Intraoperative esketamine for postoperative analgesia and depression in pancreatic cancer surgery: protocol for a multicenter randomized controlled trial

Abstract

Introduction

Patients undergoing pancreatic cancer surgery frequently experience severe postoperative pain and a high prevalence of depression. Esketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, offers rapid-onset analgesic and antidepressant properties, yet its efficacy in this high-risk population remains unknown. We hypothesize that intraoperative esketamine infusion improves multidimensional analgesic benefit and reduces postoperative depression compared with placebo.

Patients and methods

This prospective, multicenter, randomized, double-blind, placebo-controlled trial will be conducted at three tertiary hospitals in China. We will enroll 280 adult patients (aged 18–80 years, ASA physical status I–III) undergoing elective pancreatectomy for pancreatic cancer. Participants will be randomized (1:1) to receive either intraoperative intravenous esketamine (0.15 mg/kg/h, maximum 0.6 mg/kg over 4 h) or volume-matched 0.9% saline, stratified by center and surgical approach (open vs. laparoscopic). The co-primary endpoints are (1) the Overall Benefit of Analgesia Score at 24 h postoperatively and (2) the incidence of moderate-to-severe depression (Patient Health Questionnaire-9 ≥ 10) at 7 days postoperatively. A two-sided significance level is α = 0.025 for each primary endpoint with Bonferroni correction. Secondary endpoints include Numerical Rating Scale pain scores and the incidence of moderate-to-severe depression at 1 month and 3 months. Exploratory long-term endpoints are 5-year disease-free and overall survival.

Discussion

This trial will generate high-quality evidence on the use of esketamine as a dual-action perioperative intervention targeting both analgesic quality and psychological outcomes after pancreatic cancer surgery. The findings will inform enhanced recovery after surgery protocols and may provide mechanistic insights into NMDA receptor modulation in perioperative outcomes.

Trial registration

Chinese Clinical Trial Registry (ChiCTR2600119701; registered on March 2, 2026).

Introduction

Pancreatic cancer remains one of the most lethal malignancies, with a 5-year survival rate of approximately 13% [1]. For eligible patients, radical pancreatectomy offers the best chance for long-term survival; however, this procedure produces substantial surgical trauma, and patients often experience severe postoperative pain and depression (20–50%), substantially compromising patient recovery and long-term outcomes [2–5].

Current analgesic strategies rely heavily on opioids, which are associated with dose-dependent adverse effects including nausea, vomiting, sedation, and ileus [6]. Accumulating evidence suggests that opioids may promote tumor recurrence through immunosuppressive effects on the tumor microenvironment [7,8]. Although epidural analgesia may enhance pain management, it has not consistently translated into improved recovery or reduced morbidity [9]. Concurrently, conventional antidepressants require weeks to achieve therapeutic effect, rendering them unsuitable for the perioperative setting and raising concerns regarding drug interactions [10].

Esketamine, the S-enantiomer of ketamine, is a high-affinity N-methyl-D-aspartate (NMDA) receptor antagonist. By inhibiting central sensitization, it effectively reduces postoperative pain and opioid consumption [11,12]. Esketamine also exerts rapid-onset antidepressant effects, making it uniquely suited for the perioperative window when psychological distress is most acute [13]. Although previous studies have demonstrated these benefits separately in various surgical or psychiatric settings [14], the combined analgesic and antidepressant efficacy of esketamine specifically in pancreatectomy, a population facing extreme burden in both domains, has not been evaluated.

The Overall Benefit of Analgesia Score (OBAS) is a validated multidimensional tool for patient-centered outcomes, integrating pain intensity, opioid-related adverse effects, and patient satisfaction [15]. We designed this multicenter randomized clinical trial to test the co-primary hypotheses that intraoperative esketamine infusion would (1) improve the OBAS at 24 h postoperatively and (2) reduce the incidence of moderate-to-severe depression at 7 days after pancreatic cancer surgery.

Patients and methods

Study design, ethics, and registration

This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled trial conducted at three tertiary teaching hospitals in China: the First Affiliated Hospital of Soochow University, the Affiliated Hospital of Nantong University, and Taizhou People’s Hospital. The trial protocol has been approved by the Medical Ethics Committee of the First Affiliated Hospital of Soochow University and two participating centers. The study will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Written informed consent will be obtained from all participants before any study-related procedures. The trial has been registered at the Chinese Clinical Trial Registry (identifier: ChiCTR2600119701). This protocol is reported in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2025 statement (Supplement 1) [16]. The flow diagram is shown in Figure 1.

