布比卡因脂质体在膝关节置换术后镇痛中的应用
Application of Liposomal Bupivacaine in Postoperative Analgesia after Total Knee Arthroplasty
DOI: 10.12677/acm.2025.1572023, PDF, HTML, XML,   
作者: 彭丽静:吉首大学研究生院,湖南 吉首;娄底市中心医院麻醉科,湖南 娄底;伍国芳*:娄底市中心医院麻醉科,湖南 娄底;黄大元:吉首大学研究生院,湖南 吉首
关键词: 布比卡因脂质体膝关节置换术术后镇痛安全性Liposomal Bupivacaine Total Knee Arthroplasty Postoperative Analgesia Safety
摘要: 膝关节置换术患者术后会出现剧烈疼痛,术后充分的镇痛可以提高患者舒适度、增加患者满意度、促进患者快速康复及缩短住院时间。布比卡因脂质体是采用脂质体技术制备而成的缓释布比卡因,局部镇痛作用时间可长达72 h,是一种理想的术后镇痛药。本文综述布比卡因脂质体的相关研究,重点介绍布比卡因脂质体的药理特点、在膝关节置换术患者中的应用及安全性。
Abstract: Patients may suffer from severe pain after total knee arthroplasty. Adequate postoperative analgesia can improve patients’ comfort, increase patients’ satisfaction, promote rapid recovery and shorten the length of hospital stay. Liposomal bupivacaine is a sustained-release bupivacaine prepared by liposome technology. The local analgesic effect can last up to 72 hours, and it is an ideal postoperative analgesic. This review focuses on the pharmacological characteristics and application and safety of liposomal bupivacaine in patients undergoing total knee arthroplasty.
文章引用:彭丽静, 伍国芳, 黄大元. 布比卡因脂质体在膝关节置换术后镇痛中的应用[J]. 临床医学进展, 2025, 15(7): 555-560. https://doi.org/10.12677/acm.2025.1572023

1. 引言

膝关节置换术(total knee arthroplasty, TKA)术后大部分患者会出现中重度疼痛,良好的镇痛能促进TKA患者的术后快速康复,提高患者的就医体验。TKA术后常用的镇痛方法包括局部浸润、椎管内阻滞及外周神经阻滞,其常用的镇痛药物包含:非甾体消炎药(NSAIDs)、阿片类药物、局部麻醉药物及镇痛辅助药[1]。阿片类药物是临床最常用的镇痛药物,其镇痛效果确切,但存在成瘾性、呼吸抑制、肠梗阻[2]、恶心呕吐及尿潴留等不良反应,限制了阿片类药物大量或长期的使用。多模式镇痛(multimodal analgesia, MMA)是指联合应用不同镇痛技术或不同作用机制的镇痛药[1],作用于疼痛传导通路的不同靶点,发挥镇痛的相加或协同作用,从而增强镇痛效果,减少药物的不良反应[3]。布比卡因脂质体(LB)用于多模式镇痛可显著减少阿片类药物用量,最小化阿片药物相关不良反应,符合当前临床“少阿片”或“去阿片化”的镇痛主旋律。

2. 布比卡因脂质体

LB有效成分仍然是布比卡因(plain bupivacaine),因而LB的药物动力学与PB一致[4],但二者进入体内的血药浓度峰值有区别。LB属于长效缓释制剂,利用特有的DepoFoam技术将布比卡因封装在多囊脂质体中,多囊脂质体的水性腔室以非同心圆的形式构成,被磷脂膜和甘油三酯隔开并且腔室之间彼此独立,具有包封率高、包封量大、渗漏率小的优点,正是这种多层囊泡结构保证了LB的稳定性和缓慢释放的能力。PB血药浓度高峰只有一次,而LB的血药浓度呈现双相峰值[5] [6]。LB首次峰值在给药后30 min,第二次峰值是在给药后24~48 h。

相比于盐酸布比卡因有效镇痛时间不足,单次应用不能满足常规的术后镇痛(48~72 h)的特点,LB术后镇痛时间可长达72小时[7] [8]并且无需置管或持续输注,LB在术后镇痛中的应用降低了医疗技术的要求、避免了镇痛导管渗漏及术后感染等医疗风险、节省了医疗费用、满足了临床对于持久安全镇痛且医疗操作简便的术后镇痛需求,是一种理想的术后局部镇痛药,是多模式镇痛的重要组成部分。

