经关节注射阿片类药物用于膝关节置换后镇痛：现状与进展

doi:10.3969/j.issn.2095-4344.2015.37.024

摘要/Abstract

摘要：

背景：经关节药物注射在膝关节置换后镇痛中应用广泛，给药途径包括关节内注射和关节周围注射。近年研究表明常用于关节注射的麻醉剂、激素类和非类固醇类抗炎药具有潜在风险，阿片类药物相对安全，但是既往研究对其镇痛效果争议较大。

目的：综述关节周围和关节内注射阿片类药物用于膝关节置换后镇痛的临床和基础研究现状及进展。

方法：检索1967年1月至2015年5月PubMed数据库、Embase数据库中有关膝关节置换后阿片类药物经关节注射镇痛的临床研究和相关基础研究文献。英文检索词为“opioids；peri-articular injection；intra-articular injection；analgesia；knee arthroplasty”。排除与研究目的无关、相关性差或内容重复的研究。

结果与结论：阿片类药物经关节注射的镇痛有效性存在争议，但部分研究认为阿片类可提供程度有效镇痛，其疗效呈剂量依赖性；经关节注射与全身用药相比，恶心呕吐不良反应发生率降低；基础研究指出关节内注射阿片类药物可避免麻醉剂、激素及非类固醇类抗炎药存在的软骨细胞和干细胞毒性，对今后预计将广泛开展的膝关节置换后镇痛有重要指导意义；未来重点研究方向是探索更合理用药方案，提高阿片类药物镇痛强度时间。

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

关键词: 组织构建, 骨组织工程, 关节周围注射, 关节内注射, 阿片类药物, 镇痛, 膝关节置换, 组织工程

Abstract:

BACKGROUND: Articular injections of opioids are widely adopted for pain management of total knee arthroplasty, with both peri-articular and intra-articular administration routes. Recent studies have indicated that commonly used anesthetics, steroids and non-steroidal anti-inflammatory drugs are associated with potential adverse effects. Peripheral opioids are relatively safe with lower complication rates, but great controversy exits regarding the analgesic effects.

OBJECTIVE: To introduce the current clinical application status and basic research progress in peri-articular and intra-articular opioid injections for postoperative analgesia of knee arthroplasties.

METHODS: A computer-based search in PubMed and Embase databases was conducted for clinical and basic research articles related to pain management of knee arthroplasties using peri-articular and intra-articular injections of opioids published from January 1967 to May 2015, using the keywords of “opioids; peri-articular injection; intra-articular injection; analgesia; knee arthroplasty” in English. Irrelevant, poorly related and repetitive studies were excluded.

RESULTS AND CONCLUSION: Peri-articular and intra-articular opioids injection plans vary greatly between different institutions, which does not support reliable quantitative data synthesis for a meta-analysis. Controversy exists regarding its efficacy, but there are studies supporting the usage of opioids for providing effective analgesia in a dose-dependent manner. The peri-articular administration route is associated with lower complication rates including nausea and vomiting compared to systematic injections. Applications of opioids help to avoid potential chondrocyte and stem cell cytotoxicity caused by other anesthetics, steroids and non-steroidal anti-inflammatory drugs, which is important for pain management of total knee arthroplasties. Future investigations are required to promote articular analgesic effects and time duration by exploring more advanced drug combinations and dosage forms.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: Opium, Analgesia, Injections, Intra-Articular, Arthroplasty, Replacement, Knee

中图分类号:

R318

张淼，张旭然，孙羽. 经关节注射阿片类药物用于膝关节置换后镇痛：现状与进展[J]. 中国组织工程研究, 2015, 19(37): 6037-6041.

Zhang Miao, Zhang Xu-ran, Sun Yu. Articular injection of opioids for postoperative pain management of knee arthroplasty: current status and progress[J]. Chinese Journal of Tissue Engineering Research, 2015, 19(37): 6037-6041.

图/表（结果） 1

Current status of intra- or peri-articular opioids injection for TKA analgesia

Severe pain prior to and after TKA presents a challenge that influences patient expectations of outcome. Multimodal intra- and peri-articular injections containing opioids have been recommended. But the conclusions

from different institutions regarding analgesic efficacy of intra- or peri-articular opioids are conflicting with no consensus reached. The obvious variability of injection drugs’ constitution does not support reliable quantitative data synthesis for a meta-analysis.

