Resistance to local anaesthetics: a literature review

Abstract

Editor—Anaesthetists, 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 colleagues1Steiner L.A. Hauenstein L. Ruppen W. Hampl K.F. Seeberger M.D. Bupivacaine concentrations in lumbar cerebrospinal fluid in patients with failed spinal anaesthesia.Br J Anaesth. 2009; 102: 839-844Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar 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.1Steiner L.A. Hauenstein L. Ruppen W. Hampl K.F. Seeberger M.D. Bupivacaine concentrations in lumbar cerebrospinal fluid in patients with failed spinal anaesthesia.Br J Anaesth. 2009; 102: 839-844Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar 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.2Weiskopf R.B. Unexplained failure of a continuous spinal anesthetic.Anesthesiology. 1970; 33: 114-116Crossref PubMed Scopus (8) Google Scholar 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 colleagues3Clendenen N. Cannon A.D. Porter S. Robards C.B. Parker A.S. Clendenen S.R. Whole-exome sequencing of a family with local anesthetic resistance.Minerva Anestesiol. 2016; 82: 1089-1097PubMed Google Scholar 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 mutation3Clendenen N. Cannon A.D. Porter S. Robards C.B. Parker A.S. Clendenen S.R. Whole-exome sequencing of a family with local anesthetic resistance.Minerva Anestesiol. 2016; 82: 1089-1097PubMed Google Scholar appears incorrect since a tendency towards depolarisation could potentiate the LA effect as outlined in Table 1. However, the mutation might influence LA effects via other mechanisms listed in Table 1.Table 1Published studies of resistance to local anaesthetics. EDS, Ehlers-Danlos syndrome; LA, local anaesthetic; MCR1, melanocortin-1 receptor; VGSC, voltage-gated sodium channel.Study and subjectMechanism proposedComments and critical appraisal of the authors' hypothesisVoltage-gated sodium channel3Clendenen N. Cannon A.D. Porter S. Robards C.B. Parker A.S. Clendenen S.R. Whole-exome sequencing of a family with local anesthetic resistance.Minerva Anestesiol. 2016; 82: 1089-1097PubMed Google ScholarOnly family members with clinical LA resistance were carriers of the A572D mutation, whereas the others were notMutation A572D in the SCN5A gene encoding for Nav1.5 increases nerve depolarisation threshold unspecificallyThe 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.Scorpion stings4Panditrao M.M. Panditrao M.M. Panditrao A.M. Development of resistance to the effect of local anesthetic agents administered via various routes due to single or multiple, previous scorpion bites: a proposed hypothesis and reporting a yet unrecognized phenomenon.J Anesth Crit Care Open Access. 2015; 3https://doi.org/10.15406/jaccoa.2015.03.00110Crossref Google ScholarComparison of LA effects in patients having experienced scorpion stings and controlsPoison induces antibodies that interact with the LA binding site of the VGSCThe 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.Ehlers-Danlos syndrome5Arendt-Nielsen L. Kaalund S. Bjerring P. Høgsaa B. Insufficient effect of local analgesics in Ehlers Danlos type III patients (connective tissue disorder).Acta Anaesthesiol Scand. 1990; 34: 358-361Crossref PubMed Scopus (59) Google ScholarTopical and intradermal application of lidocaine in patients with EDS and controlsAltered LA dispersal in EDS patientsThe hypothesis of altered LA dispersal was questioned by Oliver and colleagues6Oliver D.W. Balan K.K. Burrows N.P. Hall P.N. Dispersal of radioisotope labelled solution following deep dermal injection in Ehlers-Danlos syndrome.Br J Plast Surg. 2000; 53: 308-312Abstract Full Text PDF PubMed Scopus (10) Google Scholar 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.Opioid consumers7Hashemian A.M. Omraninava A. Kakhki A.D. et al.Effectiveness of local anesthesia with lidocaine in chronic opium abusers.J Emergencies, Trauma Shock. 2014; 7: 301-304Crossref PubMed Scopus (15) Google ScholarComparison of effect and duration of digital block in opioid consumers and controlsVarious mechanisms include changes in the shape, function, and concentration of opioid receptors, and interaction and cross-tolerance between LA and opioidsThe 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.9Liu Q. Gold M.S. Opioid-induced loss of local anesthetic potency in the rat sciatic nerve.Anesthesiology. 2016; 125: 755-764Crossref PubMed Scopus (11) Google Scholar However, the underlying mechanism remains unclear and clinical relevance seems unlikely. Leffler and colleagues8Leffler A. Frank G. Kistner K. et al.Local anesthetic-like inhibition of voltage-gated Na+ channels by the partial μ-opioid receptor agonist buprenorphine.Anesthesiology. 2012; 116: 1335-1346Crossref PubMed Scopus (79) Google Scholar 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.8Leffler A. Frank G. Kistner K. et al.Local anesthetic-like inhibition of voltage-gated Na+ channels by the partial μ-opioid receptor agonist buprenorphine.Anesthesiology. 2012; 116: 1335-1346Crossref PubMed Scopus (79) Google ScholarRed-haired patients10Liem E.B. Joiner T.V. Tsueda K. Sessler D.I. Increased sensitivity to thermal pain and reduced subcutaneous lidocaine efficacy in redheads.Anesthesiology. 2005; 102: 509-514Crossref PubMed Scopus (130) Google ScholarComparison of pain sensitivity and temperature thresholds in red- and dark-haired womenMutation 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 receptorsLiem and colleagues10Liem E.B. Joiner T.V. Tsueda K. Sessler D.I. Increased sensitivity to thermal pain and reduced subcutaneous lidocaine efficacy in redheads.Anesthesiology. 