Morphine distribution in the spinal cord after chronic infusion in pigs

Continuous intrathecal drug delivery provides new options for chronic delivery of drugs that target the spinal cord, but therapeutic efficacy is highly variable. Using an acute porcine model, we have previously demonstrated that continuous intrathecal drug delivery efficacy may be highly variable because of severely limited drug distribution in the cerebrospinal fluid and spinal cord. We designed this study to determine whether the limited drug distribution observed in our acute studies occurs with chronic administration as well.

Four farm-bred pigs were implanted with intrathecal infusion pumps delivering morphine (1 mg/mL) at 20 μL per hour. Because of a programming error, 1 additional pig received intrathecal morphine at 2 μL per hour. Drug infusion continued for 14 days, during which time animal activity was unrestricted. At the end of 2 weeks the animals were anesthetized and euthanized and their spinal cords removed. The spinal cords were divided into 1-cm sections and morphine concentrations measured.

As with previous acute animal studies, drug distribution was extremely limited. Morphine concentration decreased exponentially as a function of distance from the catheter tip, resulting in a 5- to 10-fold decrease over a distance of only 5 to 10 cm.

Morphine distribution is very limited during chronic intrathecal delivery in ambulatory pigs, and there are significant spinal cord drug concentration gradients as a function of distance from the infusion point. Consequently, catheter tip position may be critical, particularly when infusing isobaric solutions. These data also support the hypothesis that inflammatory masses complicating chronic intrathecal opioid delivery occur at the catheter tip because limited drug distribution results in extremely high drug concentrations at that point.