Background and Objectives: Ketamine and magnesium sulfate (MgSO4) are NMDA receptor antagonists that act through distinct mechanisms. Preclinical data indicate that their analgesic interaction is sequence-dependent: ketamine administered before MgSO4 produces synergistic antinociception, whereas the reversed sequence is antagonistic. The primary outcomes were postoperative pain intensity (Numerical Rating Scale, NRS 0–10, at rest and on movement) and cumulative intravenous morphine consumption over 48 h, evaluated in patients undergoing open radical nephrectomy to test the hypothesis of sequence-dependent analgesic interaction. Materials and Methods: In this randomized, double-blind, placebo-controlled trial, 208 patients scheduled for elective open radical nephrectomy received two sequential intravenous boluses intraoperatively: Drug A immediately after induction, Drug B 10 min later. Agents were ketamine 0.2 mg/kg, MgSO4 15 mg/kg, or placebo (0.9% NaCl) in all nine possible combinations. Primary outcomes were postoperative pain intensity (NRS 0–10, at rest and on movement) and cumulative intravenous morphine consumption, assessed at 14 time points over 48 h. Secondary outcomes included sedation, nausea, vomiting, and the presence of hallucinations. Results: The ketamine → MgSO4 (K → Mg) sequence significantly reduced NRS pain scores compared to placebo at multiple time points, including 30 min, 1 h, 3 h, 6 h, and 32 h postoperatively, with differences exceeding the minimum clinically important difference of 2 NRS points at the earliest assessments. The MgSO4 → ketamine (Mg → K) sequence did not differ from placebo at any time point. Cumulative morphine consumption was comparable across groups. No hallucinations or psychomimetic events were observed. Conclusions: Intraoperative ketamine followed by MgSO4 (K → Mg) provides clinically meaningful postoperative analgesia after open radical nephrectomy; the reversed sequence (Mg → K) offers no benefit over placebo. These findings provide the first clinical confirmation of sequence-dependent NMDA receptor antagonism and support the K → Mg protocol as a safe, simple addition to multimodal perioperative analgesia. Trial registration: ISRCTN registry, ISRCTN83633282.
Ladjevic et al. (Wed,) studied this question.