2005; 102: 509-514Crossref PubMed Scopus (130) Google Scholar 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. Open table in a new tab Secondly, resistance to LA was systematically investigated in patients stung by a scorpion by measuring time for onset of sensory and motor block after spinal anaesthesia in 35 patients.4Panditrao M.M. Panditrao M.M. Panditrao A.M. Development of resistance to the effect of local anesthetic agents administered via various routes due to single or multiple, previous scorpion bites: a proposed hypothesis and reporting a yet unrecognized phenomenon.J Anesth Crit Care Open Access. 2015; 3https://doi.org/10.15406/jaccoa.2015.03.00110Crossref Google Scholar Spinal anaesthesia was effective in all controls, whereas all patients with a history of scorpion stings reported spinal anaesthesia failure with partial or patchy blocks and the majority experienced delayed onset of action.4Panditrao M.M. Panditrao M.M. Panditrao A.M. Development of resistance to the effect of local anesthetic agents administered via various routes due to single or multiple, previous scorpion bites: a proposed hypothesis and reporting a yet unrecognized phenomenon.J Anesth Crit Care Open Access. 2015; 3https://doi.org/10.15406/jaccoa.2015.03.00110Crossref Google Scholar 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 antagonism, but this appears flawed for several reasons outlined in Table 1.4Panditrao M.M. Panditrao M.M. Panditrao A.M. Development of resistance to the effect of local anesthetic agents administered via various routes due to single or multiple, previous scorpion bites: a proposed hypothesis and reporting a yet unrecognized phenomenon.J Anesth Crit Care Open Access. 2015; 3https://doi.org/10.15406/jaccoa.2015.03.00110Crossref Google Scholar 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 patients with EDS and controls.5Arendt-Nielsen L. Kaalund S. Bjerring P. Høgsaa B. Insufficient effect of local analgesics in Ehlers Danlos type III patients (connective tissue disorder).Acta Anaesthesiol Scand. 1990; 34: 358-361Crossref PubMed Scopus (59) Google Scholar 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 60–120 min after application. Arendt-Nielsen and colleagues5Arendt-Nielsen L. Kaalund S. Bjerring P. Høgsaa B. Insufficient effect of local analgesics in Ehlers Danlos type III patients (connective tissue disorder).Acta Anaesthesiol Scand. 1990; 34: 358-361Crossref PubMed Scopus (59) Google Scholar suggested rapid LA diffusion in patients with EDS because of increased vascular uptake or clearance through the structurally looser connective tissue in EDS type III. This was questioned by Oliver and colleagues6Oliver D.W. Balan K.K. Burrows N.P. Hall P.N. Dispersal of radioisotope labelled solution following deep dermal injection in Ehlers-Danlos syndrome.Br J Plast Surg. 2000; 53: 308-312Abstract Full Text PDF PubMed Scopus (10) Google Scholar who reported no dispersal of a radioisotope-labelled solution from the dermal injection site in patients with EDS.6Oliver D.W. Balan K.K. Burrows N.P. Hall P.N. Dispersal of radioisotope labelled solution following deep dermal injection in Ehlers-Danlos syndrome.Br J Plast Surg. 2000; 53: 308-312Abstract Full Text PDF PubMed Scopus (10) Google Scholar They suggested a molecular mechanism of LA resistance and hypothesised that increasing LA dose would not overcome resistance.6Oliver D.W. Balan K.K. Burrows N.P. Hall P.N. Dispersal of radioisotope labelled solution following deep dermal injection in Ehlers-Danlos syndrome.Br J Plast Surg. 2000; 53: 308-312Abstract Full Text PDF PubMed Scopus (10) Google Scholar 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.7Hashemian A.M. Omraninava A. Kakhki A.D. et al.Effectiveness of local anesthesia with lidocaine in chronic opium abusers.J Emergencies, Trauma Shock. 2014; 7: 301-304Crossref PubMed Scopus (15) Google Scholar This finding might be explained by a cross-tolerance between LA and opioids. Leffler and colleagues8Leffler A. Frank G. Kistner K. et al.Local anesthetic-like inhibition of voltage-gated Na+ channels by the partial μ-opioid receptor agonist buprenorphine.Anesthesiology. 2012; 116: 1335-1346Crossref PubMed Scopus (79) Google Scholar found an inhibitory effect of opioids on central and peripheral VGSCs comparable to the effects of LA. However, 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 influencing nociception in patients on regular opioid intake is another suggested mechanism for LA resistance in these patients. Persistent loss of lidocaine potency in the isolated sciatic nerve of rats was detected after s.c. morphine application, indicating changes in the peripheral nervous system. Loss in potency depended on lidocaine dose and number of injections.9Liu Q. Gold M.S. Opioid-induced loss of local anesthetic potency in the rat sciatic nerve.Anesthesiology. 2016; 125: 755-764Crossref PubMed Scopus (11) Google Scholar Finally, LA failure has also been reported in patients with naturally red hair. Liem and colleagues10Liem E.B. Joiner T.V. Tsueda K. Sessler D.I. Increased sensitivity to thermal pain and reduced subcutaneous lidocaine efficacy in redheads.Anesthesiology. 2005; 102: 509-514Crossref PubMed Scopus (130) Google Scholar 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 mechanisms of LA resistance in red-haired people remain subject to speculation.10Liem E.B. Joiner T.V. Tsueda K. Sessler D.I. Increased sensitivity to thermal pain and reduced subcutaneous lidocaine efficacy in redheads.Anesthesiology. 2005; 102: 509-514Crossref PubMed Scopus (130) Google Scholar 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 failure 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. The authors declare that they have no conflicts of interest. The following is the Supplementary data to this article: Download .docx (.05 MB) Help with docx files Multimedia component 1

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