title: The neuraxial effects of intraspinal amitriptyline at low concentrations.
abstract: BACKGROUND
  As a result of amitriptyline's vast array of actions, it could potentially be used as an intraspinal adjuvant in neuraxial anesthesia and/or in the treatment of refractory neuropathic pain. None of the previous studies examining the safety profile of intraspinal single doses of amitriptyline found signs of toxicity at concentrations below 15.4 mM/L (0.5%) and the current hypothesis regarding the pathophysiology of amitriptyline toxicity suggests it might be safe at low concentrations while still having relevant clinical effects. Hence, we conducted this study to assess the clinical and histological toxicity of intraspinal amitriptyline at the lowest dosages previously known to be effective.
  
  
  METHODS
  Twenty-one dogs were randomized to receive a 1-mL single intraspinal dose of one of the three solutions: saline (0.9%), amitriptyline (0.15%), or amitriptyline (0.3%). The dogs were evaluated clinically 1 h after awakening from anesthesia and 21 days later. At 21 days, all animals were killed, and histological sections of the spinal cord and surrounding meninges were retrieved for analysis.
  
  
  RESULTS
  All dogs recovered motor function, anal sphincter tone and sensibility. With the exception of one dog in the 0.15% amitriptyline group, all animals in both amitriptyline groups had marked adhesive arachnoiditis, which was absent in the control group. No evidence of direct neural damage was found on histological sections stained by glial fibrillary acidic protein technique in any of the study animals.
  
  
  CONCLUSIONS
  The intraspinal administration of amitriptyline to dogs even in low concentrations is strongly associated with the development of intense meningeal adhesive arachnoiditis and is not safe even at low concentrations for which there was no previous evidence of toxicity.
authors.affiliation: Department of Anesthesiology, São Paulo State University-UNESP, Botucatu/SP, Brazil. fernandafukushima@gmail.com
authors.forename: Fernanda B
authors.initials: FB
authors.lastname: Fukushima
authors.forename: Guilherme A M
authors.initials: GA
authors.lastname: Barros
authors.forename: Mariângela E A
authors.initials: ME
authors.lastname: Marques
authors.forename: Edison I O
authors.initials: EI
authors.lastname: Vidal
authors.forename: Eliana M
authors.initials: EM
authors.lastname: Ganem
mesh_terms: D000639:Amitriptyline / Q000008:administration & dosage*; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage*; D000758:Anesthesia; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects; D004285:Dogs; D005260:Female; D007278:Injections, Spinal / Q000379:methods*; D008297:Male; D009437:Neuralgia; D009474:Neurons / Q000473:pathology; D010146:Pain; D011897:Random Allocation; D013116:Spinal Cord / Q000187:drug effects* / Q000473:pathology; D013997:Time Factors
chemical_list: D018712:Analgesics, Non-Narcotic; D000639:Amitriptyline