Characterization of Toxicity with Spinal Opiates

脊髓阿片类药物的毒性表征

• 批准号: 6807006
• 负责人: TONY L. YAKSH
• 金额: $ 30.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6807006
• 关键词: analgesia; cerebrospinal fluid; cytokine; dogs; drug administration rate /duration; drug administration routes; drug adverse effect; drug screening /evaluation; dura mater; granuloma; inflammation; injection /infusion; leukocyte activation /transformation; mast cell; morphine; opiate alkaloid; patient safety /medical error

DESCRIPTION (provided by applicant): Continuous intrathecal infusion of concentrated morphine is widely used in pain therapy. Surprisingly, until recently there has been no study of the safety of such infusions. We investigated the effects of 28-day intrathecal morphine infusion in a canine model. Unexpectedly, at high morphine concentrations (as used in humans), we noted an aseptic mass of inflammatory cells (granuloma) arising from the dura-arachnoid, not the parenchyma, proximal to the catheter tip. Granulomas were not seen with vehicle or a variety of non-opioid agents. The alpha2 adrenergic agonist clonidine suppressed the granuloma. These observations lead to four hypotheses. 1. Granuloma induction by morphine is proportional to local concentration in cerebrospinal fluid and not simply total dose. 2: Effect is mediated by an opioid agonist action and is not limited to morphine. 3. The granuloma results from a local degranulation of dural mast cells leading to movement of inflammatory cells from the dural vessels. Accordingly, granuloma-inducing potency will be proportional to the ability to degranulate dural mast cells in ex vivo dural preparations. 4. Granuloma-inducing effects and dural mast cell activation are suppressed by local alpha2 receptor agonists and by a mast cell stabilizer. We will address these hypotheses using the canine model to examine the effects of continuous intrathecal infusion of equipotent doses of mu opioid agonists (morphine, morphine-6-glucuronide, L-methadone, hydromorphone, fentanyl or DAMGO) or equimolar concentrations of inactive opioid molecules (naloxone, morphine-3-glucronidc, D-methadone). In vivo treatment with a mast cell stabilizer, nedocromil sodium, will be examined for its effect on granuloma formation. In parallel studies, kinetics studies will permit comparisons based on measured CSF concentrations. Interaction between morphine and alpha2 agonists (clonidine, dexmedetomidine) will be studied by co-delivery. Granuloma formation and local mast cell degranulation and cytokines will be assessed histochemically and by CSF analysis. In summary, our initial work, provides the first definitive preclinieal data defining the effect, the attenuation by clonidine, and a novel mechanistic hypothesis for drug-induced degranulation of dural mast cells which suggests a novel method for the ex vivo screening of new agents. These studies are significant: 1) increasing incidence of reports of morphine-granulomas emphasize it is not rare; 2) our investigation of other opioids provide the first time assessment of the spinal safety of agents which are now in wide clinical use; and 3) this issue impacts on all agents targeted for intrathecal delivery. Accordingly, data obtained here regarding the role of local CSF concentration, the safety of non-morphine agents and the potential ameliorating effects of adjuvant agents all provide novel information to refine the utility of this important therapeutic regime.

描述（由申请人提供）： 持续鞘内输注浓缩吗啡广泛应用于疼痛治疗。令人惊讶的是，直到最近还没有对此类输液的安全性进行研究。我们研究了犬模型中鞘内注射吗啡 28 天的效果。出乎意料的是，在高吗啡浓度（如在人类中使用）时，我们注意到导管尖端附近的硬脑膜蛛网膜而不是实质中产生了无菌性炎症细胞团（肉芽肿）。媒介物或各种非阿片类药物未观察到肉芽肿。 α2 肾上腺素能激动剂可乐定抑制肉芽肿。这些观察结果引出了四个假设。 1. 吗啡诱导的肉芽肿与脑脊液中的局部浓度成正比，而不是简单地与总剂量成正比。 2：作用是由阿片类激动剂作用介导的，并且不限于吗啡。 3. 肉芽肿是由于硬脑膜肥大细胞局部脱颗粒导致炎性细胞从硬脑膜血管移动所致。因此，肉芽肿诱导效力将与离体硬脑膜制剂中硬脑膜肥大细胞脱颗粒的能力成正比。 4.肉芽肿诱导作用和硬脑膜肥大细胞活化被局部α2受体激动剂和肥大细胞稳定剂抑制。我们将使用犬模型来解决这些假设，以检查连续鞘内输注等量剂量的μ阿片受体激动剂（吗啡、吗啡-6-葡萄糖醛酸、L-美沙酮、氢吗啡酮、芬太尼或DAMGO）或等摩尔浓度的非活性阿片分子（纳洛酮、吗啡-3-葡萄糖醛酸、 D-美沙酮）。将检查肥大细胞稳定剂奈多罗米钠的体内治疗对肉芽肿形成的影响。在平行研究中，动力学研究将允许根据测量的脑脊液浓度进行比较。将通过联合给药来研究吗啡和 α2 激动剂（可乐定、右美托咪定）之间的相互作用。肉芽肿形成和局部肥大细胞脱颗粒和细胞因子将通过组织化学和脑脊液分析进行评估。总之，我们的初步工作提供了第一个明确的临床前数据，定义了可乐定的作用、减弱作用，以及药物诱导硬脑膜肥大细胞脱颗粒的新机制假设，这提出了一种离体筛选新药物的新方法。这些研究具有重要意义：1）吗啡肉芽肿的报告发病率不断增加，强调它并不罕见； 2) 我们对其他阿片类药物的研究首次对目前临床广泛使用的药物的脊柱安全性进行了评估； 3) 该问题影响所有鞘内给药药物。因此，这里获得的关于局部脑脊液浓度的作用、非吗啡药物的安全性以及辅助药物的潜在改善作用的数据都为完善这一重要治疗方案的实用性提供了新的信息。