Figure 1.

Trial flow diagram.

Inclusion criteria

(1) Aged 18–80 years; (2) American Society of Anesthesiologists (ASA) physical status I–III; (3) scheduled for elective open or laparoscopic pancreatectomy (including pancreaticoduodenectomy, distal pancreatectomy, or total pancreatectomy); and (4) provision of written informed consent.

Exclusion criteria

(1) Uncontrolled hypertension (systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg); (2) history of angina pectoris or myocardial infarction within the past 3 months; (3) severe hepatic dysfunction (Child-Pugh class C); (4) severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73m2); (5) increased intracranial pressure, intracranial tumor, or history of epilepsy; (6) glaucoma; (7) hyperthyroidism; (8) pre-existing psychiatric disorders or current use of antipsychotic medication; (9) long-term use (≥3 months) of analgesics or psychotropic drugs; or (10) inability to communicate effectively or understand the study scales.

Randomization and blinding

Eligible patients will be randomly assigned in a 1:1 ratio to receive either esketamine or placebo. The randomization sequence will be generated by an independent statistician using computer-generated random numbers, with stratification by center and surgical approach (open vs. laparoscopic). A permuted block design (sizes 2 and 4) will be used to ensure balanced allocation. Randomization codes will be placed in sequentially numbered, opaque, sealed envelopes stored in the central drug distribution center. An independent research nurse not involved in patient care or outcome assessment will prepare the study drugs according to the randomization code: esketamine or an equal volume of 0.9% saline will be drawn into identical 50-mL syringes labeled only with the subject number. All patients, anesthesiologists, surgeons, data collectors, outcome assessors, and statisticians will remain blinded to group allocation throughout the study. Blinding integrity will be assessed at study completion by asking patients and assessors to guess treatment allocation.

Anesthesia and postoperative analgesia

All patients will receive a standardized anesthetic protocol. Standard monitoring includes electrocardiography, pulse oximetry, non-invasive blood pressure, bispectral index (BIS), and invasive arterial blood pressure via radial artery cannulation. Anesthesia will be induced with propofol 1–2 mg/kg or etomidate 0.1–0.2 mg/kg, combined with sufentanil 0.2–0.3 μg/kg and rocuronium 0.6 mg/kg to facilitate tracheal intubation. Anesthesia will be maintained with sevoflurane 1–3%, titrated to BIS values of 40–60. To provide adequate intraoperative analgesia, supplemental sufentanil (0.1 μg/kg bolus) or remifentanil (0.05–0.1 μg/kg/min infusion) will be administered when heart rate or mean arterial pressure increases >20% from baseline for >1 min, despite sufficient anesthetic depth. All supplemental opioid doses will be recorded in the case report form and reported.

All patients will receive wound infiltration with 0.375% ropivacaine 20 mL by the surgical team at the end of surgery. Patient-controlled intravenous analgesia (PCIA) will be applied for 48 h postoperatively, containing sufentanil 100 μg diluted with 0.9% saline to a total volume of 100 mL (concentration: 1 μg/mL). The PCIA device will be programmed to deliver a background infusion of 1 mL/h, a patient-controlled bolus of 2 mL, and a lockout interval of 10 min. The target for postoperative pain control is Numerical Rating Scale (NRS, 0–10) pain scores ≤ 3 at rest. Rescue analgesia with intravenous opioids (e.g. oxycodone, tramadol, dezocine) will be administered at the discretion of the attending physician.

Study interventions

Patients in the esketamine group will receive a continuous intravenous infusion of esketamine at 0.15 mg/kg/h via a syringe pump, commencing immediately after anesthesia induction and prior to surgical incision, and continuing until skin closure or for a maximum of 4 h (total dose not exceeding 0.6 mg/kg to minimize psychotomimetic side effects). Those in the control group will receive an equal volume of 0.9% saline infused at an identical rate via a syringe pump.

The 0.15 mg/kg/h infusion rate was selected based on published perioperative data [17,18]. The 4-hour window was determined to balance therapeutic exposure with the risk of neuropsychiatric side effects. Given that median operative durations for pancreatic resection are typically 4–5 h [19,20], this window will cover the complete infusion in the majority of patients. For procedures exceeding 4 h, cessation at this prespecified maximum represents completion of the planned intervention. The antidepressant effect is supported by a recent meta-analysis demonstrating that esketamine infusion at 0.1–0.3 mg/kg/h and protocols of 0.25 mg/kg bolus followed by 0.125 mg/kg/h reduced postoperative depression [14].

