title: Severe toxic damage to the rabbit spinal cord after intrathecal administration of preservative-free S(+)-ketamine.
abstract: BACKGROUND
  Ketamine and S(+)-ketamine have been advocated for neuraxial use in the management of postoperative pain and severe intractable pain syndromes unresponsive to opioid escalation. Although clinical experience has accumulated with S(+)-ketamine, safety data on toxicity in the central nervous system after neuraxial administration of S(+)-ketamine are conflicting. In this study, neurologic and toxicologic effects on the spinal cord from repeated daily intrathecal administration of commercially available, preservative-free S(+)-ketamine were evaluated against placebo in a randomized, blinded design.
  
  
  METHODS
  Eighteen white New Zealand rabbits were assigned to two groups receiving either 0.5 ml intrathecal S(+)-ketamine, 0.5% solution (12 rabbits), or 0.5 ml saline (6 rabbits) once a day for 7 consecutive days. During general anesthesia, an intrathecal catheter was placed between the fifth and sixth spinous processes (lumbar). Neurologic (according to Tarlov criteria) and histopathologic assessments were performed after 7 days of treatment.
  
  
  RESULTS
  Postmortem investigation of the spinal cord and nerve roots revealed histopathologic lesions suggestive of toxic damage in 11 rabbits, from the group of 12 animals receiving S(+)-ketamine. These results were significantly different compared with 5 control animals (no histologic changes observed). There was no significant difference in neurologic status between the two groups after 7 days of intrathecal treatment.
  
  
  CONCLUSIONS
  The authors conclude that repeated intrathecal administration of preservative-free S(+)-ketamine in a clinically relevant concentration and dosage has, considering the extent and severity of the lesions, a toxic effect on the central nervous system of rabbits.
authors.affiliation: Pain Relief Unit, Department of Anesthesiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. j.h.vranken@amc.uva.nl
authors.forename: Jan H
authors.initials: JH
authors.lastname: Vranken
authors.forename: Dirk
authors.initials: D
authors.lastname: Troost
authors.forename: Peter
authors.initials: P
authors.lastname: de Haan
authors.forename: Fritz A
authors.initials: FA
authors.lastname: Pennings
authors.forename: Marinus H
authors.initials: MH
authors.lastname: van der Vegt
authors.forename: Marcel G W
authors.initials: MG
authors.lastname: Dijkgraaf
authors.forename: Markus W
authors.initials: MW
authors.lastname: Hollmann
mesh_terms: D000775:Anesthesia, Spinal; D000778:Anesthetics, Dissociative / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D007278:Injections, Spinal; D007649:Ketamine / Q000008:administration & dosage / Q000633:toxicity*; D009069:Movement Disorders / Q000209:etiology / Q000503:physiopathology; D011817:Rabbits; D013116:Spinal Cord / Q000473:pathology; D013118:Spinal Cord Diseases / Q000139:chemically induced* / Q000473:pathology; D013237:Stereoisomerism
chemical_list: D000778:Anesthetics, Dissociative; D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine