Characterization of Effect of Repeated Bolus or Continuous Intrathecal Infusion of Morphine on Spinal Mass Formation in the Dog

Abstract

Background We determined whether intrathecally delivering the same daily dose of morphine (MS) at a fixed concentration of 25 mg/mL by periodic boluses versus continuous infusion would reduce intrathecal mass (IMs) formation in dogs. Methods Adult dogs (hound cross, n = 32) were implanted with intrathecal catheters connected to SynchroMed II infusion pumps. Animals were randomly assigned to receive infusion of 0.48 mL/day of saline or MS dosing (12 mg/day at 25 mg/mL) as boluses: x1 (q24hour), x2 (q12hour), x4 (q6hour), or x8 (q3hour) given at the rate of 1000 μL/hour, or as a continuous infusion (25 mg/mL/20 μL/hour). Results With IT saline, minimal pathology was noted. In contrast, animals receiving morphine displayed spinally compressing durally derived masses with the maximal cross‐sectional area being greatest near the catheter tip. Histopathology showed that IMs consisted of fibroblasts in a collagen (type 1) matrix comprised of newly formed collagen near the catheter and mature collagen on the periphery of the mass. The rank order of median cross‐sectional mass area (mm2) was: Saline: 0.7 mm2; x2: 1.8 mm2; x4: 2.7 mm2; x1: 2.7 mm2; x8: 4.2 mm2; Continuous: 8.1 mm2, with statistical difference from saline being seen with continuous (p < 0.0001) and x8 (p < 0.05). Bench studies with a 2D diffusion chamber confirmed an increase in dye distribution and lower peak concentrations after bolus delivery versus continuous infusion of dye. Conclusions Using multiple bolus dosing, IMs were reduced as compared to continuous infusion, suggesting relevance of bolus delivery in yielding reduced intrathecal masses.

Enhanced intrathecal drug dispersion achieved by high volume injection and natural micromixing

“…Accordingly, chronic administration with drug pumps may be governed by conditions of natural oscillation (phase-2) for its entire time course discussed below. For more recent developments for effective infusion protocols from drug pumps we refer to the work by Yaksh [33].…”

Intrathecal Drug Delivery: Advances and Applications in the Management of Chronic Pain Patient

“…In recent work, it has been shown that delivering a fixed volume of concentrated morphine as a continuous infusion (20 µL/h) leads to spinal masses. In contrast, delivering the same total dose/volume in multiple-divided fast boluses resulting in greater local movement reduces the incidence of such masses (175).…”

“…The incidence of granuloma has been reported to be significantly less frequent with bolus administration compared to a continuous flow rate, meaning that bolusing increases local pericatheter dilution (but not rostral distribution of drugs) (175).…”

“…Management is typically conservative with expeditious wean of intrathecal opioids and replacement with saline, followed by revision of the intrathecal catheter to a different location and the use of non-granuloma, inducing medication if the patient desires to continue to use IDD. Surgical management is reserved to limited cases with larger lesions and progressive acute neurological deterioration (175). Recent experimental data have suggested that multiple daily bolus dosing results in lesser granuloma formation compared to continuous intrathecal infusion (175).…”

“…Surgical management is reserved to limited cases with larger lesions and progressive acute neurological deterioration (175). Recent experimental data have suggested that multiple daily bolus dosing results in lesser granuloma formation compared to continuous intrathecal infusion (175). The use of multiple small boluses vs. continuous low rates of infusion is believed to lower the mass formation incidence as the bolus results in increased dilution of the high solute concentration.…”