Patient selection and safety of lidocaine–esketamine analgesia after hepatectomy

Xu et al. report a double-blind randomised trial in which combining intravenous lidocaine with low-dose esketamine reduced movement-evoked pain, modestly lowered opioid consumption and improved quality of recovery during the first 72 h after hepatectomy [1]. The trial is rigorous and tackles a real problem, as movement-evoked pain after liver resection is common and impedes early mobilisation. The authors are admirably candid that the average effects were small and, at best, marginally meaningful. We offer two observations that may explain this modest signal and shape a more informative successor trial. The first observation pertains to who was studied. Much of the rationale for adding esketamine rests on its non-analgesic actions, namely antagonism of central sensitisation and improvement of mood and anxiety [2], and the authors themselves note that postoperative pain is shaped by anxiety and depression. Yet the protocol did not include patients with significant psychiatric disease and those using opioids chronically. These are the very groups in whom an N-methyl-D-aspartate antagonist with antidepressant properties might be expected to benefit most, and in whom acute pain and analgesic demand tend to be highest. Testing the combination in a psychologically robust, opioid-naive population may therefore have muted the mechanism that distinguishes esketamine from lidocaine alone, diluting the overall effect. A successor trial enriched for baseline anxiety, depression, pain catastrophising or established opioid exposure and reporting validated psychological measures would prevent a responder subgroup being lost within an unremarkable mean, and would align the question with the move towards phenotype-guided peri-operative analgesia [3]. The second observation pertains to safety, which we think is presented with more reassurance than the data justify. In the pharmacokinetic substudy, total plasma lidocaine exceeded the accepted toxicity threshold of 5.0 μg.ml-1 in three of the first nine patients within 10 min of the bolus. This is easy to discount, but it arises where lidocaine clearance may already be reduced by hepatic resection, and simultaneously, every patient received a transversus abdominis plane block with ropivacaine 2 mg.kg-1, adding to the total local anaesthetic load. The regimen also ran the infusion for 72 h and delivered the block concurrently, both of which depart from the international consensus, which advises limiting such infusions to 24 h and separating them from local anaesthetic blocks [4]. With concentrations measured only as total drug in nine patients, and the steady state during a 72-h infusion uncharacterised, the absence of clinical toxicity cannot be read as a wide safety margin. This caution is timely, as recent pharmacovigilance data show that lidocaine-specific toxicity and mortality are rising even as overall local anaesthetic poisoning is falling [5]. Before a marginal analgesic gain justifies routine use, an adequately powered study measuring free drug concentrations at steady state and stratifying by hepatic reserve would be reassuring. Neither point diminishes a careful trial that shows a multimodal infusion can deliver a consistent, if small, benefit. They suggest that the most valuable next step is not a larger trial of the same design, but one that directs the intervention towards the patients most likely to benefit and characterises its safety with the rigour this combination demands. Such a study would clarify whether lidocaine with low-dose esketamine earns a defined place in enhanced recovery after liver surgery or remains an adjunct of limited clinical importance.