Primary endpoints

This study has two co-primary endpoints. The first is the OBAS assessed at 24 h postoperatively. The OBAS is a validated 7-item patient-reported questionnaire evaluating pain intensity, opioid-related side effects (including vomiting, pruritus, sweating, chills, and dizziness), and patient satisfaction with analgesia [15]. Each item is scored 0–4, yielding a total score of 0–28, with lower scores indicating greater overall benefit.

The second co-primary endpoint is the incidence of moderate-to-severe depression at 7 days postoperatively, defined as Patient Health Questionnaire-9 [PHQ-9] scores ≥10 [21]. The PHQ-9 is a validated 9-item screening tool for depression (scored 0–3 per item, total 0–27), with higher scores indicating more severe depressive symptoms. The 7-day timepoint was selected to capture the antidepressant effect of esketamine within the first postoperative week, which is the most extensively evaluated short-term window in randomized trials of perioperative esketamine [14].

Secondary and exploratory endpoints

Secondary endpoints are NRS pain scores at 1 month and 3 months postoperatively, and the incidence of moderate-to-severe depression at 1 month and 3 months. Exploratory endpoints include OBAS at postoperative days 2–5; cumulative opioid consumption within 24 h; time to first flatus; incidence of postoperative nausea and vomiting (PONV); psychotomimetic adverse events; postoperative complications (Clavien-Dindo classification ≥ IIIa); unplanned intensive care unit (ICU) admission; length of postoperative hospital stay; in-hospital mortality; and 5-year disease-free survival (DFS) and overall survival (OS).

Quality assurance

To ensure protocol adherence and consistency across the three participating centers, the following quality assurance measures will be implemented. First, all investigators and research staff will undergo standardized training before patient enrollment, covering the anesthesia protocol, outcome assessment procedures (OBAS, PHQ-9), adverse event reporting, and electronic data capture system use. Second, a detailed operations manual will be provided to all centers. Third, an independent Data and Safety Monitoring Board will review enrollment progress, protocol deviations, and safety data periodically. Fourth, study drugs will be prepared independently with identical syringes labeled only with the subject number. Fifth, periodic inter-center consistency checks for baseline characteristics and outcome distributions will be conducted.

Data collection

Table 1 presents the SPIRIT schedule of patient enrollment, study intervention, and outcome assessment. Data will be collected by trained outcome assessors blinded to group allocation using standardized case report forms. Baseline data include demographic characteristics (age, sex, and body mass index), ASA physical status, comorbidities, history of abdominal surgery, preoperative chemoradiotherapy, and baseline PHQ-9 score. Intraoperative data comprise intraoperative anesthetic and analgesic consumption, fluid infusion, transfusion, blood loss, urine output, duration of surgery, surgical approach, length of recovery room stay, and any adverse events.

Table 1.

SPIRIT schedule of patient enrollment, study intervention, and outcome assessment.

				Study period
	Enrollment	Allocation	Post-allocation						Closeout
Timepoint	Preoperative visit	Before surgery	During surgery	24 h	2–7 d	Hospital discharge	1 m	3 m	1–5 y
Enrollment
Inclusion criteria	×
Exclusion criteria	×
Written informed consent	×
Baseline data	×
Randomization		×
Allocation		×
Study intervention
Esketamine			×
0.9% saline			×
Outcome assessment
Overall analgesia benefit (OBAS)				×	×
Depression (PHQ-9)					×		×	×
Pain intensity				×			×	×
Cumulative opioid consumption				×
Time to first flatus				×	×
Nausea and vomiting				×	×
Psychotomimetic adverse events				×	×
Postoperative complications						×
Unplanned ICU admission						×
Length of hospital stay						×
Disease-free survival									×
Overall survival									×

OBAS: Overall Benefit of Analgesia Score; ICU: intensive care unit; PHQ-9: Patient Health Questionnaire-9.

