Physicians occasionally treat patients who report feeling no relief following local anesthesia administration [1]. This situation occurs across a wide variety of patients with various conditions, from Ehlers-Danlos Syndrome (EDS) to Complex Regional Pain Syndrome (CRPS) to Crohn’s Disease [2, 3, 4]. Resistance has also been documented across several anesthetic compounds, including lidocaine, mepivacaine, and bupivacaine [5]. This form of failure–tied to a patient’s resistance to local anesthesia rather than any technical difficulties–remains an uncertainty to the medical community [6].
One hypothesis as to how local anesthesia resistance operates centers on sodium channels [5]. Voltage-gated sodium channels (VGSCs) are the avenue through which local anesthesia produces pain relief [5]. By blocking the nerve’s sodium channels, the anesthetic halts the process of depolarization, thereby interrupting nerve signals and preventing pain processing [1]. Patients who experience local anesthesia resistance may have atypical receptor sites that minimize or entirely negate anesthesia’s efficacy [5].
Genetic variation may be the reason for certain patient’s abnormal receptor sites [4, 5]. If a patient contains a mutation in the amino acid sequence that codes for the construction of their sodium channels, receptor sites might be negatively impacted to the extent that local anesthesia becomes ineffective [5]. This genetic perspective has been supported by some family-based studies. One study exome-sequenced a family consisting of a mother, father, a son, and a daughter [7]. The daughter, mother, and son experienced little effect from local anesthesia, while the father displayed the typical response [7]. Upon sequencing the three family members for crucial genetic variants that may explain their conditions, the researcher found a nerve-based variant, Nav 1.5, that may point to a genetic basis for local anesthesia resistance [7].
An alternative but similar explanation for the mechanism behind local anesthesia resistance emerged from a case study of a 12-year-old girl with CRPS [3]. The young girl did not respond to epidural local anesthetic block, exhibiting resistance to anesthesia in the area of her body associated with her pain [3]. Researchers suggested that the patient’s resistance may have been due to having highly sensitive and dysfunctional wide dynamic range (WDR) neurons in the spinal cord’s dorsal horn [3]. This could explain why her resistance was so localized and help scientists understand the pathophysiology behind CRPS [3]. This theory could be consistent with the aforementioned one, assuming that the patient’s dysfunctional neurons are the product of genetic mutations.
Despite the relative strength of these hypotheses, neither can yet explain why some patients only experience resistance to certain anesthetic agents [5]. This is an important question to address in medical research. Resistance to local anesthesia increases patients’ suffering from acute bouts of pain [3]. It also can lead to traumatic experiences during routine operations, such as dental visits, during which patients have no choice but to bear extreme pain and discomfort [2]. While developing future local anesthetic techniques, scientists must work to create substances that can address the current gap, which will require further investigations and larger studies to identify the root cause of this phenomenon.
References
[1] A. M. Trescot, “Local Anesthetic ‘Resistance’,” Pain Physician, vol. 6, no. 3, p. 291-293, 2003. [Online]. ISSN: 1533-3159
[2] J. R. Schubart et al., “Resistance to local anesthesia in people with the Ehlers-Danlos Syndromes presenting for dental surgery,” Journal of Dental Anesthesia and Pain Medicine, vol. 19, no. 5, p. 261-270, October 2019. [Online]. Available: https://doi.org/10.17245/jdapm.2019.19.5.261.
[3] F. R. Maneksha, H. Mirza, and P. J. Poppers, “Complex regional pain syndrome (CRPS) with resistance to local anesthetic block: A case report,” Journal of Clinical Anesthesia and Pain Medicine, vol. 12, no. 1, p. 67-71, January 2000. [Online]. Available: https://doi.org/10.1016/s0952-8180(99)00126-9.
[4] S. S. Schutte and T. Euliano, “Local anesthetic resistance in a Crohn’s patient undergoing cesarean delivery,” Regional Anesthesia and Pain Medicine, vol. 45, no. 8, p. 669-670, August 2021. [Online]. Available: https://doi.org/10.1136/rapm-2020-101516.
[5] D. Batas, M. R. G. Nejad, and P. K. Prabhu, “Resistance to Local Anaesthetics: a case report,” British Journal of Anaesthesia, vol. 99, p. 410-417, January 2007. [Online]. Available: https://doi.org/10.1093/bja/el_1576.
[6] P. Anand, S. Kamath, and J. Yarmush, “Failed regional anesthesia: local anesthetic resistance possibly due to voltage gated sodium channellopathy: A Case Report,” Journal of Pain, vol. 18, no. 4, p. S30, January 2017. [Online]. Available: https://doi.org/10.1016/j.jpain.2017.02.379.
[7] S. N. Clendenen et al., “Whole-exome sequencing of a family with local anesthetic resistance,” Minerva Anestesiologica, vol. 82, no. 10, p. 1089-1097, October 2016. [Online]. Available: https://doi.org/10.1136/rapm-2020-101516.
