Characterization of Toxicity with Spinal Opiates

描述(由申请人提供)： 鞘内持续输注高浓度吗啡被广泛应用于疼痛治疗。令人惊讶的是，直到最近，还没有关于这种输液安全性的研究。我们研究了28天鞘内注射吗啡对犬的影响。出乎意料的是，在高浓度的吗啡(用于人类)下，我们注意到无菌的炎性细胞团(肉芽肿)来自导管末端近端的硬脑膜，而不是实质。赋形剂或多种非阿片类药物均未见肉芽肿。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，而不是简单的总剂量。2：作用是由阿片类激动剂作用介导的，并不局限于吗啡。3.肉芽肿是由于硬脑膜肥大细胞的局部脱颗粒导致炎症细胞从硬脑膜血管中移动所致。因此，肉芽肿的诱导效力将与体外硬脑膜制剂中硬膜肥大细胞脱颗粒的能力成正比。4.局部α2受体激动剂和肥大细胞稳定剂可抑制肉芽肿诱导效应和硬脑膜肥大细胞活化。我们将使用犬模型来检验鞘内持续输注等剂量的MU阿片激动剂(吗啡、吗啡-6-葡萄糖醛酸苷、L-美沙酮、氢化吗啡、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-葡萄糖苷、D-美沙酮)的效果。使用肥大细胞稳定剂奈多康钠进行体内治疗，将检测其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。吗啡和α2激动剂(可乐定、右美托咪定)之间的相互作用将通过联合传递的方式进行研究。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。综上所述，我们的初步工作提供了第一个明确的临床前数据，定义了可乐定的影响，并提出了药物诱导的硬膜肥大细胞脱颗粒的新机制假说，为新药物的体外筛选提供了一种新的方法。这些研究具有重要意义：1)越来越多的吗啡肉芽肿报告强调它并不罕见；2)我们对其他阿片类药物的调查首次提供了对目前广泛使用的药物的脊髓安全性的评估；以及3)这个问题影响到所有鞘内给药的靶向药物。因此，在这里获得的关于局部脑脊液浓度的作用、非吗啡类药物的安全性以及辅助剂的潜在改善作用的数据都为完善这一重要治疗方案的有效性提供了新的信息。

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.