3. LB在TKA术后患者镇痛中的应用

TKA不可避免的造成组织创伤,严重的术后疼痛会引起应激反应、炎症因子的释放及体内激素分泌失衡等多种不良反应,因而充分的术后镇痛对TKA后患者的康复至关重要。

3.1. 股神经阻滞(Femoral Nerve Block, FNB)

从发展历程看,股神经阻滞用于TKA术后镇痛的通用方法,镇痛效果显著[9] [10],很多研究都是以股神经阻滞方式作为参照。Admir Hadzic等[11]评估了在TKA术后股神经阻滞的镇痛效果,266 mg LB AUC NRS-R0-72少于安慰剂组(419比516,P < 0.0001),首次使用阿片类药物的时间晚于安慰剂组(1.29 h比0.41 h),术后阿片类药物总用量少于安慰剂组(76 mg比103 mg,P = 0.0016),两组不良反应的发生率相似,表明使用LB可以适度降低术后72 h内平均疼痛程度和阿片类药物的使用量。Sean W. Dobson等[12]对TKA术后三种镇痛方式的研究表明,与收肌管导管组和关节周围浸润组相比,股神经导管组的疼痛评分降低最多,首次使用阿片类药物的时间最长,累计阿片类药物消耗量较少。然而目前采用LB行股神经阻滞的研究逐渐被其他周围神经阻滞方式取代,因其可导致术后股四头肌无力,不利于术后快速康复。

3.2. 关节周围注射镇痛(Periarticular Injection, PAI)

PAI操作简单,可以减少术后肢体乏力及跌倒风险,受到广泛关注[13]。一项回顾性研究显示罗哌卡因持续皮下关节周围浸润TKA术后静息和活动时的疼痛评分降低,阿片类药物用量减少[14]。一项单中心、前瞻性、平行、随机对照试验研究显示罗哌卡因关节周围浸润的镇痛效果与硬膜外导管相当[15]。但是使用LB行PAI镇痛效果存在争议[16]。Thomas W Hamilton等[17]在533例TKA患者中开展了一项多中心、随机、患者设盲、活性药物对照、优效性临床试验,评估LB联合盐酸布比卡因与单独使用盐酸布比卡因(对照组)在膝关节置换术后恢复及疼痛方面的临床疗效和成本效益,以指导最佳临床实践。干预组接受了266 mg LB与100 mg盐酸布比卡因的混合液,对照组则接受了100 mg盐酸布比卡因,两组均通过标准化的PAI给药,研究结果显示,两组在术后恢复和疼痛方面没有差异,布比卡因脂质体并未改善术后恢复情况或减轻疼痛,与对照治疗相比,布比卡因脂质体不具有成本效益。Feng JE等[18]对接受LB的连续患者组(888例)与未接受LB的后续患者组(789例)进行了比较,所有患者都接受了相同的阿片类药物节省方案,结果显示,与使用LB相比,停用LB对术后72小时内的VRS疼痛评分、术后96小时内的阿片类药物使用情况或术后24小时内的AM-PAC评分均无显著差异,表明TKA后采用PAI方案并未因添加LB而得到改善。一项纳入17项RCT研究的meta分析同样表明[19],同样采用PAI方法镇痛,LB与普通布比卡因在术后第2天和第3天疼痛控制、阿片类药物消耗方面没有差异。此外,布比卡因脂质体似乎没有改善任何术后镇痛、功能性结局以及安全性结局。这些发现不支持使用布比卡因脂质体行PAI用于TKA术后镇痛。

3.3. 收肌管阻滞(Adductor Canal Blocks, ACB)

