium
channels.
Potassium channels
Potassium channels exert many physiological functions in
excitable cells. The major classes comprise voltage-gated (KV),
calcium-activated (KCa), inwardly rectifying (Kir), and tandem
pore domain (K2P) potassium channels, mediating a wide va-
riety of biological functions.65 In neurotransmission, potas-
sium channels represent important regulators of resting
potential, firing rate of action potentials, and repolarisation.66
Certain types of potassium channels are involved in pain
modulation and are possible future targets in pain therapy, in
particular, specific KV subunits and the K2P channel families.67
 338 - Hermanns et al.

Fig 2. Graphical representation of known pharmacological targets of lidocaine. All concentrations are given as lowest known half-maximal
effective concentration, except for the toxicity thresholds. Only selected targets, which are being discussed in this review article, are
displayed. Please refer to the main text for references. ASIC, acid-sensing ion channel; HCN, hyperpolarisation-activated cyclic nucleotide-
gated cation channel; KCNK, potassium channel subfamily K member; Kir2.x, inward rectifier potassium channel; Kv, voltage-gated po-
tassium channels; nAChR, nicotinic acetylcholine receptor; Nav, voltage-gated sodium channel; NMDAR, N-methyl-D-aspartate receptor;
P2X7, P2X purinoceptor 7; TLR4, Toll-like receptor 4; TRPA1, transient receptor potential cation channel, subfamily A, member 1; VGCC,
voltage-gated calcium channel; 2PK, two-pore domain potassium channels; 5-HT3, 5-hydroxytryptamine 3 receptor.

In demyelinated Xenopus laevis nerve fibres, lidocaine
blocked the voltage-insensitive ‘flicker’ Kþ channel, which
generates the resting membrane potential of these fibres, with
an IC50 of 220 mM.68 Furthermore, lidocaine blocks KV in sciatic
nerve fibres (but with a much lower affinity than for VGSCs:
IC50 of 1118 mM),69 and also rat brain KV1.1 channels70 and in
isolated DRG.71,72 In SH-SY5Y neuroblastoma cells and human
embryonic kidney 293 cells expressing KV1.1 and KV3.1 chan-
nels, lidocaine reversibly inhibited both channels in a
concentration-dependent manner, with IC50 values of 4.6 mM
(KV1.1) and 607 mM (KV3.1), respectively.73
K2P channels are a family of 15 members with six sub-
families (TREK, TASK, TWIK, THIK, TRESK, and TALK) that
mediate background or ‘leak’ Kþ currents, and hence, being
essential regulators of the resting membrane potential and
excitability. Kindler and colleagues74 investigated the effects of
local anaesthetics on five K2P channels expressed in X. laevis
oocytes, and showed that TASK was inhibited most potently by
lidocaine (IC50 of 220 mM). In other experiments by the same
group, TASK-2 was the most sensitive of the K2P channels to
lidocaine.75 The TWIK-related channel, TREK1, is also inhibited
by lidocaine (IC50 of 180 mM) at concentrations as low as 10 mM.76
Recently, lidocaine’s effect on inward rectifier Kþ channels
(Kir) has been investigated. Lidocaine induced fast and
reversible inhibition of three channels of the Kir2.x subfamily
(Kir2.1, Kir2.2, and Kir2.3), albeit clearly above clinically relevant
concentrations (IC50 of 1.5e2.7 mM)77,78 (Fig. 2). In light of the
importance of the Kir family in opioid-induced analgesia,79 a
synergistic action of local anaesthetics, even at clinically
observed concentrations, together with opioids is likely, but
has yet not been investigated.
