title: Safety assessment and pharmacokinetics of intrathecal methylprednisolone acetate in dogs.
abstract: BACKGROUND
  Intrathecal methylprednisolone acetate (MPA) has been used in patients with chronic pain syndromes. Its safety has been debated after reports of adverse events. No systematic preclinical evaluation of MPA has been reported. In the current study, the acute and long-term effects of intrathecal MPA on dog spinal tissue was studied with the injectate reformulated to include minimal adjuvants.
  
  
  METHODS
  Seventeen dogs were implanted with intrathecal catheters and randomized to three groups: vehicle (lidocaine; 4 dogs), MPA 20 mg/ml (human dose; 7 dogs), and MPA 80 mg/ml (maximum deliverable dose; 6 dogs). In parallel with the human protocols, dogs received four injections at 7-day intervals. Clinical observations and plasma methylprednisolone measurements were done before and at intervals after intrathecal delivery. One week (acute) or 6 weeks (long-term) after the last injection, animals were sacrificed and spinal tissues harvested for histopathology.
  
  
  RESULTS
  Other than a brief motor block, no adverse clinical event occurred in any animal. Group A (vehicle) showed minimal histologic changes (median histology-score; acute: 1.3, long-term: 1.0). Group B (MPA 20 mg/ml) had a diffuse inflammatory reaction (acute: 2.0, long-term: 3.0), group C (MPA 80 mg/ml) a severe inflammatory response, with large inflammatory masses (acute: 4.0, long-term: 7.0) The severity of the inflammatory reaction increased significantly with increasing dose at long-term sacrifice (acute P = 0.167, long-term P = 0.014). No neuronal injury, demyelination, or gliosis was seen in any animal.
  
  
  CONCLUSIONS
  These results, showing dose-dependent intrathecal inflammatory reactions at MPA doses and injectate concentrations comparable to those used in humans, indicate that the continued use of this modality in humans is not recommended.
authors.affiliation: Anesthesiology and Critical Care Department, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Mienke
authors.initials: M
authors.lastname: Rijsdijk
authors.forename: Albert J M
authors.initials: AJ
authors.lastname: van Wijck
authors.forename: Cor J
authors.initials: CJ
authors.lastname: Kalkman
authors.forename: P C Willem
authors.initials: PC
authors.lastname: Meulenhoff
authors.forename: Marjorie R
authors.initials: MR
authors.lastname: Grafe
authors.forename: Joanne
authors.initials: J
authors.lastname: Steinauer
authors.forename: Tony L
authors.initials: TL
authors.lastname: Yaksh
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D003692:Delayed-Action Preparations; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D007249:Inflammation / Q000473:pathology; D007278:Injections, Spinal; D008297:Male; D008581:Meningitis / Q000139:chemically induced / Q000473:pathology; D008775:Methylprednisolone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D051474:Neuralgia, Postherpetic / Q000188:drug therapy; D010147:Pain Measurement / Q000187:drug effects; D016612:Paraffin Embedding; D011310:Preservatives, Pharmaceutical; D012449:Safety
chemical_list: D000893:Anti-Inflammatory Agents; D003692:Delayed-Action Preparations; D011310:Preservatives, Pharmaceutical; D008775:Methylprednisolone