长期鞘内输注吗啡后在猪脊髓的分布

背景鞘内持续药物输注为脊髓靶控长期给药提供了新的方法，但其疗效并不确切。采用急性猪模型的前期研究已表明：由于脑脊液和脊髓中药物分布非常有限，持续鞘内给药疗效不稳定。本研究目的是观察急性给药时有限的药物分布是否在慢性模型中仍然存在。方法4头圈养猪，植入鞘内输注泵，泵注吗啡20μl／h（1mg／ml）。由于程序错误，另有1头猪泵注吗啡剂量为2μl／h。持续泵注14天，给药期间动物活动不受限。给药结束时，麻醉并处死动物采集脊髓，制备1cm厚度切片，测定吗啡含量。结果与前期急性动物模型研究结果相似，吗啡药物分布相当局限。随着与导管尖端距离增加，吗啡含量呈指数级减少，远离5—10cm，即减少5～10倍。结论活动不受限的猪，长期鞘内输注吗啡后其分布局限，且远离输注点吗啡含量呈梯度下降。故导管尖端的位置非常重要，尤其在输注等比重液体时。因为药物分布受限可导致局部药物浓度过高，长期鞘内输注阿片类药可并发导管尖端局部炎症。

BACKGROUND： 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. METHODS： Four farm-bred pigs were implanted with intrathecal infusion pumps delivering morphine （1 mg/ml） at 20 μlper hour. Because of a programming error, 1 additional pig received intrathecal morphine at 2 μ1 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. RESULTS： 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. CONCLUSIONS： 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.