Calcium channels
Voltage-gated Ca2þ channels (VGCCs) regulate numerous
physiological processes, including neurotransmitter
release.80,81 Several types of VGCCs have been described and
are categorised according to their voltage sensitivity. High-
voltage-activated calcium channels comprise the L-type
(CaV1.1eCaV1.4), P/Q-type (CaV2.1), N-type (CaV2.2), and R-type
(CaV2.3) channels.81 Under pathological conditions, like nerve
injuries, dysregulation of VGCC is associated with increased
pain sensation.82 Because of their considerable influence on
neurotransmitter release, they are considered potential

targets for chronic pain therapy.83 Lidocaine inhibits neuronal
VGCCs in isolated nerve cell bodies of frog DRG at concentra-
tions in the millimolar range,84 and also in mammalian DRG
neurones. Much higher doses (~100-fold) of lidocaine are
needed to inhibit VGCCs compared with VGSCs,85 such that
the degree of Ca2þ channel blockade by lidocaine is limited.
Transient receptor potential channels
Transient receptor potential (TRP) ion channels play a key role
in the detection of environmental stimuli. Some members of
the TRP family deserve special attention in pain research, as
they are expressed in nociceptors and convey thermal,
chemical, and mechanical stimuli (TRPV1e4, TRPM8, and
TRPA1), and are also involved in the development and main-
tenance of chronic pain.86
In TRPV1 expressing human embryonic kidney cells, lido-
caine increased the intracellular Ca2þ, but decreased the
capsaicin (a specific TRPV1 agonist)-induced Ca2þ influx.87
Similar effects on TRPV1 and TRPA1 receptors have been
observed in vitro. As lidocaine activated TRPV1 and TRPA1, TRP
channel activation might contribute to pain upon injection of
lidocaine, and neuroinflammatory and neurotoxic pro-
cesses.88 A TRPA1-activating effect of lidocaine was subse-
quently confirmed in substantia gelatinosa neurones. Here,
lidocaine increased the frequency of spontaneous excitatory
postsynaptic currents.89,90 Interestingly, lidocaine inhibited
TRPA1 to a much greater extent in rodent than in human
TRPA1.91 Similarly, lidocaine desensitised TRPA1 ion channels
in isolated rat saphenous nerves. This TRPA1-desensitising
effect of lidocaine might contribute to the pain-ameliorating
properties of lidocaine in neuropathic pain.92 However, those
effects were observed at concentrations of >1 mM, mostly
10e30 mM. Thus, effects on the TRP receptor family occur at
concentrations >100 times higher than plasma concentrations
observed after i.v. lidocaine (Fig. 2).
Hyperpolarisation-activated cyclic nucleotide-gated
channels
Hyperpolarisation-activated cyclic nucleotide-gated (HCN)
channels, of which four subtypes (HCN 1e4) have been iden-
tified, play a major role in neuronal excitability by regulation of
cell activity via the hyperpolarisation-activated current (Ih).93
HCN channels are expressed throughout the nervous system
and have been shown to be involved in nociceptive signal-
ling.94,95 Furthermore, HCN channel antagonists can alleviate
allodynia.96,97 In rat DRG, lidocaine inhibited Ih with an IC50 of
0.1 mM.98 Subsequent studies confirmed that lidocaine and its
major metabolite, MEGX, inhibit HCN 1, 2, and 4 with a similar
IC50.99,100 In rat thalamocortical neurones, lidocaine inhibited
Ih (IC50 of 72 mM).101 Likewise, in neurones of the substantia
gelatinosa in rat spinal-cord slices, which are known to be
involved in pain processing, lidocaine reversibly inhibited Ih
(IC50 of 80 mM), and thus, possibly reducing excitability in
dorsal-horn neurones.102
Acid-sensing ion channels
Acid-sensing ion channels (ASICs) are voltage-insensitive
cation-selective ion channels that sense protons and are
activated by extracellular acidosis. Evidence suggests that
ASICs are involved in nociceptive circuits.103 In cultured
Mechanisms of action of systemic lidocaine - 339
mouse cortical neurones, lidocaine blocked ASIC currents at
high concentrations (IC50 of 11.8 mM).
