Correspondence - e43
of the dihydropyridine receptor (CACNA1S) coding regions
for variants associated with malignant hyperthermia in
Australian families. Anaesth Intensive Care 2015; 43: 157e66
10. Brandom BW, Bina S, Wong CA, et al. Ryanodine receptor
type 1 gene variants in the malignant hyperthermia-
© 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
Resistance to local anaesthetics: a literature review
Florian Marti1,*, Gregor Lindner2,3 and Svenja Ravioli2
1
Department of Anaesthesiology and Intensive Care Medicine, Buergerspital Solothurn, Solothurn,
Switzerland, 2Department of Internal and Emergency Medicine, Buergerspital Solothurn, Solothurn, Switzerland and
3
Department of Emergency Medicine, Inselspital, University Hospital Bern, Bern, Switzerland
*Corresponding author. E-mail: florian_marti@bluewin.ch
Keywords: chronic opioid use; Ehlers-Danlos syndrome; local anaesthetic; resistance; voltage-gated sodium channel
EditordAnaesthetists, general practitioners, surgeons, and
dentists use local anaesthetics (LA) in their daily practice.
Insufficient analgesic effect may result from various causes:
wrong expectations or fears by the patient, incorrect mode of
application, errors in dosage, product preparation, or tissue
inflammation. However, there exist reports of absent or
insufficient LA effect even after correctly performed LA
administration suggesting a true resistance. Steiner and col-
leagues1 investigated CSF samples after inadequate block after
subarachnoid injection of bupivacaine and found
concentrations that would usually lead to adequate block in
12 out of 20 samples. Interestingly, spinal anaesthesia was
sufficient in all patients receiving an additional rescue LA
injection.1 The report of a patient having suffered
inexplicable failure after accurately performed spinal
anaesthesia, but experiencing sufficient analgesic effect after
intradermal LA application, indicates different underlying
mechanisms.2 Current evidence points out several
conditions associated with LA resistance that will be
discussed in this short review.
Firstly, a gene mutation associated with the voltage-gated
sodium channels (VGSC) is suspected to cause LA resistance
with possible alteration of nociception and perception of
temperature. Thus, Clendenen and colleagues3 performed
whole-exome sequencing in a family reporting LA resistance:
a gene mutation in the VGSC, namely in the SCN5A gene
encoding for Nav1.5, was identified in all three persons
suffering from LA resistance, whereas no mutation was found
in the family member without LA resistance. This mutation
does not alter the LA binding site of the VGSC and therefore LA
affinity for binding is not impaired. The authors’ hypothesis of
increased probability of membrane depolarisation as a result
of the mutation3 appears incorrect since a tendency towards
depolarisation could potentiate the LA effect as outlined in
susceptible population of the United States. Anesth Analg
2013; 116: 1078e86
11. Semino O, Passarino G, Oefner PJ, et al. The genetic legacy
of Paleolithic Homo sapiens sapiens in extant Europeans: a Y
chromosome perspective. Science 2000; 290: 1155e9
doi: 10.1016/j.bja.2022.04.029
Advance Access Publication Date: 17 June 2022
Table 1. However, the mutation might influence LA effects via
other mechanisms listed in Table 1.
Secondly, resistance to LA was systematically investi-
gated in patients stung by a scorpion by measuring time for
onset of sensory and motor block after spinal anaesthesia in
35 patients.4 Spinal anaesthesia was effective in all controls,
whereas all patients with a history of scorpion stings re-
ported spinal anaesthesia failure with partial or patchy
blocks and the majority experienced delayed onset of ac-
tion.4 Resistance to LA was more prominent the more the
patients had been stung and the shorter the time since the
last sting. The authors hypothesise that antibodies against
the scorpion venom bind to the LA binding site of the
VGSC and neutralise the LA through competitive antago-
nism, but this appears flawed for several reasons outlined in
Table 1.4
Thirdly, LA failure has been reported during skin biopsy
in patients suffering from Ehlers-Danlos syndrome (EDS) of
the hypermobility type. Consequently, the effect of topical
EMLA (Eutectic Mixture of Local Anesthetics) cream and
infiltration with lidocaine 1% was investigated in eight pa-
tients with EDS and controls.5 Both groups experienced
anaesthesia 5 min after lidocaine infiltration. The LA effect
wore off 60 min after injection in patients with EDS and
persisted in controls. Application of EMLA cream did not
lead to sufficient analgesic effect in patients with EDS
whereas controls reported full anaesthesia 60e120 min af-
ter application. Arendt-Nielsen and colleagues5 suggested
rapid LA diffusion in patients with EDS because of
increased vascular uptake or clearance through the struc-
turally looser connective tissue in EDS type III. This was
questioned by Oliver and colleagues6 who reported no
dispersal of a radioisotope-labelled solution from the
dermal injection site in patients with EDS.6 They suggested
e44 - Correspondence
Table 1 Published studies of resistance to local anaesthetics. EDS, Ehlers-Danlos syndrome; LA, local anaesthetic; MCR1,
melanocortin-1 receptor; VGSC, voltage-gated sodium channel.
