Characterization of Toxicity with Spinal Opiates

描述（由申请人提供）： 鞘内持续输注浓吗啡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。我们在犬模型中研究了28天鞘内注射吗啡的效果。出乎意料的是，在高吗啡浓度下（如在人体中使用的），我们注意到导管尖端近端的硬脑膜-蛛网膜而不是实质中出现无菌性炎性细胞团（肉芽肿）。使用溶媒或各种非阿片类药物时未观察到肉芽肿。α 2肾上腺素能激动剂可乐定抑制肉芽肿。这些观察导致四个假设。1.吗啡诱发的肉芽肿与脑脊液中的局部浓度成正比，而不仅仅是总剂量。2：作用由阿片类激动剂作用介导，不限于吗啡。3.肉芽肿是由于硬脑膜肥大细胞的局部脱颗粒，导致炎性细胞从硬脑膜血管中移动。因此，肉芽肿诱导效力将与在离体硬脑膜制剂中去除硬脑膜肥大细胞的能力成比例。4.局部α 2受体激动剂和肥大细胞稳定剂可抑制肉芽肿诱导作用和硬脑膜肥大细胞活化。我们将使用犬模型来研究连续鞘内输注等剂量μ阿片受体激动剂（吗啡、吗啡-6-葡萄糖醛酸苷、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-葡萄糖醛酸苷、D-美沙酮）的作用，从而解决这些假设。将检查用肥大细胞稳定剂奈多罗米钠进行的体内治疗对肉芽肿形成的影响。在平行研究中，动力学研究将允许基于测量的CSF浓度进行比较。将通过共递送研究吗啡和α 2激动剂（可乐定、右美托咪定）之间的相互作用。将通过组织化学和CSF分析评估肉芽肿形成和局部肥大细胞脱粒和细胞因子。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的效果，可乐定的衰减，和一个新的机制假说的药物诱导的硬脑膜肥大细胞的脱粒，这表明一种新的方法，离体筛选新的代理商。这些研究意义重大：1）吗啡肉芽肿报告发生率的增加强调了它并不罕见; 2）我们对其他阿片类药物的研究首次评估了目前广泛临床使用的药物的脊柱安全性; 3）该问题影响了所有靶向鞘内给药的药物。因此，在此获得的关于局部CSF浓度的作用、非吗啡剂的安全性和佐剂的潜在改善作用的数据都提供了新的信息来改进这种重要治疗方案的效用。

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.