收肌管阻滞主要作用于股神经的感觉支隐神经,能够减轻下肢疼痛的同时不会造成股四头肌乏力,有利于术后快速康复[20]-[22]。越来越多的研究表明,采用LB行收肌管阻滞表现出良好的镇痛效果。Collin P. Hubler等[23]开展了一项单中心随机双盲对照试验,评估LB行收肌管阻滞用于TKA患者的术后镇痛效果,两组均进行术前单次收肌管阻滞,实验组31名患者接受了266 mg LB (20 mL),而对照组32名患者接受了标准配方的0.5%盐酸布比卡因(20 mL),结果显示,与SB相比,使用LB行收肌管阻滞有更低的活动时疼痛评分,更少的术后阿片类药物使用量,而在步态速度、膝关节活动范围、膝关节伸展力量或患者满意度方面,两组之间没有统计学上的显著差异。Aurora Quaye等[24]开展的一项前瞻性随机对照试验,目的是探究在全TKA中使用LB与布比卡因(PB)进行收肌管阻滞(ACB)的镇痛效果差异,结果表明,两组患者在疼痛评分和住院时间方面无显著差异,但是LB组累计阿片类药物消耗量显著减少。Ajith Malige等[25]进行了一项前瞻性随机对照双盲研究,旨在评估膝关节置换术后采用Exparel (布比卡因脂质体商品名)与罗哌卡因进行收肌管阻滞的疗效,结果显示,Exparel组可降低疼痛程度,缩短住院时间,减少住院期间阿片类药物的消耗量,并改善WOMAC评分(评分越高代表骨关节炎越严重),因此他们认为这种周围神经阻滞方式应成为TKA术后镇痛的主要方式。

4. LB的安全性

LB的治疗效能取决于注射部位布比卡因的浓度,安全性或副作用取决于血浆布比卡因浓度。一项单臂、I期、开放标签的研究[5]旨在评估LB的药代动力学和安全性,在纳入的20名华裔参与者中检测到的最高血浆布比卡因浓度Cmax为374.0 ng/mL,Cmax的几何平均数为170.9 ng/mL,远低于中毒阈值(神经毒性阈值2000 ng/mL和心脏毒性阈值4000 ng/mL),该研究支持266 mg LB局部浸润给药在华裔成年人中是安全且耐受性良好的。在另外一项非裔美国人(70%)和白人(30%)的健康志愿者中也显示出类似的结论[26]。Bryan D. Springer等[27]进行了一项前瞻性研究,纳入15例双侧TKA的患者,每侧膝关节注入266 mg LB、75 mg布比卡因,结果显示布比卡因浓度的平均峰值水平为0.8 ug/mL (范围0.4~1.2 ug/mL),低于2~4 ug/mL的中毒水平。在一项使用LB进行腘窝坐骨神经阻滞的拇囊炎切除手术中,LB与PB混合后血浆布比卡因浓度呈现双相峰值,早期峰值的几何平均最大浓度范围在235至421 ng/mL之间,而晚期峰值比早期峰值低约30%至50%,同样低于中毒水平[28]。欧洲药品管理局也批准LB用于成人臂丛神经阻滞、股神经阻滞和区域阻滞。

LB用于儿科手术镇痛是安全的。356例小儿外科手术患者使用LB进行伤口浸润镇痛,只有3例患者可能出现与局麻药毒性有关的体征或症状,没有发现局麻药全身毒性综合征(local anesthetic systemic toxicity (LAST) syndrome)的病例[29]。Christopher F Tirotta等开展了一项多中心研究(PLAY研究) [30],旨在评估6至17岁以下儿童使用LB进行脊柱手术和心脏手术的药代动力学和安全性,在所有的患者中检测到个体最高血浆浓度分别为436 ng/mL (脊柱手术组)和1290 ng/mL (心脏手术组),不良事件通常较为轻微或中度,没有因不良事件而停止治疗的情况,也没有出现死亡病例。这些数据表明,在6至17岁以下的儿科患者中使用LB局部浸润给药是安全的。因此美国食品药品监督管理局(FDA)批准了脂质体布比卡因局部浸润用于6岁及以上儿科患者的适应症,推荐剂量为4 mg/kg,6至17岁以下的儿科患者最大剂量不超过266 mg [31]。欧洲药品管理局也批准LB用于成人臂丛神经阻滞、股神经阻滞和区域阻滞[32]

LB是多模式疼痛管理中的重要部分,LB镇痛时间持久,可以降低阿片类药物的用量,缩短住院时间,降低医疗费用,不良反应更轻、更加安全,有广阔的应用前景。

NOTES

*通讯作者。

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