title: Chronically infused intrathecal morphine in dogs.
abstract: BACKGROUND
  Despite the extensive use of intrathecal morphine infusion for pain, no systematic safety studies exist on its effects in high concentrations. The authors assessed the effects of morphine and clonidine given 28 days intrathecally in dogs.
  
  
  METHODS
  Beagles with lumbar intrathecal catheters received solutions delivered by a vest-mounted infusion pump. Six groups (n = 3 each) received infusions (40 microl/h) of saline or 1.5, 3, 6, 9, or 12 mg/day of morphine for 28 days. Additional groups received morphine at 40 microl/h (1.5 mg/day) plus clonidine (0.25-1.0 mg/day) or clonidine alone at 100 microg/h (4.8 mg/day).
  
  
  RESULTS
  In animals receiving 9 or 12 mg/day morphine, allodynia was observed shortly after initiation of infusion. A concentration-dependent increase in hind limb dysfunction evolved over the infusion interval. Necropsy revealed minimal reactions in saline animals. At the higher morphine concentrations (all dogs receiving 12 mg/day), there was a local inflammatory mass at the catheter tip that produced significant local tissue compression. All animals with motor dysfunction displayed masses, although all animals with masses did not show motor dysfunction. The mass, arising from the dura-arachnoid layer, consisted of multifocal accumulations of neutrophils, monocytes, macrophages, and plasma cells. Inflammatory cells and endothelial cells displayed significant IL1beta, TNFalpha, iNOS, and eNOS immunoreactivity. No evidence of bacterial or fungal involvement was detected. There were no other changes in spinal morphologic characteristics. In four other groups of dogs, clonidine alone had no effect and in combination with morphine reduced the morphine reaction.
  
  
  CONCLUSIONS
  The authors found that high intrathecal morphine concentrations lead to aseptic intrathecal inflammatory masses. The lack of effect of clonidine and the possible suppressive effects of clonidine on the local reaction suggest the utility of such coadministration.
authors.affiliation: Department of Anesthesiology, University of California San Diego, La Jolla 92093, USA. tyaksh@ucsd.edu
authors.forename: Tony L
authors.initials: TL
authors.lastname: Yaksh
authors.forename: Kjersti A
authors.initials: KA
authors.lastname: Horais
authors.forename: Nicolle A
authors.initials: NA
authors.lastname: Tozier
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Allen
authors.forename: Michael
authors.initials: M
authors.lastname: Rathbun
authors.forename: Steven S
authors.initials: SS
authors.lastname: Rossi
authors.forename: Claudia
authors.initials: C
authors.lastname: Sommer
authors.forename: Carol
authors.initials: C
authors.lastname: Meschter
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Richter
authors.forename: Keith R
authors.initials: KR
authors.lastname: Hildebrand
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001143:Arousal / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000008:administration & dosage / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D006339:Heart Rate / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D011595:Psychomotor Agitation / Q000523:psychology; D011597:Psychomotor Performance / Q000187:drug effects; D015656:Respiratory Mechanics / Q000187:drug effects; D013116:Spinal Cord / Q000473:pathology
chemical_list: D000316:Adrenergic alpha-Agonists; D000701:Analgesics, Opioid; D004338:Drug Combinations; D009020:Morphine; D003000:Clonidine