Peripheral Nerve Blocks with Multimodal Analgesics

描述（由申请人提供）：在骨科手术麻醉学子专业中，过去12年通过定期使用外周神经阻滞在阿片类药物保留镇痛方面取得了显着进展。然而，局部麻醉剂的单次注射神经阻滞仅提供12小时的镇痛，导致阿片类药物很少保留。因此，连续周围神经阻滞已发展成为术后2-4天阿片类药物保留镇痛的新“金标准”。然而，使用局部麻醉剂的连续神经阻滞是昂贵的、劳动密集型的，需要亚专业培训，并且具有独特的并发症（例如，由于电机故障而导致的坠落风险）。这些障碍似乎可能会阻止连续的神经阻滞对公众健康的影响超出了亚专科利基的地位。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（例如，微囊化布比卡因）尚未成功地达到这些目的。通过结合不同机制的药物，“多模式”镇痛剂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外周神经安全且有效，那么可能会取得重要的公共卫生进步。这个职业发展奖的目的是利用以前的临床研究经验与连续神经阻滞，并补充此之前的临床经验，在伤害感受，镇痛和周围神经毒理学的基础科学的额外的正式培训2年。候选人的目标是开发适当的动物模型来解决这些问题，从而加快多模式镇痛神经阻滞开发的科学进展。这种阻滞将进一步推进阿片类药物保留镇痛，并旨在减少患者对阿片类镇痛药的依赖，这是骨科手术后第一周的主要镇痛机制。骨科手术（对骨骼、关节和肌肉的手术）后，疼痛通常被评定为“中度”至“重度”。“治疗手术后疼痛的最常见方法是使用阿片类镇痛药（麻醉剂），它既有许多副作用，也有成瘾性。连续的神经阻滞有助于减少阿片类药物的需求，但技术上复杂且亚专业化，而局部麻醉剂可能产生不必要的运动阻滞，可能导致无感觉的肢体受伤。本申请旨在开发一种改善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，以及（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.