title: Rufinamide attenuates mechanical allodynia in a model of neuropathic pain in the mouse and stabilizes voltage-gated sodium channel inactivated state.
abstract: BACKGROUND
  Voltage-gated sodium channels dysregulation is important for hyperexcitability leading to pain persistence. Sodium channel blockers currently used to treat neuropathic pain are poorly tolerated. Getting new molecules to clinical use is laborious. We here propose a drug already marketed as anticonvulsant, rufinamide.
  
  
  METHODS
  We compared the behavioral effect of rufinamide to amitriptyline using the Spared Nerve Injury neuropathic pain model in mice. We compared the effect of rufinamide on sodium currents using in vitro patch clamp in cells expressing the voltage-gated sodium channel Nav1.7 isoform and on dissociated dorsal root ganglion neurons to amitriptyline and mexiletine.
  
  
  RESULTS
  In naive mice, amitriptyline (20 mg/kg) increased withdrawal threshold to mechanical stimulation from 1.3 (0.6-1.9) (median [95% CI]) to 2.3 g (2.2-2.5) and latency of withdrawal to heat stimulation from 13.1 (10.4-15.5) to 30.0 s (21.8-31.9), whereas rufinamide had no effect. Rufinamide and amitriptyline alleviated injury-induced mechanical allodynia for 4 h (maximal effect: 0.10 ± 0.03 g (mean ± SD) to 1.99 ± 0.26 g for rufinamide and 0.25 ± 0.22 g to 1.92 ± 0.85 g for amitriptyline). All drugs reduced peak current and stabilized the inactivated state of voltage-gated sodium channel Nav1.7, with similar effects in dorsal root ganglion neurons.
  
  
  CONCLUSIONS
  At doses alleviating neuropathic pain, amitriptyline showed alteration of behavioral response possibly related to either alteration of basal pain sensitivity or sedative effect or both. Side-effects and drug tolerance/compliance are major problems with drugs such as amitriptyline. Rufinamide seems to have a better tolerability profile and could be a new alternative to explore for the treatment of neuropathic pain.
authors.affiliation: Pain Center, Department of Anesthesiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland. marc.suter@chuv.ch
authors.forename: Marc R
authors.initials: MR
authors.lastname: Suter
authors.forename: Guylène
authors.initials: G
authors.lastname: Kirschmann
authors.forename: Cedric J
authors.initials: CJ
authors.lastname: Laedermann
authors.forename: Hugues
authors.initials: H
authors.lastname: Abriel
authors.forename: Isabelle
authors.initials: I
authors.lastname: Decosterd
mesh_terms: D000639:Amitriptyline / Q000008:administration & dosage; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000150:complications / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000150:complications / Q000188:drug therapy*; D010812:Physical Stimulation; D014230:Triazoles / Q000494:pharmacology*; D061566:Voltage-Gated Sodium Channels / Q000187:drug effects*
chemical_list: D018712:Analgesics, Non-Narcotic; D000927:Anticonvulsants; D014230:Triazoles; D061566:Voltage-Gated Sodium Channels; D000639:Amitriptyline; C079703:rufinamide