The Science of Local Anesthesia : Basic Research, Clinical Application, and Future Directions

Most local anaesthetics used clinically are relatively hydrophobic molecules that gain access to their blocking site on the sodium channel by diffusing into or through the cell membrane. These anaesthetics block sodium channels and thereby the excitability of all neurons, not just sensory neurons. We tested the possibility of selectively blocking the excitability of primary sensory nociceptor (pain-sensing) neurons by introducing the charged, membrane-impermeant lidocaine derivative QX-314 through the pore of the noxious-heat-sensitive TRPV1 channel. Here we show that charged sodium-channel blockers can be targeted into nociceptors by the application of TRPV1 agonists to produce a pain-specific local anaesthesia. QX-314 applied externally had no effect on the activity of sodium channels in small sensory neurons when applied alone, but when applied in the presence of the TRPV1 agonist capsaicin, QX-314 blocked sodium channels and inhibited excitability. Inhibition by co-applied QX-314 and capsaicin was restricted to neurons expressing TRPV1. Injection of QX-314 together with capsaicin into rat hindpaws produced a long-lasting (more than 2 h) increase in mechanical and thermal nociceptive thresholds. Long-lasting decreases in pain sensitivity were also seen with regional injection of QX-314 and capsaicin near the sciatic nerve; however, in contrast to the effect of lidocaine, the application of QX-314 and capsaicin together was not accompanied by motor or tactile deficits.

Congenital indifference to pain (CIP) is a rare condition in which patients have severely impaired pain perception, but are otherwise essentially normal. We identified and collected DNA from individuals from nine families of seven different nationalities in which the affected individuals meet the diagnostic criteria for CIP. Using homozygosity mapping and haplotype sharing methods, we narrowed the CIP locus to chromosome 2q24-q31, a region known to contain a cluster of voltage-gated sodium channel genes. From these prioritized candidate sodium channels, we identified 10 mutations in the SCN9A gene encoding the sodium channel protein Nav1.7. The mutations completely co-segregated with the disease phenotype, and nine of these SCN9A mutations resulted in truncation and loss-of-function of the Nav1.7 channel. These genetic data further support the evidence that Nav1.7 plays an essential role in mediating pain in humans, and that SCN9A mutations identified in multiple different populations underlie CIP.

Regional anesthesia (RA) provides excellent anesthesia and analgesia for many surgical procedures. Anesthesiologists and patients must understand the risks in addition to the benefits of RA to make an informed choice of anesthetic technique. Many studies that have investigated neurological complications after RA are dated, and do not reflect the increasing indications and applications of RA nor the advances in training and techniques. In this brief narrative review we collate the contemporary investigations of neurological complications after the most common RA techniques. We reviewed all 32 studies published between January 1, 1995 and December 31, 2005 where the primary intent was to investigate neurological complications of RA. The sample size of the studies that investigated neurological complications after central and peripheral (PNB) nerve blockade ranged from 4185 to 1,260,000 and 20 to 10,309 blocks, respectively. The rate of neuropathy after spinal and epidural anesthesia was 3.78:10,000 (95% CI: 1.06-13.50:10,000) and 2.19:10,000 (95% CI: 0.88-5.44:10,000), respectively. For common PNB techniques, the rate of neuropathy after interscalene brachial plexus block, axillary brachial plexus block, and femoral nerve block was 2.84:100 (95% CI 1.33-5.98:100), 1.48:100 (95% CI: 0.52-4.11:100), and 0.34:100 (95% CI: 0.04-2.81:100), respectively. The rate of permanent neurological injury after spinal and epidural anesthesia ranged from 0-4.2:10,000 and 0-7.6:10,000, respectively. Only one case of permanent neuropathy was reported among 16 studies of neurological complications after PNB. Our review suggests that the rate of neurological complications after central nerve blockade is <4:10,000, or 0.04%. The rate of neuropathy after PNB is <3:100, or 3%. However, permanent neurological injury after RA is rare in contemporary anesthetic practice.