Early repetitive transcranial magnetic stimulation for preventing chronic postoperative pain in older adults: a randomized clinical sub-study

BACKGROUND: Chronic postsurgical pain (CPSP) is particularly relevant in thoracoscopic lung cancer surgery, a procedure predominantly performed in older adults, yet it remains a major clinical challenge with few effective preventive strategies. Repetitive transcranial magnetic stimulation (rTMS) has demonstrated analgesic potential and may offer a novel approach for CPSP prevention. This study investigated whether early postoperative rTMS could reduce CPSP in older patients undergoing thoracoscopic surgery and explored its potential mechanisms. METHODS: In this randomized controlled trial, 286 patients were screened and 230 undergoing thoracoscopic surgery were randomized to receive either active or sham rTMS targeting the left dorsolateral prefrontal cortex (10 Hz, 100% resting motor threshold, 2000 pulses per session) immediately after extubation in the PACU. A total of 198 patients completed the 3-month follow-up, during which clinical and biochemical outcomes were assessed by blinded evaluators. RESULTS: In the modified intention-to-treat analysis, the incidence of CPSP was significantly lower in the active rTMS group than in the sham group (24.3% vs 43.5%; RR, 0.56; 95% CI, 0.39-0.80; P = 0.002). In addition to reducing CPSP, active rTMS resulted in significant improvements in anxiety (26.0 [IQR, 25.0-26.0] vs 29.0 [IQR, 27.5-30.0]; P < 0.001) and depression scores (26.0 [IQR, 25.0-26.0] vs 29.0 [IQR, 27.5-30.0]; P < 0.001) at 3 months. Additionally, serum CXCL10 levels-an inflammation-related biomarker associated with chronic pain-were significantly lower in the active rTMS group (68.9 [48.1-85.7] vs 82.6 [67.3-105.5] ng/mL; P = 0.018). Exploratory analyses further demonstrated that CXCL10 had good predictive accuracy for CPSP (AUC = 0.90; cutoff = 90.5 pg/mL). CONCLUSIONS: Early postoperative rTMS targeting the DLPFC effectively reduces the development of CPSP after thoracoscopic surgery and may be associated with CXCL10-related inflammatory processes. CXCL10 may represent a promising candidate biomarker for identifying patients at high risk of CPSP. TRIAL REGISTRATION: ClinicalTrials.gov (NCT06392919).