Peripheral Nerve Blocks with Multimodal Analgesics

描述(申请人提供)：在整形外科麻醉学专科，在过去的12年里，通过常规使用周围神经阻滞，在非阿片类药物的止痛方面取得了显著的进展。然而，单次注射局部麻醉剂的神经阻滞只能提供12小时的止痛，导致几乎没有阿片类药物的节省。因此，持续周围神经阻滞已演变为术后2-4天阿片类药物非阿片类药物止痛的新“金标准”。然而，使用局部麻醉剂的持续神经阻滞费用昂贵，劳动密集型，需要专科培训，并且有独特的并发症(例如，运动阻滞导致摔倒的风险)。这些障碍似乎可能阻止持续的神经阻滞对公共健康产生影响，而不仅仅是一个专门领域的地位。术后神经阻滞镇痛的下一个突破将涉及单次注射，提供持续的止痛(24-48小时)，而不会产生不必要的运动阻滞或神经损伤。缓释局麻药(如微囊化布比卡因)未能成功地达到这些目标。通过结合不同机制的药物，一种“多模式”止痛剂可能会减少或消除术后阿片类药物止痛的需要；如果这样的药物组合对周围神经安全且有效，那么公共卫生方面的重大进步是可能的。这一职业发展奖的目的是利用先前的连续神经阻滞临床研究经验，并在伤害、镇痛和周围神经毒理学的基础科学方面额外接受两年的正式培训，以补充这一先前的临床经验。候选人的目标是开发解决这些问题的适当动物模型，从而加快多模式止痛神经阻滞开发的科学进步。这样的阻断将进一步推进非阿片类药物的止痛，并旨在减少患者在骨科手术后第一周对阿片类止痛药作为主要止痛机制的依赖(S)。骨科手术(骨骼、关节和肌肉手术)后，疼痛通常被评为“中度”到“重度”。治疗术后疼痛最常见的方法是使用阿片类镇痛剂(麻醉剂)，它既有许多副作用，也会上瘾。持续的神经阻滞有助于减少阿片类药物的需求，但技术复杂且不专门，而局部麻醉剂可能会产生不必要的运动阻滞，可能导致肢体麻木。本申请旨在开发一种改进单次注射神经阻滞的方法，以提供(I)术后持续的疼痛缓解，(Ii)减少运动阻滞，(Iii)减少阿片类药物的需求。

DESCRIPTION (provided by applicant): In the subspecialty of anesthesiology for orthopedic surgery, the past 12 years have provided remarkable advances in opioid-sparing analgesia via the regular use of peripheral nerve blocks. However, single injection nerve blocks with local anesthetics provide only 12 hours of analgesia, leading to little opioid sparing. As a result, continuous peripheral nerve blocks have evolved into a new "gold standard" in opioidsparing analgesia for 2-4 days after surgery. However, continuous nerve blocks with local anesthetics are expensive, labor-intensive, require subspecialty training, and have unique complications (e.g., risk of falling due to motor block). These barriers seem likely to prevent continuous nerve blocks from having an impact on public health beyond the status of a subspecialty niche. The next breakthrough in postoperative nerve block analgesia will involve single-injections that provide sustained analgesia (24-48 hours) without producing unwanted motor block or nerve damage. Sustained-release local anesthetics (e.g., microcapsulated bupivacaine) have not been successful in meeting these objectives. By combining drugs of varying mechanisms, a "multimodal" analgesic may prove to reduce or eliminate the need for postoperative opioid analgesia; if such a drug combination is both safe to the peripheral nerve and efficacious, then an important public health advance is possible. The objective of this Career Development Award is to capitalize on previous clinical research experience with continuous nerve blocks, and to supplement this prior clinical experience with 2 years of additional formal training in the basic science of nociception, analgesia, and peripheral nerve toxicology. The candidate aims to develop appropriate animal models addressing these questions, and thus accelerate scientific progress on the development of a multimodal analgesic nerve block. Such a block would further advance opioid-sparing analgesia, and aim to reduce patient dependence on opioid analgesics as the primary mechanism of analgesia in the first week(s) after orthopedic surgery. After orthopedic surgery (surgery on the bones, joints, and muscles), pain is commonly rated as "moderate" to "severe." The most common method to treat pain after surgery is with opioid analgesics (narcotics), which can both have many side effects and also be addictive. Continuous nerve blocks have helped to reduce opioid requirements, but are technically complicated and subspecialized, while local anesthetics can produce unwanted motor block that may lead to the injury of an insensate extremity. This application is presented to develop a method to improve single-injection nerve blocks, in order to provide (i) sustained pain relief after surgery, (ii) reduced motor block, and (iii) reduced opioid requirements.