Peripheral Nerve Blocks with Multimodal Analgesics

描述（由申请人提供）：在骨科麻醉学亚专科，过去12年通过常规使用周围神经阻滞在阿片类药物节约镇痛方面取得了显著进展。然而，局部麻醉剂的单次注射神经阻滞只能提供12小时的镇痛，导致很少的阿片类药物节约。因此，持续的周围神经阻滞已发展成为术后2-4天阿片类镇痛的新“金标准”。然而，局部麻醉的连续神经阻滞是昂贵的，劳动密集型的，需要亚专科培训，并且有独特的并发症（例如，由于运动阻滞而跌倒的风险）。这些障碍似乎有可能阻止持续神经阻滞对公共卫生产生超出亚专业生态位地位的影响。术后神经阻滞镇痛的下一个突破将涉及单次注射，提供持续的镇痛（24-48小时），而不会产生不必要的运动阻滞或神经损伤。缓释局部麻醉剂（如微胶囊布比卡因）未能成功实现这些目标。通过结合不同机制的药物，“多模式”镇痛药可能会减少或消除术后阿片类镇痛的需要；如果这种药物组合对周围神经既安全又有效，那么就有可能在公共卫生方面取得重大进展。该职业发展奖的目标是利用之前在连续神经阻滞方面的临床研究经验，并通过2年额外的伤害感受、镇痛和周围神经毒理学基础科学的正式培训来补充之前的临床经验。该候选人的目标是开发适当的动物模型来解决这些问题，从而加速多模态镇痛神经阻滞的科学进展。这样的阻断将进一步推进阿片类镇痛，旨在减少患者对阿片类镇痛药物的依赖，使其成为骨科术后第一周镇痛的主要机制。骨科手术（对骨骼、关节和肌肉进行的手术）后，疼痛通常被评为“中度”到“重度”。手术后治疗疼痛最常见的方法是使用阿片类镇痛药（麻醉剂），这既有许多副作用，也容易上瘾。持续的神经阻滞有助于减少阿片类药物的需求，但在技术上是复杂的和亚专业化的，而局部麻醉剂可以产生不必要的运动阻滞，可能导致麻木的肢体损伤。本应用旨在开发一种改进单次注射神经阻滞的方法，以提供(i)术后持续疼痛缓解，（ii）减少运动阻滞，（iii）减少阿片类药物需求。

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.