Time Course and Role of Morphine Dose and Concentration in Intrathecal Granuloma Formation in Dogs A Combined Magnetic Resonance Imaging and Histopathology Investigation

Background: Intrathecal morphine infusion leads to intrathecal granulomas. In dogs, the authors examined time course of granuloma formation and the role of concentration in granuloma development. Methods: Dogs were prepared with lumbar intrathecal catheters and vest-mounted pumps. To define the time course of granuloma formation, serial magnetic resonance imaging was performed in animals receiving 10 or 31 days of morphine infusion (12.5 mg/ml at 40 l/h). At these times, morphine was removed from the infusate, and further magnetic resonance images were acquired over 14‐35 additional days. To assess dose versus concentration, dogs received 28-day infusions of vehicle, 12 mg morphine/day as 12.5 mg/ml at 40 l/h, or 1.5 mg/ml at 334 l/h (12 mg/day) for 28 days. Additional dogs received 3 mg/day as 12.5 mg/ml at 10 l/h. Results: Serial magnetic resonance images in dogs receiving morphine (12.5 mg/ml at 40 l/h) revealed pericatheter-enhancing tissues as early as 3 days with a prominent signal by 10 days. Removal of morphine reduced the mass volume within 7 days. At a fixed infusion rate, the incidence of granuloma formation with the continuous intrathecal infusion of morphine ranged from 0 in vehicle-treated dogs to 100% in dogs treated with 12.5 mg/ml at 40 l/h (12 mg/day). Infusion of 12 mg/day at 1.5 mg/ml (334 l/h) resulted in granuloma in one of four animals. The authors found that infusion of morphine in different concentrations at a fixed rate resulted in a dose-dependent increase in concentration, with the granuloma-producing, dose-yielding lumbar cerebrospinal fluid morphine concentrations around 40 g/ml. Conclusions: Serial magnetic resonance imaging showed a rapid formation and regression of the masses initiated by intrathecal morphine infusion. These masses are dependent on local concentration.