Effect of Subanesthetic Doses of Esketamine on Early Postoperative Pain Sensitivity in Patients Undergoing Salpingectomy: A Randomized Clinical Trial

Introduction

Ectopic pregnancy(EP), defined as the implantation and development of a fertilized ovum outside the uterine cavity, accounts for approximately 2% of all pregnancies, with tubal pregnancy being the most common form.¹ Emergency salpingectomy remains the primary treatment modality.² However, the urgency of surgical intervention often limits comprehensive preoperative psychological support. This increases the risk of postoperative complications such as pain and psychological distress. Among these perioperative complications in patients with ectopic pregnancy, postoperative pain is particularly prominent,³ a randomized controlled trial from Korea indicated that over 41% of patients experienced severe pain after gynecological laparoscopic surgery.⁴ Beyond genetic polymorphisms, acute postoperative pain in the early postoperative phase represents a key trigger for the elevation of pain sensitivity.⁵ A crucial insight from previous pain-related research is that elevated pain sensitivity may occur early in the postoperative period,⁶ and its onset is often accompanied by intensification of pain and the resulting physiological and psychological stress, which negatively impacts the postoperative recovery process. Furthermore, increasing evidence suggests that elevated pain sensitivity observed a few days after surgery may be linked to the subsequent development of chronic pain, leading to long-term adverse effects on patients’ daily lives.^7,8 Therefore, it is crucial to explore effective perioperative pain management strategies to improve early pain sensitivity after gynecological laparoscopic surgery.

Table 1 Baseline Characteristics and Intraoperative Variables of the Patients

Esketamine, the dextrorotatory isomer of ketamine, exerts its principal effects via non-competitive antagonism of the N-methyl-D-aspartate (NMDA) receptor, to which it has approximately twice the binding affinity of ketamine.⁹ Compared with ketamine, esketamine exhibits faster metabolism, higher clearance, and shorter recovery time, thereby offering distinct pharmacological advantages. Perioperative administration of esketamine has been shown to extend the duration of postoperative analgesia without delaying extubation, while simultaneously improving patient comfort.¹⁰ In addition, esketamine demonstrates opioid-sparing properties, contributes to the prevention and treatment of hyperalgesia, and has been increasingly recognized for its antidepressant efficacy. For instance, adjunctive use of esketamine in patient-controlled intravenous analgesia (PCIA) following cesarean delivery has been reported to reduce both postoperative depressive symptoms and pain within the first 48 hours, without increasing adverse events.¹¹ Nevertheless, its clinical utility in the context of post-salpingectomy pain has not yet been established. Given that existing analgesic studies on esketamine mostly focus on elective surgeries, its impact on the interaction between pain sensitivity and psychological stress in emergency settings has not yet been clarified, and the optimization of sub-anesthetic doses in multimodal analgesia lacks sufficient evidence-based support. Compared with elective surgery, emergency surgery may be associated with a more pronounced acute stress response, inflammatory activation, and psychological distress, which may collectively facilitate pain sensitization and contribute to heightened postoperative pain sensitivity.^12,13 We conducted a prospective, double-blind, placebo-controlled randomized clinical trial to evaluate the effect of perioperative intravenous esketamine on early postoperative pain sensitivity in patients undergoing laparoscopic salpingectomy for ectopic pregnancy.

Materials and Methods

Ethical Considerations

This prospective, double-blind, placebo-controlled randomized clinical trial has been approved by the Ethics Committee of Fuzhou university affiliated Provincial Hospital (No. K2023-11-022, approval date: November 23, 2023), and the trial has been prospectively registered in the U.S. Clinical Trial Registry (https://register.clinicaltrials.gov/prs/beta/records, NCT06559280). All participants provided written informed consent. We conducted this study in accordance with China legal requirements, the World Medical Association Declaration of Helsinki and the Guidelines for Good Clinical Practice. No protocol changes were made after the start of the trial. This manuscript follows the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines. Because this study was conducted in an emergency surgical setting, special attention was paid to the informed consent process. Eligible patients were approached only after the diagnosis of ectopic pregnancy and the surgical plan had been established, and before anesthesia induction. Written informed consent was obtained only when the patient was fully conscious, clinically stable, able to communicate effectively, and judged by the investigators to have adequate understanding and decisional capacity. Baseline psychological and pain sensitivity assessments were then completed before surgery. Patients with uncontrolled pain (NRS pain score≥4), marked emotional distress, or impaired ability to understand the study were not enrolled at that time.