G-protein-coupled receptors
G-protein-coupled receptors (GPCRs) represent the largest
family of membrane signalling proteins. GPCRs are complex
signalling machines that can adopt numerous conformations
that are influenced not only by ligands, but also by other
mechanisms.104,105 In pain states, their expression and sub-
type composition may change considerably.104 Furthermore,
GPCRs represent major targets in pharmacological pain ther-
apy. The larger GPCR groups that can affect anti-nociception
comprise opioid, cannabinoid, a-2 adrenergic, muscarinic
cholinergic, gamma-aminobutyric acid receptor B (GABAB),
metabotropic glutamate, neurokinin, bradykinin, histaminer-
gic, serotoninergic, adenosine, prostaglandin, and somato-
statin receptors.106 This list is far from complete, as this
receptor family has more than 850 members.104
The first finding pointing to lidocaine-mediated effects on
GPCRs about 20 yr ago was that lidocaine interfered with
muscarinic, thromboxane A2 (TXA2), and lysophosphatidic
signalling.107,108 An in-depth analysis revealed that lidocaine
blocked m1 and m3 muscarinic receptors at low concentra-
tions (IC50 of 18 nM for m1 and 370 nM for m3) by binding
intracellularly to the Gq protein a-subunit of the respective
receptors.105 Consistently, the angiotensin 1A receptor, which
does not couple via Gaq, was not sensitive to lidocaine.105
Furthermore, the lidocaine effect on Gaq protein is not
confined to X. laevis, but is also seen in mammalian Gaq pro-
tein.109 Prolonged exposure to lidocaine increased the inhibi-
tory potency on GPCRs in a reversible manner,110 and the
effect on muscarinic receptors was time dependent.111 TXA2
and adenosine-1 receptor signalling was also inhibited by
lidocaine.112,113
There is thus strong experimental evidence that lidocaine
exerts effects on GPCRs primarily via the Gaq subunit even at
concentrations far below those observed clinically after i.v.
lidocaine (Fig. 2). A more detailed description of the lidocaine
effect on specific receptors within the GPCR family follows.
Acetylcholine receptors
Nicotinic and muscarinic acetylcholine (ACh) receptors are
ligand-gated receptors that are activated via binding of the
neurotransmitter, ACh. Whilst the nicotinic ACh receptor
(nAChR) is an ion channel that can be found in the CNS,
autonomic ganglia, and neuromuscular junction, the musca-
rinic ACh receptor (mAChR) belongs to the GPCR family, and
its five distinct subtypes (m1em5) are widely expressed in the
central and peripheral nervous systems. Both receptor types
have been implicated in pain transmission and are potential
targets for analgesics.106,114
Picardi and colleagues111 and Hollmann and col-
leagues115,116 examined the potential blockade of m1 and m3
muscarinic receptors by lidocaine. M1 muscarinic receptor
signalling was inhibited with an IC50 of 18 nM, which is about
1000-fold lower than that for sodium channel blockade (Fig. 2).
Lidocaine inhibited the m3 muscarinic receptor less potently
(IC50 of 370 nM) because of the absence of an extracellular site
for charged local anaesthetics.105 Prolonged exposure of m1
and m3 receptors to lidocaine resulted in a biphasic time
course with initial inhibition, followed by enhanced
signalling.111
 340 - Hermanns et al.
The nAChRs are also targets of lidocaine. Both the muscle-
type nAChR117e119 and the neuronal nAChR117,120 are inhibited
with an IC50 in a low micromolar range (Fig. 2). At the same
time, investigations in vivo suggest that i.v. lidocaine increases
the intra-spinal release of ACh.121
Glutamate receptors
Glutamate, the major excitatory neurotransmitter in the CNS,
is heavily involved in nociception. Its effects are mediated by
both ionotropic and metabotropic glutamate receptors.
