N-phenylethyl amitriptyline in rat sciatic nerve blockade

Abstract

Background: The antidepressant amitriptyline is commonly used orally for the treatment of chronic pain, particularly neuropathic pain, which is thought to be caused by high-frequency ectopic discharge. Among its many properties, amitriptyline is a potent Na + channel blocker in vitro, has local anesthetic properties in vivo, and confers additional blockade at high stimulus-discharge rates (use-dependent blockade). As with other drug modifications, adding a phenylethyl group to obtain a permanently charged quaternary ammonium derivative may improve these advantageous properties. Methods: The electrophysiologic properties of N-phenylethyl amitriptyline were assessed in cultured neuronal GH 3 cells with the whole cell mode of the patch clamp technique, and the therapeutic range and toxicity were evaluated in the rat sciatic nerve model. Results: In vitro, N-phenylethyl amitriptyline at 10 μM elicits a greater block of Na + channels than amitriptyline (resting block of approximately 90% vs. approximately 15%). This derivative also retains the attribute of amitriptyline in evoking high-degree use-dependent blockade during repetitive pulses. In vivo, duration to full recovery of nociception in the sciatic nerve model was 1,932 ± 72 min for N-phenylethyl amitriptyline at 2.5 mM (n = 7) versus 72 ± 3 min for lidocaine at 37 mM (n = 4; mean ± SEM). However, there was evidence of neurotoxicity at 5 mM. Conclusion: N-phenylethyl amitriptyline appears to have a narrow therapeutic range but is much more potent than lidocaine, providing a block duration several times longer than any clinically used local anesthetic. Further work in animal models of neuropathic pain will assess the potential use of this drug.