Study Design and Participants

This prospective, double-blind, randomized controlled trial was conducted between August 24, 2024, and May 20, 2025, in patients scheduled for emergency laparoscopic salpingectomy under general anesthesia. Eligible participants were women aged >18 years, with a BMI of 18–30 kg/m², and classified as ASA physical status I–II. Additional inclusion criteria comprised a confirmed diagnosis of ectopic pregnancy requiring emergency laparoscopic surgery, preserved cognitive and communicative function.

Exclusion criteria were as follows: (1) severe dysfunction of vital organs (heart, lung, liver, or kidney); defined as chronic kidney disease (glomerular filtration rate <30 mL/min/1.73 m² or requiring renal replacement therapy for end-stage renal disease), acute or decompensated heart failure, or other severe organ dysfunction meeting clinical criteria for end-stage or decompensated disease;¹⁴ (2) severe psychiatric disorders; (3) chronic use of sedatives, analgesics, alcohol, or tobacco; (4) documented hypersensitivity to esketamine or related agents; (5) contraindications to esketamine, such as uncontrolled hypertension, elevated intracranial pressure, or hyperthyroidism; (6) history of chronic pain syndromes; and (7) refusal to participate.

Randomization and Blinding

Participants were randomly assigned in a 1:1 ratio to either the esketamine group or the control group using a computer-generated randomization sequence. Allocation details (random number, group assignment, and intervention) were concealed in sequentially numbered, opaque, sealed envelopes, prepared in duplicate for each participant. One envelope was stored by the study supervisor as an emergency backup, while the other was delivered to an anesthesia nurse one day before surgery. This nurse, who was not involved in outcome assessment, was solely responsible for drug preparation, ensuring that esketamine and placebo solutions were visually indistinguishable.

Interventions were administered at standardized doses. The control group received equivalent volumes of 0.9% normal saline. All patients, anesthesiologists, surgeons, follow-up assessors, and investigators involved in data collection or analysis remained blinded to treatment allocation throughout the study.

Anesthesia Protocol

Upon entry into the operating room, patients underwent standard monitoring, including electrocardiography, non-invasive blood pressure, and pulse oximetry. Preoxygenation was achieved with pure oxygen at 8–10 L/min for 3–5 minutes. Anesthesia induction followed a standardized protocol: intravenous injection of midazolam 1mg, penehyclidine 0.5 mg, and sufentanil 0.5 μg/kg; then intervention drugs were administered according to group allocation. patients in the esketamine group received an intravenous bolus of 0.25 mg/kg esketamine,^10,15 while the control group received the same volume of saline. The induction dose of esketamine was selected as a subanesthetic dose to provide perioperative analgesic adjunctive effects while maintaining an acceptable safety profile. Both groups used a combined intravenous-inhalation regimen to maintain anesthesia. Propofol and desflurane were titrated according to hemodynamic responses, bispectral index (BIS) monitoring, and clinical indicators. Supplemental sufentanil was administered in 5 μg boluses, with the goal of maintaining blood pressure and heart rate within ±20% of baseline and BIS between 40 and 60. Postoperative analgesia was provided using a patient-controlled intravenous analgesia (PCIA) pump for 48 hours. In the esketamine group, the PCIA solution contained esketamine 1 mg/kg, sufentanil 1 μg/kg, tropisetron 10 mg, and flurbiprofen axetil 200 mg, diluted to 100 mL with saline. In the control group, the PCIA solution contained sufentanil 2 μg/kg, tropisetron 10 mg, flurbiprofen axetil 200 mg, and saline, also diluted to 100 mL. The postoperative esketamine dose was selected as part of a multimodal analgesic regimen, with reference to prior perioperative studies and clinical experience supporting esketamine-containing postoperative analgesia strategies.^16–18 The postoperative sufentanil dose was set higher in the control group to partially compensate for the anticipated analgesic contribution of esketamine and to maintain adequate postoperative analgesia in both groups.¹⁹ The PCIA settings were standardized: background infusion at 2 mL/h, bolus dose of 2 mL, and lockout interval of 15 minutes. Pump activations were recorded by blinded personnel. Rescue analgesia was administered when patients experienced breakthrough pain with an NRS score ≥4 despite PCIA use.

Outcomes

Baseline data included demographic characteristics, ASA classification, marital status, reproductive intention (preconception or unintended pregnancy), and fertility requirements. Intraoperative variables comprised surgical and anesthetic duration, blood loss, and anesthetic and fluid administration.