It is previously accepted that morphine runs via opioid receptors in the central nervous system, while Stein et al ^[35] found small doses of intra-articular morphine produced analgesic effects, which could be reversed by opioid antagonists, indicating opioid receptors in joint cavity and pointing out new directions for clinical use of opioids for local intra-articular analgesia. Later research proved that analgesia rather than local anesthetics can be achieved by intra-articular administration of morphine^[36]. But the study by Ritter et al ^[9] reported no or contrary results. In the following years, although peri- and intra-articular analgesia involving morphine has been investigated by RCTs, and clinicians have achieved both negative and positive results^[7-24], but the question of opioids’ ef?cacy remains unresolved. On one side, the constitution and concentrations of local anesthetics, NSAIDs, steroids, epinephrine and opioids used in the articular injections are different. On the other side, the peri- or intra-articular dosage of opioids also vary in different studies.

There is relatively little information on the role of single articular opioids for post-TKA pain management^{[8, 10, 14]}. Previous studies using drug cocktails documented pain relief and functional recovery, but less examined sole effect of the opioids. Based on our literature research, articular application of 1 mg morphine does not produce effective analgesia after TKA^[10], while bene?cial effects are observed in other studies involving larger dose of morphine (10 mg)^[14]. Besides, articular injections of opioids are associated with lower incidence of postoperative nausea and vomiting^[15].

Toxicity of articular injection drugs

Peri- or intra-articular injection cocktail protocols may contain local anesthetics, NSAIDs, steroids, epinephrine and opioids according to the multimodal pain management concept, but recent studies have demonstrated potential toxic effects of the above components. Clinically administered concentrations of bupivacaine, levobupivacaine, ropivacaine, mepivacaine and lidocaine have signi?cant cytotoxic effect on articular chondrocytes in a time- and dose-dependent manner, to influence cell metabolism and induce apoptosis and chondrolysis^[25-27], which may lead to un-favored postoperative complications for patients undergoing unicondylar or unicompartmental knee arthroplasties. Moreover, these local anesthetic drugs such as bupivacaine, ropivacaine or mepivacaine also possess cytotoxic effects on myocytes, neuronal cells, human mesenchymal stem cells and human hamstring-derived stem/progenitor cells, which should be taken into consideration when performing posterior cruciate ligament-preserving prosthesis TKA^[28-29]. Epinephrine is potentially toxic to articular chondrocytes and should be avoided for prolonged continuous usage via catheters^[30]. Besides, NSAIDs should be used with caution in older people for gastrointestinal, renal and cardiovascular side effects, especially in patients with ischemic heart and cerebrovascualar diseases, and steroids should be used with caution in patients with diabetes and high risks of infection^[31].

In contrast, the presented in vitro study suggests that the most frequently used opioid, morphine, acts as a less toxic drug for peri- or intra-articular application in clinical practice, which does not affect cell survival, metabolism, or apoptosis, and provide analgesic effects with prolonged durations. Other clinical and in vitro studies also suggest another opioid, fentanyl, as a potentially safe peri- or intra-articular analgesic with comparable pain control^[32].

Other advantages of peri- and intra-articular opioids injection

It has been reported that postoperative TKA pain was intensi?ed by movement, suggesting the existence of a pain mechanism speci?c to movement and activated by mechanoreceptors on the afferent nerves, and pain experienced at rest and during movement respond differently to analgesics^[33]. One study investigated pain control at rest and during movement in MIA-induced arthritic rats, finding that the analgesics acting on opioid receptors (morphine and tramadol) were more effective in improving the gait paradigm than diclofenac, indicating that peri- or intra-articular injection of morphine or other opioids may better address both rest and movement pain, which are more effectively than NSAIDs, thus facilitating early rehabilitation and decreasing postoperative complications^[34].

参考文献

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[2] Busch CA, Whitehouse MR, Shore BJ, et al. The efficacy of periarticular multimodal drug infiltration in total hip arthroplasty. Clin Orthop Relat Res. 2010;468(8):2152-2159.

[3] Kang H, Ha YC, Kim JY, et al. Effectiveness of multimodal pain management after bipolar hemiarthroplasty for hip fracture: a randomized, controlled study. J Bone Joint Surg Am. 2013;95(4):291-296.

[4] [4] Lo IK, Sciore P, Chung M, et al. Local anesthetics induce chondrocyte death in bovine articular cartilage disks in a dose- and duration-dependent manner. Arthroscopy. 2009;25(7):707-715.

[5] Dragoo JL, Korotkova T, Kanwar R, et al. The effect of local anesthetics administered via pain pump on chondrocyte viability. Am J Sports Med. 2008;36(8):1484-1488.

[6] Rosseland LA. No evidence for analgesic effect of intra-articular morphine after knee arthroscopy: a qualitative systematic review. Reg Anesth Pain Med. 2005;30(1): 83-98.

[7] Badner NH, Bourne RB, Rorabeck CH, et al. Addition of morphine to intra-articular bupivacaine does not improve analgesia following knee joint replacement. Reg Anesth. 1997;22(4):347-350.

