QUATERNARY AMMONIUM DERIVATIVE OF LIDOCAINE AS A LONG-ACTING LOCAL-ANESTHETIC

Background: Use of long-acting local anesthetics that elicit complete neural blockade for more than 3 h often is desirable in pain managemen t. Unfortunately, clinically available local anesthetics are in genera l not suitable for prolonged analgesia. This report describes the orga nic synthesis and functional testing of a lidocaine derivative that ap pears to fulfill the criteria of long-acting local anesthetics. Method s: A lidocaine derivative, N-beta-phenylethyl lidocaine quaternary amm onium bromide, was synthesized, and its ability to inhibit Na+ current s in cultured rat neuronal GH(3) cells was tested in vitro under whole -cell voltage clamp conditions. Neurologic evaluation of sciatic nerve block of sensory and motor functions in vivo was subsequently perform ed in rats. Results: N-beta-phenylethyl lidocaine was found to be a po tent Na+ channel blocker in vitro. It produced both tonic and use-depe ndent blocks of Na+ currents that exceeded lidocaine's effects by a fa ctor of >2 (P < 0.05). In vivo N-beta-phenylethyl lidocaine elicited a prolonged and complete sciatic nerve block of the motor function and the withdrawal response to noxious pinch that was 3.6- and 9.3-fold lo nger than that of lidocaine (P < 0.001), respectively. Conclusions: In an attempt to elicit prolonged local anesthesia, a quaternary ammoniu m derivative of lidocaine containing a permanent charge and an additio nal hydrophobic component was synthesized. Complete sciatic neural blo ckade of more than 3 h was achieved with this derivative. Of note, sen sory blockade was prolonged to a greater extent than motor blockade. T he approach used in this study may prove useful for developing new dru gs applicable in pain management.