Prolonged duration and triggered local anesthesia

疼痛是一个非常常见的临床问题，给数百万人带来痛苦。治疗持续的疼痛 长于一个简短的程序可能是困难的，并可能需要使用阿片类药物，及其副作用和 有可能上瘾和消遣。在这项研究中，我们试图开发注射给药系统。 (DDS)使用缓释技术提供持续延长持续时间的局麻(PDLA) 持续数小时至数天的围术期疼痛，甚至数周的慢性疼痛。此外，我们正在 开发DDS，患者可以确定她或他何时接受局部麻醉，强度如何 麻醉是，以及它能持续多久。这些按需DDS(称为触发式局部麻醉药)是可控制的 由近红外光和超声波等外部能源提供。连续DDS和触发式DDS 有可能给疼痛管理带来革命性的变化，并推动药物输送科学的进步。他们可以 还可以减少或避免阿片类药物的使用。 理想情况下，所有DDS应：一次注射；易于管理；不需要一般情况下 麻醉或手术开始；最后几天-几周；不会造成局部炎症、局部神经或肌肉毒性，或 全身性毒性；完全可生物降解和可逆；具有成本效益，易于制造，并且稳定。 可触发系统应易于与安全和方便的设备一起使用。 我们的策略一直是使用缓释载体来递送站点1钠通道阻滞剂 (S1SCB)与已知可增强其功能的化合物 神经阻滞的持续时间，如常规的局麻药和类固醇。在PDLA，我们已经实现了 含S1SCBS等药物的大鼠坐骨神经阻滞脂质体制剂 持续一周，全身和局部毒性最小。在触发的局部麻醉中，我们已经产生了 含有S1SCB和其他药物的脂质体，这些药物产生最初的神经阻滞，在此之后 用近红外光或红外线靶向注射部位可安全、反复地再次诱导神经阻滞 超音波。这项工作在过去5年中发表了31篇论文，其中许多发表在著名期刊上。 在PDLA中，我们提出了一系列潜在的方法来生产更长的块，同时改进 安全。在触发式LA中，我们提出了调节或否定初始神经阻滞的方法，扩大了 可触发事件，并延长可触发事件的时间框架-允许用于慢性疼痛。 应对这些挑战需要克服生物材料/药物输送/纳米科学方面的挑战， 包括增加DDS中高度水溶性带电药物的负载量，将其最初的快速降至最低 (“突发”)释放，延长其释放持续时间，和/或最大限度地减少其基线(非触发)释放。 重要的是，新方法对组织反应的影响将被研究，使用组织学和 毒理基因组学方法。

Pain is a very common clinical problem, causing suffering in millions of people. Treatment of pain that lasts longer than a brief procedure can be difficult and can entail the use of opioids, with their side effects and potential for addiction and diversion. In this research we seek to develop injectable drug delivery systems (DDS) using sustained release technology to provide continuous prolonged duration local anesthesia (PDLA) lasting many hours to days for perioperative pain, or even weeks for chronic pain. In addition, we are developing DDS where the patient could determine when she or he receives local anesthesia, how intense the anesthesia is, and how long it lasts. Those on-demand DDS (termed triggered local anesthetics) are controlled by external energy sources such as near-infrared light and ultrasound. Both the continuous and triggered DDS have the potential to revolutionize pain management, and advance the science of drug delivery. They could also mitigate or obviate opioid use. All the DDS should ideally: be delivered by a single injection; be easy to administer; not require general anesthesia or surgery to initiate; last days-weeks; cause no local inflammation, local neuro- or myotoxicity, or systemic toxicity; be fully biodegradable and reversible; be cost effective, easy to make, and stable. Triggerable systems should be easy to use with a safe and convenient device. Our strategy has been to use sustained release vehicles to deliver site 1 sodium channel blockers (S1SCBs) such as saxitoxin and tetrodotoxin in combination with compounds that are known to enhance their duration of nerve blockade, such as conventional local anesthetics and steroids. In PDLA, we have achieved a liposomal formulation containing S1SCBs and other drugs, which can achieve sciatic nerve blocks in the rat lasting a week with minimal systemic and local toxicity. In triggered local anesthesia, we have produced liposomes containing S1SCBs and other drugs which produce an initial nerve block that resolves, after which nerve block can be safely and repeatedly re-induced by targeting the injection site with near-infrared light or ultrasound. This work produced 31 papers in the past 5 years, many in prominent journals. In PDLA, we propose a spectrum of potential approaches to produce yet longer blocks while improving safety. In triggered LA, we propose means to modulate or negate the initial nerve block, extend the number of triggerable events, and extend the time frame over which they can be triggered – allowing use in chronic pain. Addressing these challenges will entail overcoming challenges in biomaterials / drug delivery / nanoscience, including enhancing the loading of highly water-soluble charged drugs in DDS, minimizing their initial rapid (“burst”) release, extending their duration of release, and /or minimizing their baseline (un-triggered) release. Importantly, the impact of new approaches on tissue reaction will be studied, using histological and toxicogenomic approaches.