[8] Mauerhan DR, Campbell M, Miller JS, et al. Intra-articular morphine and/or bupivacaine in the management of pain after total knee arthroplasty. J Arthroplasty. 1997;12(5): 546-552.

[9] Ritter MA, Koehler M, Keating EM, et al. Intra-articular morphine and/or bupivacaine after total knee replacement. J Bone Joint Surg Br. 1999;81(2):301-303.

[10] Klasen JA, Opitz SA, Melzer C, et al. Intraarticular, epidural, and intravenous analgesia after total knee arthroplasty. Acta Anaesthesiol Scand. 1999;43(10):1021-1026.

[11] Tanaka N, Sakahashi H, Sato E, et al. The efficacy of intra-articular analgesia after total knee arthroplasty in patients with rheumatoid arthritis and in patients with osteoarthritis. J Arthroplasty. 2001;16(3):306-311.

[12] Rasmussen S, Kramhøft MU, Sperling KP, et al. Increased flexion and reduced hospital stay with continuous intraarticular morphine and ropivacaine after primary total knee replacement: open intervention study of efficacy and safety in 154 patients. Acta Orthop Scand. 2004;75(5): 606-609.

[13] Fu P, Wu Y, Wu H, et al. Efficacy of intra-articular cocktail analgesic injection in total knee arthroplasty - a randomized controlled trial. Knee. 2009;16(4):280-284.

[14] Garcia JB, Barbosa Neto JO, Vasconcelos JW, et al. Analgesic efficacy of the intra-articular administration of high doses of morphine in patients undergoing total knee arthroplasty. Rev Bras Anestesiol. 2010;60(1):1-12.

[15] Fu PL, Xiao J, Zhu YL, et al. Efficacy of a multimodal analgesia protocol in total knee arthroplasty: a randomized, controlled trial. J Int Med Res. 2010;38(4):1404-1412.

[16] Joo JH, Park JW, Kim JS, et al. Is intra-articular multimodal drug injection effective in pain management after total knee arthroplasty? A randomized, double-blinded, prospective study. J Arthroplasty. 2011;26(7):1095-1099.

[17] Lombardi AV Jr, Berend KR, Mallory TH, et al. Soft tissue and intra-articular injection of bupivacaine, epinephrine, and morphine has a beneficial effect after total knee arthroplasty. Clin Orthop Relat Res. 2004;(428):125-130.

[18] Busch CA1, Shore BJ, Bhandari R, et al. Efficacy of periarticular multimodal drug injection in total knee arthroplasty. A randomized trial. J Bone Joint Surg Am. 2006;88(5):959-963.

[19] Mullaji A, Kanna R, Shetty GM, et al. Efficacy of periarticular injection of bupivacaine, fentanyl, and methylprednisolone in total knee arthroplasty:a prospective, randomized trial. J Arthroplasty. 2010;25(6):851-857.

[20] Koh IJ, Kang YG, Chang CB, et al. Does periarticular injection have additional pain relieving effects during contemporary multimodal pain control protocols for TKA?: A randomised, controlled study. Knee. 2012;19(4):253-259.

[21] Koh IJ, Kang YG, Chang CB, et al. Use of reduced-dose periarticular injection for pain management in simultaneous bilateral total knee arthroplasty. J Arthroplasty. 2012; 27(9): 1731-1736.e1.

[22] Tammachote N, Kanitnate S, Manuwong S, et al. Is pain after TKA better with periarticular injection or intrathecal morphine? Clin Orthop Relat Res. 2013;471(6):1992-1999.

[23] Tsukada S, Wakui M, Hoshino A. Postoperative epidural analgesia compared with intraoperative periarticular injection for pain control following total knee arthroplasty under spinal anesthesia: a randomized controlled trial. J Bone Joint Surg Am. 2014;96(17):1433-1438.

[24] Tsukada S, Wakui M, Hoshino A. Pain control after simultaneous bilateral total knee arthroplasty: a randomized controlled trial comparing periarticular injection and epidural analgesia. J Bone Joint Surg Am. 2015;97(5):367-373.

[25] Gungor I, Yilmaz A, Ozturk AM, et al. Bupivacaine and levobupivacaine induce apoptosis in rat chondrocyte cell cultures at ultra-low doses. Eur J Orthop Surg Traumatol. 2014;24(3):291-295.

[26] Breu A, Rosenmeier K, Kujat R, et al. The cytotoxicity of bupivacaine, ropivacaine, and mepivacaine on human chondrocytes and cartilage. Anesth Analg. 2013;117(2): 514-522.

