Wu Haodong, Yao Shuxin, Huang Yuanchi, Xu Chao, Ma Jianbing
Department of Knee Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, China.
Medical College of Yan'an University, Yan'an University, Yan'an, Shannxi, China.
PLoS One. 2025 Oct 17;20(10):e0334400. doi: 10.1371/journal.pone.0334400. eCollection 2025.
Residual pain after total knee arthroplasty (TKA) often causes patient dissatisfaction. Patients with preoperative central sensitization (CS) are especially susceptible to chronic pain after TKA. Although duloxetine and pregabalin are known to relieve pain in CS patients, there is limited evidence on the precise effectiveness and safety of increasing the dosage or combining these medications. To address this gap, we designed a randomized, triple-blind clinical trial to assess the efficacy and safety of increasing the maximum dosage or combining these drugs for patients who do not respond to standard doses.
Patients scheduled to undergo primary unilateral TKA will be screened for CS using the central sensitization inventory (CSI). CS patients will then be randomly assigned to Groups 1-5, while non-CS patients will be assigned to Group 6. All groups will receive multimodal analgesia. Groups 1 and 6 will receive a placebo. During the initial 6-week period, Groups 2 and 3 will take 60 mg/day of duloxetine, while Groups 4 and 5 will take 300 mg/day of pregabalin. Subsequently, non-responders will enter a 6-week period of high-dose/combination therapy. Group 2 will receive 120 mg/day of duloxetine, Group 3 and 4 will receive a combination of 60 mg/day of duloxetine and 300 mg/day of pregabalin, and Group 5 will receive 600 mg/day of pregabalin. The primary outcome will be to compare residual pain intensity at 6 months between the high-dose monotherapy groups (Groups 2, 5 pooled) and the combination therapy groups (Groups 3, 4 pooled), which will be measured using the brief pain inventory (BPI) 24-hour average pain change. Secondary outcomes will assess pain and functionality.
This study aims to evaluate the efficacy and safety of increasing medication to the highest dose or combining two medications in patients with CS who have not responded well to standard doses of duloxetine or pregabalin after TKA. The goal is to provide clinicians with evidence-based recommendations for choosing an appropriate pain management strategy for these patients.
Chinese Clinical Trial Registry, ChiCTR2400081990. Registered on 18 March 2024.
全膝关节置换术（TKA）后残留疼痛常导致患者不满意。术前存在中枢敏化（CS）的患者在TKA后尤其易患慢性疼痛。尽管度洛西汀和普瑞巴林已知可缓解CS患者的疼痛，但关于增加剂量或联合使用这些药物的确切有效性和安全性的证据有限。为填补这一空白，我们设计了一项随机、三盲临床试验，以评估增加最大剂量或联合使用这些药物对标准剂量无反应患者的疗效和安全性。
计划接受初次单侧TKA的患者将使用中枢敏化量表（CSI）进行CS筛查。CS患者将被随机分配到1 - 5组，非CS患者将被分配到6组。所有组均接受多模式镇痛。1组和6组将接受安慰剂。在最初的6周期间，2组和3组将服用度洛西汀60毫克/天，4组和5组将服用普瑞巴林300毫克/天。随后，无反应者将进入为期6周的高剂量/联合治疗期。2组将接受度洛西汀120毫克/天，3组和4组将接受度洛西汀60毫克/天与普瑞巴林300毫克/天的联合用药，5组将接受普瑞巴林600毫克/天。主要结局将是比较高剂量单药治疗组（2组、5组合并）和联合治疗组（3组、4组合并）在6个月时的残留疼痛强度，这将使用简明疼痛量表（BPI）24小时平均疼痛变化来测量。次要结局将评估疼痛和功能。
本研究旨在评估在TKA后对标准剂量的度洛西汀或普瑞巴林反应不佳的CS患者中增加药物至最高剂量或联合使用两种药物的疗效和安全性。目标是为临床医生提供基于证据的建议，以便为这些患者选择合适的疼痛管理策略。
中国临床试验注册中心，ChiCTR2400081990。于2024年3月18日注册。
