Will Conventional Local Anesthetics Soon Be Replaced by Neurotoxins?

L ocal anesthetics are useful, but they are not discriminating compounds. Clinicians often think of them as having some degree of specificity for voltage-gated Na (Nav) channels; in fact, local anesthetics bind these channels with low affinity (dissociation constants are generally in the range of 10 to 10 mol/L). Unfortunately, this means that local anesthetic affinity for Nav channels is nearly the same as for a wide range of enzymes, channels, receptors, and other targets. Low affinity for Nav channels also underlies the lack of a specific local anesthetic antagonist. Low affinity leads to larger doses and the greater possibility of systemic toxicity when these larger doses are absorbed into the bloodstream. We generally want to inhibit Nav channels in a single tissue. When we inject a local anesthetic around the trunks of the brachial plexus during an interscalene block, we are not seeking to bind or inhibit Nav channels in the heart, skeletal muscle, brain, epidural roots, or spinal cord. Despite there being 7 distinct Nav-channel isoforms in humans (and there being tissue-specific distribution of these isoforms), local anesthetic affinity has only minimal variation among the isoforms. On the other hand, there are neurotoxins that have high affinity (dissociation constants in the range of 10 to 10 mol/L) and high specificity for Nav channels. At pH 7.2, 2 nM neosaxitoxin produces 50% inhibition of compound action potentials in peripheral nerves. In other words, neosaxitoxin is roughly 1 millionYfold more potent than lidocaine. Toxins such as neosaxitoxin and tetrodotoxin have less affinity for most cardiac Nav channels than for most Nav channels in nerve tissue. These characteristics formed the basis for the intriguing clinical trial reported in this issue of Regional Anesthesia and Pain Medicine. The exciting news is that injection of neosaxitoxin at the port sites for laparoscopic cholecystectomy provided better analgesia than injection of a comparable volume of 0.25% bupivacaine. On the other hand, the between-group differences in pain were largely limited to the first 12 to 24 postoperative hrs, and pain is generally not the limiting factor for recovery after this minimally invasive surgery. Nevertheless, these results prove the concept that neosaxitoxin might prove useful for postoperative analgesia in humans. There is much that we still do not know about this compound, and I will summarize some items that will need scientific attention. We do not have good data regarding the speed of onset of neosaxitoxin versus bupivacaine after local infiltrations. We do not know the compound’s margin of safety. Careful phase 1 studies will need to be done to determine the maximal tolerable dose of this product before it can be used in an ethical clinical trial that could determine whether neosaxitoxin might be effective for infiltration of larger, conventional ‘‘open’’ surgical wounds. Nevertheless, I eagerly await the results of such a trial in which injections of neosaxitoxin are compared with bupivacaine or ropivacaine. Given the relatively short duration of neosaxitoxin in this study, we may well need to use larger doses or infusions to provide analgesia as effective and as prolonged as can be obtained by local anesthetic infusions in surgical wounds. We do not know whether neosaxitoxin injections might produce nerve damage or some other disastrous toxic adverse effect in some patients. Using the 3/n rule, we can only exclude an incidence of 3/69 or 4% (with 95% confidence) after the very small injections of neosaxitoxin used in this study. We do not know whether prolonged numbness, paresthesias, or dysesthesias might appear at this or higher doses. Analgesia after injection at port sites confirms that neosaxitoxin blocks primary nociceptive neurons at some location (perhaps at free nerve endings or receptors), but does not confirm that this agent could substitute for conventional local anesthetics in techniques (basically all peripheral nerve blocks) that require the drug to diffuse across tissue barriers such as perineurium. Remember that at physiological conditions, the vast majority of neosaxitoxin molecules exist as EDITORIAL