[27] Cai XY, Xiong LM, Yang SH, et al. Comparison of toxicity effects of ropivacaine, bupivacaine, and lidocaine on rabbit intervertebral disc cells in vitro. Spine J. 2014;14(3): 483-490.

[28] Breu A, Eckl S, Zink W, et al. Cytotoxicity of local anesthetics on human mesenchymal stem cells in vitro. Arthroscopy. 2013;29(10):1676-1684.

[29] Haasters F, Polzer H, Prall WC, et al. Bupivacaine, ropivacaine, and morphine: comparison of toxicity on human hamstring-derived stem/progenitor cells. Knee Surg Sports Traumatol Arthrosc. 2011;19(12):2138-2144.

[30] Abdulla A, Adams N, Bone M, et al. Guidance on the management of pain in older people. Age Ageing. 2013;42 Suppl 1:i1-57.

[31] Dragoo JL, Korotkova T, Kim HJ, et al. Chondrotoxicity of low pH, epinephrine, and preservatives found in local anesthetics containing epinephrine. Am J Sports Med. 2010; 38(6):1154-1159.

[32] Ficklscherer A, Kreuz PC, Sievers B, et al. Fentanyl is less toxic on adult human mesenchymal stem cells compared to ropivacaine when used intraarticularly. A controlled in vitro study. Connect Tissue Res. 2013;54(6):403-407.

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[36] Badner NH, Bourne RB, Rorabeck CH, et al. Intra-articular injection of bupivacaine in knee-replacement operations. Results of use for analgesia and for preemptive blockade. J Bone Joint Surg Am. 1996;78(5):734-738.

引言

The past several decades has witnessed great innovations and improvements in total knee arthroplasty (TKA), which is recognized as the most cost-effective procedure for pain relief of patients suffering from end-stage arthritis. However, these innovations including minimally invasive surgical techniques, computer-assisted navigation and rapid rehabilitation protocols do not respond directly to patients concerns of severe post-TKA pain. It is estimated that over half of TKA patients have received insufficient pain control and suffered severe pain in the early postoperative days, and patients’ related fear is a reason for their delay or refusal to receive surgical treatment^[1]. Epidural, spinal analgesia and peripheral nerve blocks have been advocated, but these techniques are also associated with side effects such as headache, neurogenic bladder, respiratory depression, infection, functional damage and technical dif?culties^[2].
In recent years, articular injections of opioids with both peri-articular and intra-articular administration routes have aroused more attentions. In combination with the concept of multimodal pain management, articular cocktails injections involving multiple agents that act on different levels of the pain pathway have the potential to reduce opioid consumption and adverse effects, decrease pain and improve early function^[3]. However, recent studies have indicated that commonly combined anesthetics, steroids and non-steroidal anti-inflammatory drugs (NSAIDs) are associated with potential adverse effects, inducing chondrolysis and cardiovascular toxicity^[4-5].
Peripheral opioids are believed to be safe with low complication rates, but great controversy exits regarding the analgesic effects^[6]. The aim of this literature review is to introduce the current clinical status and basic research progress of peri- and intra-articular opioid injections for postoperative analgesia of knee arthroplasties. 中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

材料方法

Data source

A computer-based search in PubMed and Embase databases was conducted for clinical and basic research articles related to pain management of knee arthroplasties using peri-articular and intra-articular injections of opioids published from January 1967 to May 2015, and unpublished reports were not considered. Authors would be contacted for manuscripts when important data were absent.

Data selection

Inclusion criteria are randomized controlled trials (RCTs) comparing peri- and intra-articular injections containing opioids for postoperative analgesia after TKA. Besides, in vivo and in vitro basic research related to articular injections of opioids are also analyzed. The keywords are “opioids; peri-articular injection; intra-articular injection; analgesia; knee arthroplasty” in English. Irrelevant, poorly related and repetitive studies were excluded.

Data extraction and quality evaluation

Totally 341 articles were retrieved initially, and 313 were excluded for irrelevancy, poor correlation with review purpose or repetitive study. Finally, 28 of 36 articles were included in result analysis, including 18 clinical research papers and 10 basic studies and reviews. Clinical trials were summarized, data were extracted according to sample size, drug combination and opioids doses, and the authors’ conclusions were carefully reviewed. The description of method of randomization, double blinding was reviewed. There were 11 clinical research articles regarding intra-articular injections containing opioids for postoperative analgesia after TKA^[7-17], and 7 articles addressing peri-articular injections^[18-24] (Table 1). Besides there were seven articles related to in vitro toxicity of anesthetics to the articular cartilage and surrounding soft tissues^[25-31]. Three papers discussed potential advantages and new insights into articular injections of opioids for postoperative knee analgesia^[32-34].