Amongst the ionotropic glutamate receptors, the N-methyl-D-
aspartate (NMDA) receptor has been particularly implicated in
pathological pain signalling.122 Initial in vitro investigations
showed the inhibition of NMDA-induced currents by lidocaine,
albeit a 100 times above clinically relevant plasma concentra-
tions (IC50 of 2.8 mM).123 Subsequent research confirmed that
lidocaine inhibited the activation of NMDA receptors in a
concentration-dependent manner with effects in the high
micromolar range.124 In oocytes expressing human NMDA re-
ceptors, even nanomolar concentrations of local anaesthetics
led to some NMDA inhibition125 (Fig. 2). Various mechanisms
are involved in lidocaine-mediated NMDA receptor blockade,
such as inhibition of protein kinase C (PKC)125 or suppression of
phosphorylation of extracellular signal-regulated kinase (ERK),
induced by capsaicin, NMDA, Alpha-Amino-3-Hydroxy-5-
Methyl-4-Isoxazole Propionic Acid (AMPA), and ionomycin. As
ERK activation contributes to chronification of pain, inhibition
of this pathway by lidocaine might counteract this mecha-
nism.126 Beside receptor-mediated effects, lidocaine can inhibit
glutamate release from nerve terminals at clinically relevant
concentrations (IC50 of 45 mM).127
Apart from direct effects on postsynaptic glutamate re-
ceptors, lidocaine has effects on glutamate transporters.
Lidocaine enhanced the activity of the glutamate transporter,
EAAT3, mediated by PKC and phosphatidylinositol 3-kinase.128
In contrast, lidocaine did not affect the activity of glutamate
transporter, EAAT2.129 Given the significance of glutamate in
the pathogenesis of chronic pain, it may be worthwhile to
further elucidate the effects of lidocaine on other glutamate
transporters, such as EAAT 1e5 and vGLUT1e3, most of which
have been implicated in nociception.130
Whilst inhibition of NMDA receptors by lidocaine has been
shown by several groups, the effective concentrations vary
tremendously. Therefore, in vivo models are required to show
that analgesic effects of systemic lidocaı̈ne are mediated via
NMDA receptors. Furthermore, there is a lack of investigations
regarding the interaction between metabotropic glutamate
receptors and lidocaine.
Serotonin receptors
Serotonin (5-hydroxytryptamine [5-HT]) is involved in many
physiological functions in the central and peripheral nervous
system via seven distinct GPCRs (HT1e7).131 Amongst others, it
mediates dual actions in pain modulation, with both pro- and
antinociceptive effects via various 5-HT receptor subtypes.132
Some receptors seem to be specifically involved in patholog-
ical pain trafficking, such as HT1, HT3, and HT5,133,134 partially
via descending serotonergic facilitation.135
Ueta and colleagues136 showed that lidocaine concentra-
tion dependently inhibited 5-HT-induced currents by HT3 re-
ceptors albeit at relatively high concentrations (IC50 of 0.5 mM;
Fig. 2). Furthermore, in rats with neuropathic pain, the
intrathecal injection of the serotonin receptor antagonists,
ketanserin (HT2) and methysergide (HT1e2), suppressed the
pain-relieving effect of lidocaine injected into the rostral
ventromedial medulla, presumably releasing the descending
pain-inhibitory systems. This has been postulated to involve,
amongst others, the activation of spinal serotonergic
mechanisms.137
Opioid receptors
Experimental evidence suggests that, at the cellular level,
there is no direct interaction between lidocaine and recombi-
nant m-, k-, and d-opioid receptors.138 This is not surprising,
considering that all opioid receptors are GPCRs without a Gaq-
subunit and lidocaine inhibits GPCRs via Gaq subunits.109
In vivo data, however, clearly suggest that co-administration
of opioids and lidocaine synergistically potentiates anti-noci-
ception.139,140 Whether these synergistic effects are caused by
interactions at the receptor level (e.g. via Toll-like receptor
[TLR4] signalling, Kir, or Caþ channels), or regional or systemic
interplay is unknown.
