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PAIN MEDICINE

Safety of Continuous Intrathecal Midazolam Infusion in the Sheep Model

Mary J. Johansen, PharmD^*, Tamara Lee Gradert, BS, William C. Satterfield, DVM, Wallace B. Baze, DVM, PhD, Keith Hildebrand, PhD, Lawrence Trissel, BS^||, and Samuel J. Hassenbusch, MD, PhD

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

Address correspondence and reprint requests to Mary J. Johansen, PharmD, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 601, Houston, TX 77054. Address e-mail to mjohanse{at}mdanderson.org

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 µL/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 µL/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.

IMPLICATIONS: 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.

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