Impact of Intravenous Lidocaine, Dexmedetomidine, and Intrathecal Morphine on Metastasis-Related Biomarkers and Cellular Immune Profiles in Colorectal Surgery: A Prospective, Randomized Controlled Trial

BACKGROUND: Anesthetic adjuvants used in multimodal analgesia-including intravenous lidocaine, dexmedetomidine, or intrathecal morphine (ITM)-may differentially affect immune responses and metastasis-related pathways in colorectal cancer surgery. Their comparative effects on these pathways remain poorly understood. METHODS: In this prospective, randomized, patient- and assessor-blinded trial, adults undergoing elective laparoscopic or robotic colorectal cancer resection were allocated to receive intravenous lidocaine, dexmedetomidine, or ITM. The primary outcome was plasma matrix metalloproteinase-9 (MMP-9) concentration at 1 hour postoperatively. Secondary outcomes included other metastasis-promoting biomarkers (MMP-2, VEGF, IL-6), immune cell subsets (T and NK cells), and CD39/CD73 expression on T lymphocytes at 1 hour postoperatively and postoperative day 1. Clinical outcomes-including pain scores, opioid consumption, and complications-were also assessed. RESULTS: Of the 114 enrolled patients, 109 completed the study and were analyzed (ITM group = 37, DEX group = 34, LIDO group = 38). Overall group × time interaction was significant for MMP-9 (P = .028). At 1 hour, MMP-9 was higher in LIDO group than in the DEX group (difference on the log scale, 0.333; 95% confidence interval [CI], 0.0642-0.601; P = .009) and in the ITM group (0.424; 95% CI, 0.0248-0.823; P = .033). The DEX group was associated with increased CD73+CD8+ T cells compared with the LIDO group (difference on the logit scale: 0.669; 95% CI, 0.000987-1.34; P = .050), and with decreased CD39-CD73-CD8+ T cells compared with the ITM group (-0.695; 95% CI, -1.3 to -0.0908, P = .018) and the LIDO group (-0.645; 95% CI, -1.24 to -0.05, P = .029). The ITM group was associated with lower dynamic pain scores than the other groups. Rescue antiemetic use was less frequent with the DEX group, whereas other adverse events were mild and comparable across groups. CONCLUSIONS: Anesthetic adjuvants exerted differential effects on perioperative biomarkers and immune profiles relevant to tumor progression. Compared with the other groups, lidocaine was associated with higher MMP-9 levels, dexmedetomidine with relative shifts toward an immunosuppressive T-cell phenotype, and intrathecal morphine with superior analgesia with minimal immune impact. Further studies are warranted to determine whether multimodal analgesia strategies influence long-term oncologic outcomes.