Purine receptors
Purinergic receptors participate in multiple pathways,
including neuropathic pain. The three major classes comprise
P2X receptors, which are ligand-gated ion channels, and also
the P1 and P2Y receptors, which are GPCRs.141 Certain P2X
subtypes are involved in pain sensation pathways.142
Okura and colleagues143 investigated the effects of lido-
caine on purinergic receptor subunits. Lidocaine predomi-
nantly inhibited P2X7 subunits (IC50 of 282 mM) whilst leaving
P2X3 and P2X4 almost unaffected. Significant inhibition
occurred at concentrations upward of 30 mM in a use-
dependent non-competitive manner. Considering that P2X7
receptors are expressed in microglia, the contribution of P2X7
inhibition to the anti-hyperalgesic effect of lidocaine might be
attributable to interference with microglia-associated inflam-
matory mechanisms. Yet, the exact mechanism of interaction
between lidocaine and the receptor remains unclear.143
Furthermore, it is unknown whether P1 (i.e. adenosine) or
P2Y receptors are inhibited by lidocaine. At least for most
subtypes of the P2Y receptor, this is likely, as they mediate
their effects via the Gaq protein, which has been shown to be
inhibited by lidocaine.109
Toll-like receptors
TLRs are pattern recognition receptors that play a pivotal role in
the innate immune system by recognising pathogens and
consecutively initiating an immune response. TLRs are
expressed on immune and glial cells, and also on primary
sensory neurones. In recent years, especially TLR4, but also
TLR2, TLR3, TLR5, and TLR9, has been identified to play a role in
the pathophysiology of various experimental pain models.144
There is sparse evidence of interaction between lidocaine
and TLRs. Lidocaine (50 mM) inhibited the activation of TLR4, and
subsequently also nuclear factor (NF)-kB and mitogen-activated
protein kinases (MAPKs) in lipopolysaccharide (LPS)-stimulated
murine macrophages. The authors postulated that the inhibi-
tory effect of lidocaine on TLR4 is mediated by VGSCs.145
I.V. injection of lidocaine in rats with LPS-induced sepsis
significantly reduced organ failure compared with controls.
Expression of TLR4, NF-kB, and interleukin (IL)-6 was reduced

in the lidocaine group, suggesting that lidocaine protects
against organ dysfunction by down-regulating TLR4.146 Neb-
ulised lidocaine prevented allergic airway inflammation in
mice by down-regulating TLR2.147 Whether the lidocaine-
mediated inhibition of TLR2 and TLR4 seen in this investiga-
tion can be extrapolated to chronic pain models remains to be
elucidated.
GABA receptors
Inhibitory neurotransmission, especially in the spinal cord,
plays a pivotal role in the processing of nociceptive informa-
tion.148 The disturbance of spinal inhibitory circuits was
shown to contribute to pathological pain states; correspond-
ingly, the restoration of physiological inhibition is considered
a possible therapeutic strategy in chronic pain.149 With
glycine, GABA is an important inhibitory neurotransmitter in
the CNS. Interference with GABAergic signalling, especially
targeting GABAA receptor subtypes mediating hyperalgesia, is
a promising future therapeutic approach in chronic pain.150
Lidocaine can elicit convulsions at toxic doses, blocking
cortical inhibitory synapses.151 Several in vitro studies
confirmed subsequently that lidocaine inhibits GABA
release152 and GABA-induced Cle currents.153e156 In contrast,
in vitro lidocaine potentiates GABA-mediated Cle currents by
inhibiting GABA uptake.157 This might explain the
antinociceptive effects of lidocaine, given that other GABA
uptake inhibitors, such as tiagabine, have well-documented
beneficial effects in chronic pain.158
Another possible mechanism by which lidocaine alleviates
pathological pain by interfering with GABAergic neurotrans-
mission involves the descending inhibitory system. Under
physiological conditions, inhibitory GABAergic and glycinergic
neurones facilitate tonic inhibitory control on the descending
system.159 Hence, in vivo experiments showed that injection of
lidocaine into the rostral ventromedial medulla alleviates
neuropathic pain by releasing descending pain-inhibitory
systems from tonic GABAergic inhibition. This in turn results
in the activation of GABAergic, serotonergic, and adrenergic
mechanisms at the level of the spinal dorsal horn.137,160 The
GABAergic system is an example of how difficult it is to
delineate clinical conclusions from in vitro or in vivo data. On
the one hand, GABA is an inhibitory neurotransmitter in most
of the nervous system; thus, its inhibition should generally
lead to more excitation and possibly hyperalgesia rather than
anti-nociception. On the other hand, by inhibiting GABA re-
uptake and reducing the inhibition of the descending
antinociceptive pathways, it can act antinociceptive. Hence,
the role of the GABAergic system in lidocaine-induced anti-
nociception is complex, possibly multiphasic, and requires
more research.
