title: 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 microm 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. gerner@zeus.bwh.harvard.edu
authors.forename: Peter
authors.initials: P
authors.lastname: Gerner
authors.forename: Mustafa
authors.initials: M
authors.lastname: Mujtaba
authors.forename: Mohammed
authors.initials: M
authors.lastname: Khan
authors.forename: Yukari
authors.initials: Y
authors.lastname: Sudoh
authors.forename: Kamen
authors.initials: K
authors.lastname: Vlassakov
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Anthony
authors.forename: Ging Kuo
authors.initials: GK
authors.lastname: Wang
mesh_terms: D000639:Amitriptyline / Q000031:analogs & derivatives / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D008012:Lidocaine / Q000494:pharmacology; D009407:Nerve Block / Q000379:methods*; D051381:Rats; D012584:Sciatic Nerve / Q000187:drug effects*; D013997:Time Factors
chemical_list: D000779:Anesthetics, Local; C464428:N-phenylethyl amitriptyline; D000639:Amitriptyline; D008012:Lidocaine