Copyright © 2016, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. <zdoi;10.1097/ALN.0000000000001166> Anesthesiology, V 125 • No 2 378 August 2016 S INCE 1991, numerous clinical case series describe patients receiving intrathecal morphine infusion who present with neurologic signs secondary to a local compres- sive lesion. Retrospective data indicate an overall incidence of 0.1%, 1 although estimates in limited populations have been as high as 43%. 2 Studies in chronic intrathecally catheterized dogs 3–5 and sheep 6 demonstrated that intrathecal morphine, infused over 14 to 28 days, reliably produced local masses proximal to the infusion site. An important observation that we made was that the cellular mass arose from the dura/arachnoid layer and not from the parenchyma. 4 Serial magnetic resonance images showed that termination of morphine resulted in a progressive reduction in mass size. 7 Several variables charac- terize the formation of the meningeal mass, including higher drug concentration (vs. total dose), 8 lack of an efect medi- ated by an opioid receptor, 7,9 and an intermediary role of meningeal mast cell degranulation. 9 What We Already Know about This Topic • Intrathecal infusion of morphine is associated with concentra- tion and dose-dependent risks of granuloma formation and neurologic symptoms in large mammals and humans • Assessment of the mechanisms by which intrathecal morphine induces granulomas would be facilitated by a small-animal model What This Article Tells Us That Is New • In guinea pigs, intrathecal morphine infusion produced granu- loma formation with similar characteristics as observed in hu- mans, suggesting the utility of the study of mechanisms of these adverse events in these animals Copyright © 2016, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved. Anesthesiology 2016; 125:378-94 ABSTRACT Background: Intrathecal infusion of opioids in dogs, sheep, and humans produces local space-occupying masses. To develop a small-animal model, the authors examined efects of intrathecal catheterization and morphine infusion in guinea pigs. Methods: Under isofurane, polyethylene or polyurethane catheters were advanced from the cisterna magna to the lumbar enlargement. Drugs were delivered as a bolus through the externalized catheter or continuously by subcutaneous minipumps. Hind paw withdrawal to a thermal stimulus was assessed. Spinal histopathology was systematically assessed in a blinded fash- ion. To assist in determining catheter placement, ex vivo images were obtained using magnetic resonance imaging in several animals. Canine spinal tissue from previous intrathecal morphine studies was analyzed in parallel. Results: (1) Polyethylene (n = 30) and polyurethane (n = 25) catheters were implanted in the lumbar intrathecal space. (2) Bolus intrathecal morphine produced a dose-dependent (20 to 40 μg/10 μl) increase in thermal escape latencies. (3) Absent infusion, a catheter-associated distortion of the spinal cord and a fbrotic investment were noted along the catheter tract (polyethylene > polyurethane). (4) Intrathecal morphine infusion (25 mg/ml/0.5 μl/h for 14 days) resulted in intrathecal masses (fbroblasts, interspersed collagen, lymphocytes, and macrophages) arising from meninges proximal to the catheter tip in both polyethylene- and polyurethane-catheterized animals. Tis closely resembles mass histopathology from intrathecal morphine canine studies. Conclusions: Continuous intrathecal infusion of morphine leads to pericatheter masses that morphologically resemble those observed in dogs and humans. Tis small-animal model may be useful for studying spinal drug toxicology in general and the biology of intrathecal granuloma formation in particular. (ANESTHESIOLOGY 2016; 125:378-94) Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www. anesthesiology.org). This work was presented in part as a poster and oral presentation at the North American Neuromodulation Society meeting in Las Vegas, Nevada, December 10–13, 2015. Submitted for publication December 1, 2015. Accepted for publication April 5, 2016. From the Departments of Anesthesiology (K.A.E., E.S.R., V.I.S., S.A.M., J.J.S., T.L.Y.) and Radiology (M.S.), University of California, San Diego, La Jolla, California; Departamento de Medicina Veterinária, Universidade Federal de Mato Grosso do Sul, Campo Grande, Brazil (E.S.R.); Department of Anesthesiology, Veterans Affairs San Diego Healthcare System, La Jolla, California (V.I.S.); Department of Pathology, Oregon Health Sciences University, Portland, Oregon (M.R.G.); and Departments of Global Research and Neuromodulation, Medtronic, Inc., Minneapolis, Minnesota (K.R.H., L.M.P.). Intrathecal Catheterization and Drug Delivery in Guinea Pigs A Small-animal Model for Morphine-evoked Granuloma Formation Kelly A. Eddinger, B.S., R.V.T., Eric S. Rondon, D.V.M., Veronica I. Shubayev, M.D., Marjorie R. Grafe, M.D., Ph.D., Miriam Scadeng, M.D., Keith R. Hildebrand, D.V.M., Ph.D., Linda M. Page, Pharm.D., Shelle A. Malkmus, B.S., R.V.T., Joanne J. Steinauer, B.S., Tony L. Yaksh, Ph.D.