Glycine receptors
Glycine receptors are ionotropic receptors that conduct
chloride currents. Early in vitro evidence suggested a glycine-
like action of lidocaine or its metabolites in the CNS.156,161,162
Muth-Selbach and colleagues163 provided the first in vivo ev-
idence for the involvement of the spinal glycinergic system in
lidocaine-induced anti-nociception. They showed that the
anti-hyperalgesic effect of i.v. lidocaine in rats was reversed
by intrathecal pretreatment with strychnine and with mod-
ulators of the glycine B site of the NMDA receptor. Thus, at
least a part of the antinociceptive effect of systemic lidocaine
Mechanisms of action of systemic lidocaine - 341
might be attributable to glycine-like actions of lidocaine or its
metabolites.163 Subsequently, the lidocaine metabolites,
MEGX and EG, but not lidocaine itself were shown to act as
inhibitors of the glycine transporter, GlyT1, in vitro at clini-
cally relevant concentrations.164 EG has a structure similar to
that of sarcosine (Fig. 1),165 which is an endogenously occur-
ring GlyT1 inhibitor.166 As inhibitors of GlyT1 have anti-
hyperalgesic properties in a variety of experimental pain
states,167 the authors suggested that lidocaine metabolites
may be responsible for the clinical effects of systemic
lidocaine.164
In an in vivo follow-up study in rodents, the systemic
administration of EG significantly ameliorated hyperalgesia
and allodynia in both inflammatory and neuropathic pain,
remarkably without any undesired effects. Thus, systemic
lidocaine may produce anti-hyperalgesia through its metabo-
lite EG by inhibition of spinal GlyT1, and hence, facilitating
inhibitory neurotransmission. EG or other substrates of GlyT1
are possible novel therapeutic options in chronic pain.168 EG
may also enhance tonic glycinergic currents in the dorsal
horn, or interfere with other transport systems, such as the
vesicular inhibitory amino-acid transporter.169 GlyT1 in-
hibitors, such as sarcosine or bitopertin, have entered clinical
trials for treatment of cognitive symptoms in schizophrenia
and other psychiatric disturbances without significant adverse
effects170; these drugs may have potential in the treatment of
chronic pain states.
Anti-inflammatory properties
Neuro-inflammation is associated with the induction and
maintenance of chronic pain with non-neuronal cells playing
a key role.171 Activation and infiltration of leucocytes, acti-
vated glial cells and production of inflammatory mediators
drive inflammatory signalling cascades that lead to the acti-
vation of nociceptors. Numerous cell types, such as mono-
cytes, macrophages, lymphocytes, and peripheral and central
glial cells, produce multiple inflammatory mediators. Many of
these have pro-nociceptive effects, whilst others act
antinociceptive (e.g. via IL-10, IL-4, or specialised pro-
resolution mediators [such as resolvins, protectins, and
maresins]).172,173
Lidocaine affects inflammatory cells in vitro,174,175 such as
by inhibiting priming of human peripheral poly-
morphonuclear cells or neutrophils.176,177 Lidocaine can
furthermore reduce the release of mediators of inflammation,
such as IL-4, IL-6, and tumour necrosis factor-alpha (TNF-
a).178e182
Intrathecal lidocaine counteracts hyperalgesia and allody-
nia in chronic neuropathic pain.183,184 I.V. lidocaine also alle-
viated streptozotocin-induced allodynia, supposedly by
modulating the p38 pathway in spinal microglia.185 Subse-
quently, an in vitro study showed that lidocaine directly acts on
microglia by inhibiting the increase of intracellular Ca2þ trig-
gered by ATP and p38 MAPK activation. Hence, the production
of the pro-inflammatory cytokines, TNF-a, IL-1b, and IL-6, was
decreased.186 In the spinal nerve ligation model of neuropathic
pain in rats, systemic lidocaine decreased tactile allodynia,
possibly mediated by decreasing pro-inflammatory
cytokines.187
In conclusion, there is convincing evidence on the anti-
inflammatory properties of systemic lidocaine. The mecha-
nisms by which this effect conveys anti-nociception are
increasingly being recognised and understood.
