There are many anecdotal accounts of certain individuals not being affected by local anesthesia, often disrupting surgical care. However, in reality, there is a paucity of literature documenting true resistance to local anesthetics. The majority of documented cases of resistance have been retrospectively attributed to technical issues (e.g., poor technique), defective anesthetics, or infection.1 Conditions associated with resistance to local anesthesia include genetic mutations of the local anesthetic binding site, prior scorpion bite, Ehlers-Danlos Syndrome hypermobility type, frequent opioid use, and some individuals who have naturally red hair, with varying levels of evidence quality.2
Local anesthetic drugs exert their effects by binding to voltage-gated sodium channels (VGSC). In doing so, peripheral pain receptors are inhibited from sending excitatory pain signals centrally – thereby blocking the sensation of pain.3 Due to the known mechanism of local anestheic effect, it has been postulated that mutations in VGSCs may lead to local anesthetic resistance or an attenuated response.4 Resistance to local anesthetics was documented in one family. Whole-exome sequencing identified a shared mutation (i.e., A572D mutation) in the SCN5A gene, which encodes a portion of the VGSC. This mutation, found in less than 1% of the population, was attributed to the observed resistance to local anesthesia in the family.5
It has also been posited that history of prior scorpion bite leads to resistance to local anesthetics.2 A case-control study from 2013 found a direct correlation between a history of scorpion bite and documented resistance to intrathecally administered local anesthetics.6 The proposed mechanism for resistance following a scorpion bite is due to the attenuated or inhibited pumping mechanism of the VGSC – an effect of the scorpion venom – leading to resistance to local anesthetics.7
Ehlers-Danlos Syndrome, particularly the hypermobility type, has also been identified as a condition associated with resistance to local anesthetics.2 A 2019 retrospective survey reported as many as 88% of respondents with Ehlers-Danlos Syndrome reporting either complete, partial, or rapidly waning effect of local anesthetics.8 The mechanism for this hypothesized resistance is unclear. Altered dispersal of the local anesthetic has been posited as the etiology of this observed disparity.2 However, this was refuted in an experiment demonstrating no difference in dermal dispersal of local anesthesia among individuals with and without Ehlers-Danlos Syndrome.9 Microvascular differences as well as differences in pharmacokinetics have been posited as the mediator of this disparity.2
Documented cross-interactions and cross-tolerance between local anesthetics and opiates have led to the association of opioid tolerance and local anesthetic resistance.10,11 A retrospective cohort study demonstrated higher (P < 0.001) lidocaine doses administered to individuals who were opioid-tolerant.12 However, clinically, it has been suggested to continue using local anesthetics for opioid-tolerant individuals due to the paucity of data suggesting universal resistance in this population.13
Subcutaneous lidocaine was found to be less effective in individuals with naturally red hair (P = 0.005) according to one study. In the same study, this cohort was found to be more sensitive to cold pain perception (P = 0.004) and cold pain tolerance (P = 0.001).14 The mechanism for the observed findings remains unclear. However, it has been proposed that peripheral MC1R receptors, which are mutated in individuals with naturally red hair, results in compensatory, central upregulation of melanocortins leading to increased pain sensitization.14
In conclusion, few conditions are associated with resistance to local anesthesia, and several of those associations are untenable. A patient-specific approach, with an appreciation of the observed associations in scientific literature, is the best approach to local anesthetic administration for pain management in patients.
References
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2. Marti F, Lindner G, Ravioli S. Resistance to local anaesthetics: a literature review. Br J Anaesth. 2022;129(2):e43-e45. doi:10.1016/j.bja.2022.05.006
3. Fozzard HA, Sheets MF, Hanck DA. The sodium channel as a target for local anesthetic drugs. Front Pharmacol. 2011;2:68. doi:10.3389/fphar.2011.00068
4. Scholz A. Mechanisms of (local) anaesthetics on voltage-gated sodium and other ion channels. Br J Anaesth. 2002;89(1):52-61. doi:10.1093/bja/aef163
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