title: Safety of continuous intrathecal midazolam infusion in the sheep model.
abstract: We investigated the safety of midazolam administered by continuous intrathecal infusion in relevant animal models. Preservative-free midazolam was delivered to sheep and pigs by using implanted infusion systems (SynchroMed pumps plus silicone catheters). Sheep received midazolam 5 mg/d (n = 4) or 15 mg/d (n = 7) or saline (n = 2) for 43 days at 125 micro L/h. One sheep received 10 mg/d. Infusion concentrations ranged from 1.7 to 2.5 mg/mL (5 mg/d) and from 2.5 to 5.0 mg/mL (15 mg/d). Pigs were evaluated for toxicity only and received 15 mg/d (n = 2) or saline (n = 1) for 43 days at 125 micro L/h. Behavior, neurologic function, and vital signs were documented. Serum and cerebrospinal fluid chemistry and cytology were evaluated, and histology was performed on spinal cord tissue. Behavior and neurologic function remained normal in all subjects. Gross and microscopic evaluation of spinal tissue revealed mild inflammation surrounding the catheter tract in both the midazolam-treated and the saline-treated groups. This inflammation was likely attributable to the mechanical presence of the catheter. These data demonstrate that continuous intrathecal infusion of preservative-free midazolam at doses up to 15 mg/d were well tolerated.
  
  
  CONCLUSIONS
  We investigated the toxicity of preservative-free intrathecal midazolam delivered continuously via implanted infusion systems in sheep and pigs. Doses of 5-15 mg/d were well tolerated. The lack of neurotoxicity observed suggests that intrathecal midazolam may be an alternative for the treatment of intractable pain that is unresponsive to opioids.
authors.affiliation: Departments of *Experimental Therapeutics, †Neurosurgery, and ‡Veterinary Sciences and ‖Division of Pharmacy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and §Medtronic, Inc., Minneapolis, Minnesota.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Johansen
authors.forename: Tamara Lee
authors.initials: TL
authors.lastname: Gradert
authors.forename: William C
authors.initials: WC
authors.lastname: Satterfield
authors.forename: Wallace B
authors.initials: WB
authors.lastname: Baze
authors.forename: Keith
authors.initials: K
authors.lastname: Hildebrand
authors.forename: Lawrence
authors.initials: L
authors.lastname: Trissel
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Hassenbusch
mesh_terms: D000818:Animals; D007260:Infusion Pumps / Q000592:standards / Q000706:statistics & numerical data*; D007278:Injections, Spinal; D008874:Midazolam / Q000008:administration & dosage* / Q000009:adverse effects*; D012756:Sheep / Q000097:blood / Q000134:cerebrospinal fluid; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013552:Swine
chemical_list: D008874:Midazolam