 342 - Hermanns et al.
Other targets
Nitric oxide synthesis
Nitric oxide (NO) is a gaseous signalling molecule that is
regulated by the expression and activity of the enzyme, NO
synthase (NOS), catalysing NO formation from L-arginine. The
three known isoforms are neuronal, endothelial (eNOS), and
inducible (iNOS) NOS. NO is an important signalling molecule
in acute and chronic pain. Both anti- and pro-nociceptive, and
also dual, effects of NO have been described.188
Lidocaine dose dependently inhibits NO production.189
Furthermore, it inhibits iNOS, possibly involving VGSCs.190
More recently, suppression of L-arginine uptake was shown
to underlie the inhibitory effects of lidocaine on NO synthe-
sis.191 Lidocaine also inhibits the TNF-a-induced activation of
eNOS in lung microvascular endothelial cells, which prevents
NO production and further propagation of inflammatory
signalling.192
MicroRNAs
Differential regulation of gene expression has been described
in various experimental models of chronic pain.193 Small non-
coding RNAs, such as microRNAs (miRNAs), serve as impor-
tant regulators by translational inhibition or mRNA degrada-
tion. Evidence suggests that miRNAs play a role in the
development and maintenance of chronic pain. Functional
modulation of various miRNAs counteracts pathological pain
in animal models, which renders miRNAs potential molecular
targets for pain therapy.194
Sung and colleagues195 investigated the interaction be-
tween lidocaine and miRNAs in adipose stem cells. Exposure
to lidocaine up-regulates four miRNAs (miR-9a*, miR-29a,
miR296-5p, and miR-373). Further in vitro investigations in
the context of local anaesthetic neurotoxicity revealed that
lidocaine down-regulates miR-34a/c196 and let-7b,197 and up-
regulates miR-493.198 Of these, let-7b is involved in pain cir-
cuitry through activating TLR7 and TRP ankyrin subtype 1
protein (TRPA1) in nociceptors.142 It will be interesting to see
whether lidocaine affects the expression of the numerous
miRNAs known to play a role in pain pathophysiology. To date,
it is difficult to estimate whether regulation of certain miRNAs
contributes to the clinical analgesic effects of lidocaine.
Limitations
Although it is tempting to look at the IC50 values in Figure 2 in
order to judge whether a receptor is likely to be involved in the
action of systemic lidocaine, this could be misleading for a
number of reasons:
(i) Slopes of the concentrationeeffect curves (Hill co-
efficients) vary considerably. For example, lidocaine inhi-
bition of NMDA receptors starts in the nanomolar range,
but maximal inhibition is only reached in the millimolar
range.125 The same phenomenon is seen with
GPCRs.110,115 On the other hand, the
concentrationeresponse curve slope is rather steep in
ASIC receptors: whilst 1 mM lidocaine has no significant
effect, at 11.3 mM the IC50 is reached.199 A shallow slope of
the concentrationeeffect curve makes it feasible that
<50% inhibition can occur at concentrations far below the
IC50. Unfortunately, not all studies provide a
concentrationeeffect curve or other indication of its slope,
making it difficult to compare different targets properly
using only the IC50. Thus, clinical plasma concentrations
of lidocaine below 10 mM may still have effects on targets
with an IC50 in the millimolar range with a shallow
concentrationeeffect slope.
(ii) In experimental pain models with pathologically activated
targets, the IC50 of the receptor may be altered compared
with its physiological state. As shown in neuropathic pain
models, the sensitivity to systemic lidocaine increases
with the development of hyperalgesic states.