Postoperatively, the OBAS will be assessed at 24 h and the PHQ-9 will be administered at 7 days. Follow-up assessments at 1 month and 3 months will be conducted via outpatient clinic visits or telephone interviews to collect NRS pain scores and PHQ-9 scores. Exploratory endpoint assessments include cumulative opioid consumption within 24 h; time to first flatus; length of postoperative hospital stay; OBAS at postoperative days 2–5; PONV; psychotomimetic adverse events; postoperative complications; unplanned ICU admission; and in-hospital mortality. Psychotomimetic adverse events including hallucinations, agitation, confusion, nightmares, and perceptual disturbances, will be assessed during emergence from anesthesia, throughout the post-anesthesia care unit stay, and on postoperative day 1. For each event, the onset, severity, duration, and resolution will be recorded. Mild symptoms will be managed with reassurance and environmental modification; moderate-to-severe symptoms will be treated with intravenous midazolam 1–2 mg and continuous observation until resolution. DFS and OS will be assessed annually for up to 5 years through medical record review and telephone contact.

All data will be entered into a secure electronic data capture system with password protection and access restrictions. Data entry will be independently verified by two researchers to ensure accuracy. All patient information will be anonymized using unique study identifiers, with personal data stored separately from clinical data. The database will be locked after final data verification, and all records will be retained for at least 5 years after study completion.

Sample size estimation

This study is designed with two co-primary endpoints. To maintain an overall type I error rate of 0.05, a Bonferroni correction will be applied, setting the significance level at α = 0.025 (two-sided) for each primary endpoint. Sample size calculations were performed for both endpoints independently, and the larger derived sample size was selected to ensure adequate power for both comparisons.

For the OBAS at 24 h postoperatively, we assume a standard deviation of 3.0 points based on a previous study in hepato-pancreato-biliary surgery [22]. To detect a mean difference of 1.5 points between groups with 80% power at α = 0.025, 78 patients per group are required. For the incidence of moderate-to-severe depression at 7 days postoperatively, we anticipate a reduction from 20% in the placebo group to 7% in the esketamine group [23]. To detect this risk reduction with 80% power at α = 0.025, 127 patients per group are required. Taking the larger sample size requirement (127 per group) and accounting for a potential 8% dropout rate, the total target enrollment is 280 patients (140 per group). All sample size calculations were performed using PASS 2023 software (NCSS LLC, Kaysville, UT, USA).

Statistical analysis

The primary analysis will follow the intention-to-treat (ITT) principle, including all randomized patients in their assigned groups. Missing data will be handled using multiple imputation by chained equations, assuming data are missing at random. A per-protocol (PP) analysis will be performed as a sensitivity analysis, excluding patients with major protocol violations (e.g. failure to receive allocated intervention, loss to follow-up before primary endpoint assessment).

Between-group differences in OBAS scores at 24 h will be compared using the independent sample t test or Mann-Whitney U test, depending on normality assessed by Shapiro-Wilk test. The treatment effect will be reported as the mean difference (or median difference with Hodges-Lehmann estimator) and 95% confidence interval (CI). These analyses will be further adjusted for stratification factors (center and surgical approach) using multiple linear regression, with treatment effects reported as adjusted mean difference with 95% CI. The incidence of moderate-to-severe depression at 7 days will be compared using the chi-square test or Fisher’s exact test, with treatment effect expressed as relative risk and absolute risk reduction with 95% CI, and will be further analyzed using multivariable logistic regression, adjusting for stratification factors.

Sensitivity analyses (including per-protocol, complete-case, best-case, and worst-case) will be performed to assess the robustness of the primary findings. Prespecified subgroup analyses will examine treatment effects on the co-primary endpoints according to sex, surgical approach (open vs. laparoscopic), type of surgery (pancreaticoduodenectomy vs. distal or total pancreatectomy), and baseline PHQ-9 score (< 10 vs. ≥ 10). These analyses will use tests for interaction to assess whether the treatment effect differs across subgroups.

For secondary endpoints (NRS pain scores and PHQ-9 scores at 1 and 3 months), linear mixed-effects models will be used to account for within-subject correlations over time, with treatment group, time point, and their interaction as fixed effects, and patient as a random intercept. Five-year DFS and OS will be analyzed using Kaplan-Meier curves and log-rank tests, and adjusted analyses will be conducted using the Cox proportional hazards models.

To control the family-wise type I error rate at 5%, Bonferroni correction will be applied for two co-primary endpoints, requiring a two-sided significance level of α = 0.025 for each endpoint. No formal correction for multiple comparisons will be applied to secondary and exploratory endpoints, and treatment effects will be reported as point estimates with 95% CI and interpreted cautiously. No interim analysis for efficacy is planned. All statistical analyses will be performed using SPSS (version 25.0; IBM SPSS, Chicago, IL, USA) or R software (version 4.1.0; R Foundation for Statistical Computing, Vienna, Austria).

