title: Inflammatory masses associated with intrathecal drug infusion: a review of preclinical evidence and human data.
abstract: OBJECTIVE
  The phenomenon of inflammatory masses at the tips of intrathecal drug administration catheters was the subject of a recent case-compilation report and a number of animal studies. We sought to synthesize current clinical and preclinical data to formulate hypotheses about the etiology of catheter-tip masses.
  
  
  METHODS
  We reviewed the published human clinical data, new unpublished clinical data, and the results of preclinical studies in two mammalian species, beagle dogs and sheep.
  
  
  RESULTS
  Intrathecal morphine sulfate studies in beagle dogs suggested that the observed inflammatory reaction was dose or concentration dependent. Masses occurred after 28 days in one of three animals at 1.5 mg/day (the lowest morphine dose tested); in two of three animals at 3 and 9 mg/day; and in three of three animals at 12 mg/day. The addition of various amounts of clonidine to 1.5 mg/day of morphine revealed no mass formation when the clonidine dose was>0.25 mg/day. A morphine sulfate study that was performed in sheep using a commercially marketed drug administration system found catheter tip masses in two of three animals that received 12 or 18 mg/day of morphine, the highest doses tested. Human cases have occurred only in pain patients who received intrathecal opioids, alone or mixed with other drugs, or in patients who received investigational agents (such as superoxide dismutase or the partial micro-opioid-receptor agonist, tramadol) that were not labeled for long-term intrathecal use.
  
  
  CONCLUSIONS
  The evidence suggests that the long-term administration of opioids, especially morphine, caused the masses that were observed in humans and in two species of animals. A relationship probably exists between mass formation and intrathecal morphine doses or concentration. Other factors remain to be investigated.
authors.affiliation: Department of Anesthesiology, University of California, San Diego, California 92093-0818, USA. tyaksh@ucsd.edu
authors.forename: Tony L
authors.initials: TL
authors.lastname: Yaksh
authors.forename: Samuel
authors.initials: S
authors.lastname: Hassenbusch
authors.forename: Kim
authors.initials: K
authors.lastname: Burchiel
authors.forename: Keith R
authors.initials: KR
authors.lastname: Hildebrand
authors.forename: Linda M
authors.initials: LM
authors.lastname: Page
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Coffey