Cocaethylene is a naturally occurring cocaine derivative that has been used as a tool in both clinical studies of cocaine reward and as a potential model compound for agonist substitution therapy in cocaine dependence. It is equipotent to cocaine at inhibiting dopamine uptake in-vitro and in-vivo. Because it has been reported that local anesthetic properties may influence the reinforcing effects of dopamine uptake inhibitors, we investigated the local anesthetic properties of cocaethylene as well as isopropylcocaine, another potential pharmacological tool in studies of cocaine reward and agonist substitution therapy. We compared the efficacy of nerve impulse blockade by lidocaine, cocaine, cocaethylene and isopropylcocaine using rat sciatic nerves and dorsal roots (DRs). Nerves were placed in a modified sucrose gap chamber and repetitively stimulated at high frequency. The amplitude of compound action potentials (CAPs) at the beginning and end of each stimulus train was measured before and after exposure to each compound. All compounds produced concentration-dependent and use-dependent decrements in CAP amplitude, but cocaethylene and isopropylcocaine at medium to high concentration (0.375-1.875 mM) showed a more prolonged block after washout relative to cocaine or lidocaine. Patch clamp studies on dorsal root ganglion (DRG) neurons indicated a use-dependent blockade of sodium channels. These studies provide a more complete understanding of the pharmaocology of potential agonist treatment candidates, and suggest a mechanism whereby cocaethylene produces a decreased euphoria in humans compared to cocaine.