Discussion

This multicenter, randomized, double-blind, placebo-controlled trial addresses a critical clinical need in pancreatic cancer surgery by evaluating esketamine as a dual-action perioperative intervention targeting both multidimensional analgesic benefit and early postoperative depression. To our knowledge, this is the first study to simultaneously assess these interconnected outcomes, offering a strategy aligned with contemporary enhanced recovery after surgery paradigms that addresses both the physical and psychological dimensions of recovery in this high-risk group.

Pancreatic cancer surgery involves extensive tissue trauma and is frequently followed by severe postoperative pain; nevertheless, perioperative analgesia remains suboptimal. Although effective, opioids are associated with significant adverse effects and may adversely affect long-term oncological outcomes via immunosuppressive mechanisms [24]. Moreover, perioperative depression is common in this population and has been independently linked to delayed recovery and reduced survival [23,25]. Conventional antidepressants have a delayed onset of action, rendering them poorly suited to the acute perioperative setting. Esketamine, an NMDA receptor antagonist, may concurrently address both pain and mood disturbance [26,27]. While regional analgesic techniques have advanced perioperative care [28], evidence supporting perioperative strategies that target both symptom domains remains limited. The present trial is therefore designed to fill this gap within a standardized multicenter framework.

Several design features strengthen the validity of our findings. First, the use of the OBAS as a co-primary endpoint moves beyond unidimensional pain intensity to capture the patient-centered integration of pain relief, opioid-related adverse effects, and satisfaction. This metric is particularly relevant for pancreatic surgery, where opioid side effects may delay gastrointestinal recovery. Second, we employ conservative Bonferroni correction (α = 0.025) for our co-primary endpoints, ensuring robust control of type I error despite multiple comparisons. Third, rather than excluding patients with elevated baseline PHQ-9 scores (a common scenario in this population), we will conduct prespecified subgroup analysis based on this variable. Fourth, the inclusion of 5-year DFS and OS as exploratory endpoints acknowledges emerging hypotheses regarding perioperative immunomodulation and long-term oncological outcomes, though we emphasize that the trial is not powered for these survival analyses.

Several limitations also warrant acknowledgment. First, the maximum esketamine infusion duration of 4 h and total dose of 0.6 mg/kg are selected to minimize psychotomimetic side effects. However, this single intraoperative regimen may not represent the optimal dosing strategy, particularly for the antidepressant endpoint, for which repeated postoperative dosing may yield more durable effects. Second, while the Bonferroni correction ensures stringent type I error control for the co-primary endpoints, it increases the risk of type II error (false negatives). Finally, although we prospectively collect 5-year survival data, these analyses are exploratory and hypothesis-generating; any observed associations would require confirmation in adequately powered, dedicated trials with survival as the primary endpoint.

In conclusion, this multicenter randomized controlled trial addresses the intertwined physical and psychological morbidities of pancreatic cancer surgery by rigorously evaluating intraoperative esketamine as a dual-action perioperative intervention. This study is positioned to generate high-quality evidence on whether a single intraoperative pharmacologic strategy can simultaneously improve multidimensional analgesic benefit and reduce early postoperative depression, potentially informing enhanced recovery protocols for this high-risk population.

Funding Statement

This work will be supported by National Natural Science Foundation of China (82471290 to KP), Suzhou Basic Research Pilot Project (SSD2024082 to KP), and 333 High-level Talent Training Project in Jiangsu Province ((2024)3-2272 to KP). The funders have no role in the study design, data collection, data analysis, interpretation, or writing of this manuscript.

Ethics and dissemination

The trial protocol was approved by the Ethics Committee of the First Affiliated Hospital of Soochow University (Approval No. 2025-1296) and the Ethics Committees of two participating centers (Affiliated Hospital of Nantong University and Taizhou People’s Hospital). This study was registered at the Chinese Clinical Trial Registry (registration No. ChiCTR2600119701) before the enrollment of the first patient. The study implementation will follow the Declaration of Helsinki. Written consent will be obtained from all patients. The findings of this study will be considered for publication in peer-reviewed scientific journals.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

The full protocol, dataset, statistical plan, and informed consent materials are available via contacting the corresponding author after the formal publication of this trial. No new data has been generated during this article.