Background <p>Substantial interindividual variability exists in postoperative analgesic requirements among frail elderly patients. Nalbuphine has the advantages of effective analgesia and a lower risk of respiratory depression, but its dose‒response relationship in patients with varying degrees of frailty remains unclear. This study will group patients based on the preoperative Modified Frailty Index-11 (mFI-11) and utilize the modified Dixon sequential method to explore, for the first time, the median effective dose (ED₅₀) of a nalbuphine and dexmedetomidine combination administered via patient-controlled intravenous analgesia (PCIA) in elderly individuals receiving laparoscopic gastrointestinal surgery.</p> Methods <p>This will be a prospective, double-blind, interventional, dose-exploration study. The study participants will be selected from elderly patients (aged 65 years and above) undergoing elective laparoscopic gastrointestinal surgery. Based on their preoperative mFI-11 scores, patients will be assigned to the healthy (mFI = 0), pre-frailty (0 &lt; mFI &lt; 0.27), or frailty (mFI ≥ 0.27) groups. Postoperatively, all patients will receive a combination of nalbuphine and dexmedetomidine via PCIA. Dose titration will be conducted using a modified Dixon’s up-and-down sequential method. All groups will receive a uniform initial dose of 1&#xa0;mg/kg nalbuphine, with subsequent doses subject to ± 0.1&#xa0;mg/kg adjustments. Titration for each group will be terminated once seven sequential crossover events are recorded, defined as the point where analgesia transitions from effective to ineffective. Probit regression analysis will be used to estimate the ED₅₀ for each group. The primary endpoint is the ED₅₀ of nalbuphine required to achieve satisfactory analgesia (Numeric Rating Scale at rest [NRS-R] score ≤ 3) within the first 24 postoperative hours. Secondary endpoints include the 95% effective dose (ED₉₅) of nalbuphine, sedation scores, the incidence of adverse events (including respiratory depression, nausea, vomiting, pruritus, and dizziness), hemodynamic parameters (pulse oxygen saturation [SpO₂], systolic blood pressure [SBP], mean arterial pressure [MAP], diastolic blood pressure [DBP], and heart rate [HR]), and and postoperative recovery indicators (time to ambulation, time to oral diet tolerance, time to flatus, and time to urinary catheter removal).</p> Discussion <p>A novel contribution of this work is the systematic investigation into how the dose-response relationship of nalbuphine varies with preoperative frailty levels, with the aim of determining effective postoperative PCIA strategies and more precise nalbuphine analgesic dosage guidance for patients undergoing laparoscopic gastrointestinal surgery, particularly frail elderly patients. This approach is expected to mitigate non-essential adverse effects, improve patient comfort, and enhance the quality of life, thereby paving the way for a “frailty-tailored” postoperative pain management protocol.</p> Trial registration <p>ClinicalTrials.gov, Identifier NCT06953570 Registered on April 23, 2025.</p>