A Randomized Controlled Trial of Intraoperative Ketamine for Acute Postsurgical Pain after Breast Cancer Surgery: The Moderating Effect of Baseline Temporal Summation of Pain

Background: Activation of nociceptive pathways by surgical trauma can induce central sensitization, which is associated with greater pain severity and persistence. The NMDA-receptor antagonist ketamine blocks central sensitization, but has a variable track-record for preventing postsurgical pain. Patient-level factors contribute to variability in pain and may serve as markers of differential efficacy of preventive effect. Methods: This prospective, longitudinal randomized controlled trial investigated the effectiveness of intraoperatively administered ketamine to decrease postoperative pain after breast surgery. Before surgery, patients reported demographic and medical information and completed validated pain and psychosocial questionnaires. A subset of patients also underwent quantitative sensory testing to assess baseline temporal summation of pain (central sensitization tendency). Analyses of Covariance, controlling for relevant pre- and peri-operative factors, examined treatment group (ketamine vs. saline) differences in 2-week postoperative pain outcomes. Exploratory moderation analysis explored whether the efficacy of ketamine differed based on patients’ baseline temporal summation of pain. Results: Of the sample of 225 patients, 113 received ketamine and 112 received placebo. The majority of patients underwent lumpectomy (53%), with 16% undergoing mastectomy and 30% mastectomy with reconstruction. There were no significant treatment group differences in pain severity or impact reported two weeks after surgery. However, moderation analysis revealed that among patients with higher baseline temporal summation of pain, ketamine was associated with lower pain severity and impact scores. Conclusions: Ketamine was not associated with an analgesic benefit over placebo in the acute postoperative period, as measured using a variety of pain assessments. However, exploratory moderation analysis suggested that patients with evidence of a greater central sensitization at baseline may derive an analgesic effect of ketamine. These findings support future collection of baseline phenotypic patient characteristics related to relevant mechanisms in trials, to identify which patients may derive a larger benefit from analgesic interventions.