Reevaluating Perioperative Pain Control: Ketamine and Esketamine as Opioid-Sparing Agents

Perioperative ketamine and esketamine are emerging as opioid-sparing adjuncts—reducing postoperative opioid use and potentially lowering delirium risk in selected patients.

Ketamine’s antagonism of N-methyl-D-aspartate (NMDA) receptors reduces central sensitization and can blunt opioid-induced hyperalgesia, producing analgesia distinct from mu-opioid agonism; clinicians can therefore expect mechanistic complementarity when ketamine is added to multimodal regimens. The NMDA antagonist effects of ketamine also mediate anti-inflammatory and neuroprotective signaling that plausibly contributes to both analgesia and cognitive benefits in vulnerable patients. These mechanisms support targeted perioperative use of ketamine as an adjunct to standard analgesics, particularly when opioid-sparing is a priority.

Randomized trials and pooled analyses show perioperative ketamine reduces postoperative opioid consumption and improves early postoperative pain scores in many controlled studies. Most positive trials used low-dose regimens—typically an intraoperative bolus followed by a low-rate infusion or a bolus-only approach—given alongside multimodal analgesia. The evidence supports integrating short perioperative ketamine courses into opioid-sparing protocols for procedures with substantial postoperative pain, using low bolus ± infusion regimens to balance analgesia and side-effect risk.

On cognitive outcomes, several clinical series and reviews associate perioperative ketamine with lower delirium incidence in at-risk populations. Anti-inflammatory effects and modulation of excitatory neurotransmission via NMDA blockade provide plausible neuroprotective pathways after surgical stress. Careful patient selection and monitoring remain essential: avoid routine use in patients with uncontrolled psychotic or severe personality disorders, active suicidal ideation, or significant cardiovascular instability, and ensure appropriate perioperative hemodynamic and mental-status surveillance.

Esketamine, the S-enantiomer, is a promising opioid-sparing alternative but has a smaller randomized evidence base and shorter-term outcome data than racemic ketamine. Dose-dependent psychotomimetic effects and hemodynamic responses require observation during and after administration. Gaps remain around optimal dosing schedules, timing relative to incision, and direct comparative effectiveness; esketamine is therefore best deployed within protocolized pathways and research frameworks until more definitive comparative data are available.

Key Takeaways:

• Low-dose perioperative ketamine (intraoperative bolus ± low-rate infusion) reduces postoperative opioid requirements when added to multimodal analgesia and is practical for many high-pain surgical pathways.
• Ketamine has been associated with lower postoperative delirium incidence in selected, at-risk patients—likely via anti-inflammatory and NMDA-mediated mechanisms—so consider it as part of delirium-mitigation strategies with careful patient selection and monitoring.
• Esketamine shows promise but lacks the volume of comparative trial data available for racemic ketamine; use within institution-level protocols or trials while awaiting head-to-head effectiveness and safety data.