Abstract: Combinations of naturally occurring site 1 sodium channel blockers, such as tetrodotoxin (TTX), saxitoxin (STX), decarbamoyl saxitoxin, and neosaxitoxin (referred to jointly herein as “toxins”), with other agents, have been developed to give long duration block with improved features, including safety and specificity. In one embodiment, duration of block is greatly prolonged by combining a toxin with a local anesthetic, vasoconstrictor, glucocorticoid, and/or adrenergic drugs, both alpha agonists (epinephrine, phenylephrine), beta-blockers (propranalol), and mixed central-peripheral alpha-2 agonists (clonidine), or other agents. In another embodiment, the duration of nerve block from toxin can be greatly enhanced by the inclusion of amphiphilic or lipophilic solvents. In still another embodiment, the effectiveness of these compositions is enhanced by microencapsulation within polymeric carriers, preferably biodegradable synthetic polymeric carriers.