Study and subject
Voltage-gated sodium channel3
Only family members with clinical LA
resistance were carriers of the A572D
mutation, whereas the others were not
Scorpion stings4
Comparison of LA effects in patients
having experienced scorpion stings and
controls
Ehlers-Danlos syndrome5
Topical and intradermal application of
lidocaine in patients with EDS and
controls
Opioid consumers7
Comparison of effect and duration of
digital block in opioid consumers and
controls
Red-haired patients10
Comparison of pain sensitivity and
temperature thresholds in red- and
dark-haired women
Mechanism proposed
Mutation A572D in the SCN5A gene
encoding for Nav1.5 increases nerve
depolarisation threshold
unspecifically
Poison induces antibodies that interact
with the LA binding site of the VGSC
Altered LA dispersal in EDS patients
Various mechanisms include changes in
the shape, function, and concentration
of opioid receptors, and interaction
and cross-tolerance between LA and
opioids
Mutation of MC1R known in red-haired
people, but MC1R does not exist in
peripheral nerves; a hypothesis is that
there is an increase in central
nociception, and that MC1R mutation
upregulates central melanocortins
that in turn increase baseline pain
sensitivity via stimulation of
melanocortin-4 receptors
Comments and critical appraisal of the
authors’ hypothesis
The hypothesis is flawed since nerve
depolarisation leads to potentiated LA
effects rather than LA resistance and a
tendency to membrane depolarisation
potentiates LA action via shift towards
the inactivated state of the channel
with higher LA affinity. Direct
modification of the LA binding site
appears unlikely, but entrance to and
efflux from the pore or alterations in
gating among different channel states
might be underlying mechanisms.
The authors suggest that a constituent of
scorpion venom has the same binding
site as the LA. However, this
hypothesis is flawed in terms of
stoichiometry. Furthermore,
permeation of nerve membranes by
proteins such as antibodies and
consecutive interaction with the LA
binding site appears unlikely. The LA
quantity exceeds the quantity of
plasma antibodies, which makes
stoichiometric neutralisation of the LA
highly unlikely.
The hypothesis of altered LA dispersal
was questioned by Oliver and
colleagues6 after dermal dispersal of
radioisotope-labelled LA in patients
with ED showed no difference.
However, possible microvascular
effects have not yet been investigated.
Because of the altered structure of
connective tissue in patients with EDS,
a pharmacokinetic effect can be
assumed.
The reduced LA effect in opioid
consumers is highlighted in the
Supplementary material. The effect
has also been demonstrated in vitro in
peripheral nerves of rats.9 However,
the underlying mechanism remains
unclear and clinical relevance seems
unlikely. Leffler and colleagues8 found
an inhibitory effect of opioids on
central and peripheral VGSCs
comparable to the effects of LA. There
are hypotheses on cross-interactions
and cross-tolerance of opioids and LA.
However, in their in vitro study, the
buprenorphine concentration was
several orders of magnitude higher
than used in standard therapeutic
concentrations.8
Liem and colleagues10 not only detected
insufficient effects of s.c. applied
lidocaine, but also an increased
sensitivity to thermal pain in patients
with red hair. Interestingly, there was
no difference in LA effect after topical
application of lidocaine.
However, the differences between both
groups were small and might not be of
clinical relevance.

a molecular mechanism of LA resistance and hypothesised
that increasing LA dose would not overcome resistance.6
However, microvascular effects are not excluded and
there are various reports of successful anaesthesia after
increasing LA amount or dose in EDS.
Fourthly, insufficient LA effects have been described in
patients who regularly use opioids. Opioid consumers needed
higher doses of lidocaine to experience sufficient analgesia
during surgical wound treatment, and duration of onset was
longer compared with controls.7 This finding might be
explained by a cross-tolerance between LA and opioids. Leffler
and colleagues8 found an inhibitory effect of opioids on central
and peripheral VGSCs comparable to the effects of LA. How-
ever, since the concentrations of buprenorphine used in their
experiments exceeded the concentrations observed with
doses used in clinical practice, these conclusions should be
considered with caution. Opioid-induced hyperalgesia influ-
encing nociception in patients on regular opioid intake is
another suggested mechanism for LA resistance in these pa-
tients. Persistent loss of lidocaine potency in the isolated
sciatic nerve of rats was detected after s.c. morphine appli-
cation, indicating changes in the peripheral nervous system.
Loss in potency depended on lidocaine dose and number of
injections.9
Finally, LA failure has also been reported in patients with
naturally red hair. Liem and colleagues10 not only detected
insufficient effects of s.c. injected lidocaine, but also an
increased sensitivity to thermal pain in patients with red
hair. Since red-haired people are known for a mutation of
the melanocortin-1 receptor gene (MC1R), an association
was assumed. However, MC1R is not known to be expressed
in the peripheral nervous system, and therefore mecha-
nisms of LA resistance in red-haired people remain subject
to speculation.10
In view of the above, real LA resistance is likely attributable
to various causes; a summary and additional evidence are
provided in Table 1 with further information given in the
Supplementary material. The condition might be rare
compared with the majority of patients experiencing LA fail-
ure as a result of procedural errors, but should be considered
in patients experiencing LA failure repeatedly. If LA resistance
is suspected, a diagnostic dermal LA infiltration might be a first
step towards diagnosis. Increased doses of LA and adequate
latency after application might prevent LA failure particularly
in red-haired patients and opioid consumers. Further research
is needed to investigate the condition and to identify whether
a change of LA type, concentration, or dose might lead to
sufficient analgesic effect in patients suffering from real LA
resistance.
© 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
Correspondence - e45
Declarations of interest
The authors declare that they have no conflicts of interest.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.bja.2022.05.006.
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