(iii) Most studies only describe the effect of one drug at one
receptor. However, in the clinical situation, lidocaine is
frequently co-administered with other drugs, such as
opioids, NMDA antagonists, antidepressants, anti-
epileptics, etc. These may enhance the sensitivity of the
receptor or downstream mechanisms to lidocaine, or
lidocaine may increase or decrease the sensitivity to the
concomitantly applied drugs. However, in most clinical
studies, i.v. lidocaine is tested against placebo, whilst
standard pain therapy is continued in both groups. Thus,
there are no clinical studies investigating interactions
between different drugs. Focusing on the IC50 of lidocaine
alone without co-administration of other clinically used
drugs can be misleading when judging the relevance of
different receptors for the effects of i.v. lidocaine,
although this is the parameter determined in most in vitro
studies, and often the only available parameter for
comparison.
Conclusions
The analgesic and anti-hyperalgesic effects of systemic lido-
caine have been recognised for almost 70 yr. Prospective
clinical investigations have confirmed lidocaine to be a ther-
apeutic option even in cases of otherwise intractable pain. The
positive effects of perioperative i.v. lidocaine infusion as part
of multimodal pain therapies are increasingly supported by
clinical studies.
The canonical mechanism of action of lidocaine (i.e.
blockade of VGSCs) was initially believed to be responsible for
its antinociceptive properties. Experimental evidence in-
dicates that silencing of ectopic neuromas and blockade of
VGSCs in the spinal cord contribute significantly to the anal-
gesic effects of lidocaine. However, ongoing basic research has
revealed that lidocaine exerts effects on a multitude of other
molecular targets involved in acute and chronic nociception. A
great array of studies must be interpreted with caution
because of methodological and pharmacological differences.
The 100e1000 times greater sensitivity of muscarinic cholin-
ergic and NMDA receptors compared with other targets sug-
gests that these receptors likely play a major role for the
antinociceptive effects of i.v. lidocaine with the possibility of
supra-additive interactions.
A wide variety of other receptors, ion channels, and other
targets with pivotal roles in somatosensory neurotransmis-
sion and neuroplasticity are subject to the influence of lido-
caine. Its effects on neuroplasticity deserve special attention,
given that the duration of clinical effects of lidocaine often
significantly exceeds its plasma half-life. Yet, many of those
interactions have been observed at concentrations signifi-
cantly exceeding those considered clinically relevant. It is
likely that there is not just one mechanism responsible for
lidocaine-mediated anti-nociception, but rather a complex

synergy of multiple pathways. Furthermore, synergistic ef-
fects of lidocaine in concert with other pharmacological
agents used in pain treatment, such as opioids, are likely. For
example, Kir channels, which are, at first glance, insensitive to
lidocaine, when tested in combination with opioids, may turn
out to be relevant, as opioids have significant actions on Kir
channels. The study of interactions between different mech-
anisms will likely reveal more insights into the interplay of the
different targets described in this review.
There are no experimental data explaining the effects of i.v.
lidocaine on the risk for developing chronic post-surgical pain.
This important effect cannot be elucidated using in vitro
models, but requires specific models of experimental chronic
post-surgical pain. Future research should aim to explain such
long-term effects mediated by biochemical, neurological, or
epigenetic changes. In addition to elucidating the mechanisms
of action of lidocaine, this might also open new avenues to
future pain research and therapy.
Authors’ contributions
Review design: HH, MWH
Literature search: HH, MFS
Analysis: HH
Writing first draft: HH
Writing section on ion channel interactions: MFS, PL, RW
Writing section on microRNA: TB
Writing section on interaction of lidocaine with inflammatory
pathways: TP
Writing section on interactions of lidocaine metabolites: RW
Writing paper: HH, MWH, MFS, PL, TB, RW
Data collection for Figure 2: MFS
Preparation of figures: RW
Editing paper: MWH
Revising paper: PL, TB, TP, RW
Final editing: MFS
Declaration of interest
The authors declare that they have no conflicts of interest.
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