Methodological considerations for lidocaine with low‐dose esketamine analgesia after hepatectomy

Xu et al. investigated lidocaine combined with low-dose esketamine for movement-evoked pain after hepatectomy [1]. The absence of a subgroup analysis stratified by surgical approach limits the clinical applicability of their findings. With nearly half of the cohort undergoing open surgery, the substantial differences in surgical trauma and analgesic requirements between open and minimally invasive techniques are well established [2]. If the observed treatment effect is driven predominantly by the open surgery subgroup, advocating this regimen for all patients undergoing hepatectomy may lack justification. A pre-specified test for interaction would help clarify which population derives meaningful benefit from this combination. The potential antidepressant effect of esketamine, highlighted as a theoretical advantage by the authors, remains unvalidated [3]. Without assessing baseline or postoperative assessment, it is difficult to determine whether the analgesic effect stems solely from N-methyl-D-aspartate receptor antagonism or is augmented by mood modulation. Incorporating validated diagnostic tools in future studies would be valuable to identify patients who might derive preferential benefit from this psychotropic component. The exclusion criteria may have introduced selection bias. By not studying patients with anticipated postoperative tracheal intubation ≥ 6 h, the study population is skewed towards a lower-risk cohort. Even in this optimised population, the authors characterise the analgesic effect as clinically modest. Movement-evoked pain was reduced by only one point on the numeric rating pain scale, and cumulative sufentanil consumption over 72 h was reduced by only 12 μg. The net benefit of this regimen is even more uncertain with the higher-risk patients not studied. We recommend the conclusions be framed explicitly as applicable primarily to patients undergoing early postoperative tracheal extubation and that extrapolation to more critically ill populations be made cautiously. The trial provides valuable preliminary evidence for this combination therapy. However, the lack of subgroup analysis by surgical approach, the unvalidated antidepressant mechanism and the potential selection bias collectively temper the strength and breadth of the conclusions. We look forward to future studies designed to address these concerns and to define the precise role of this regimen in clinical practice.