Novel local anesthetics address the primary limitations of cocaine-derived anesthetics, specifically limited duration and risk of systemic toxicity.

1. Novel sodium channel blockers
   1. Neosaxitoxin is a paralytic shellfish toxin that binds to the tetrodotoxin-binding site on the voltage-gated sodium channel. It lacks cardiac toxicity and produces a longer block in animal models, but there are currently no ongoing clinical trials on clinicaltrials.gov.
   2. Other sodium channels blockers exist (tetrotodotoxin, alpha and beta-scorpion toxin, sea anemone toxin, brevetoxin, ciguatoxin, delta-conotoxin), with others in preclinical development, but no active candidates.
2. Extended-release formulations including liposomal bupivacaine
   1. Multivesicular bupivacaine sold under the trade name Exparel as discussed in Chapter 19, Section I.D.4.
   2. Sucrose acetate isobutyrate extended release (SABER)-bupivacaine is a formulation that improves pain relief compared with placebo but has not passed FDA review owing to safety concerns.
   3. HTX-011 is a biochromer-polymer of bupivacaine with meloxicam as an adjuvant. Phase III clinical trials support efficacy above bupivacaine alone.
   4. Other extended-release formulations of bupivacaine exist in preclinical trials.