Primary Outcome

The primary outcome was postoperative pain sensitivity, assessed using the Pain Sensitivity Questionnaire (PSQ).²⁰ The questionnaire scale used in this study is provided in Supplementary Figure 1. The PSQ consists of 17 items (3 non-pain references, 14 pain-related items), each scored from 0 (no pain) to 10 (worst imaginable pain). The mean of the 14 pain-related items was used as the total score, with higher scores indicating greater pain sensitivity. Sub scores were calculated for PSQ-moderate and PSQ-minor domains. Although the PSQ has been primarily validated as a measure of perceived pain sensitivity, it was used longitudinally in the present study as a pragmatic patient-reported tool to assess postoperative changes in this construct over time. This approach was informed by its moderate test–retest reliability (ICC = 0.635)²⁰ and by prior longitudinal use of conceptually related pain-sensitivity scales in postsurgical populations.²¹ Postoperative assessments were conducted on postoperative days 1, 2, and 7, with in-hospital evaluations performed by trained researchers and follow-up after discharge conducted by telephone. Because postoperative PSQ scores may also be influenced by recent pain experience and emotional factors, repeated measurements were interpreted cautiously. To ensure the reliability and standardization of telephone-based follow-up assessments, all follow-up researchers underwent standardized training in assessment scripts and response-recording procedures.

Secondary Outcomes

Postoperative depressive symptoms were measured using the 17-item Hamilton Depression Rating Scale (HAMD-17), with scores categorized as mild (>7–17), moderate (>17–24), or severe (>24); the corresponding questionnaire scale is provided in Supplementary Figure 2, and assessments were conducted preoperatively and on postoperative day 7. Resting and dynamic pain (during thigh flexion/extension) were evaluated for pain intensity using the Numeric Rating Scale (NRS, 0 = no pain, 10 = worst pain) at 30 min, 6 h, 12 h, 24 h, and 48 h postoperatively. Serum levels of PGE₂ and BDNF, as serum biomarkers, were detected via enzyme-linked immunosorbent assay (ELISA) preoperatively, immediately postoperatively, and on postoperative day 2. PGE₂ is a key proinflammatory mediator that modulates peripheral and central pain sensitization,²² while BDNF is a critical neurotrophic factor involved in synaptic plasticity and the regulation of pain perception and emotional responses;²³ both biomarkers are closely associated with the development of postoperative pain sensitivity and are important for exploring the potential mechanistic effects of esketamine on perioperative pain modulation. Analgesic consumption was quantified by recording the use of rescue analgesia and the number of PCIA activations. Rescue analgesia was defined as intravenous flurbiprofen axetil 50 mg when the NRS pain score remained ≥4 despite PCIA,¹⁶ with administration performed according to a standardized protocol. Adverse events were documented by recording the incidence of postoperative dizziness, drowsiness, nausea, vomiting, and other related events within 48 hours postoperatively via a structured interval assessment protocol. Trained researchers systematically inquired about and clinically assessed specific adverse events at 30 min,6 h, 12 h, 24 h and 48 h postoperatively; all events (patient-reported or investigator-identified) were recorded in a standardized case report form, rather than only based on routine clinical documentation.

Sample Size Calculation

Sample size estimation was based on our unpublished preliminary pilot data, with the PSQ total score on postoperative day 1 as the primary variable. The mean PSQ score was 3.34 ± 1.03 in the esketamine group and 4.17 ± 1.12 in the control group. Using α = 0.05 and β = 0.10, PASS 15 software calculated that 37 participants per group were required. Allowing for an anticipated 10% dropout rate, 42 patients were enrolled in each group, yielding a total sample size of 84.

Statistical Analysis

This experiment uses SPSS 23.0 software to conduct statistical analysis and processing of the test data, and the drawing is completed through GraphPadPrism 9.0 software. The analysis followed the per-protocol (PP) principle, including only participants who completed the study and adhered to the core protocol. This approach was chosen to evaluate the efficacy of the intervention under ideal conditions, thereby providing a more conservative estimate of the treatment effect in a clinically adherent population. In addition to the per-protocol (PP) analysis, an intention-to-treat (ITT) sensitivity analysis including all randomized participants was performed to evaluate the robustness of the primary outcome findings. The Kolmogorov–Smirnov test was used to determine whether the sample data was normally distributed. The normal distribution measurement data was expressed by the mean ± standard deviation (SD), and compared between groups using independent samples t-tests. The non-normal distribution data was expressed by the median and quartile (IQR), and analyzed with the Mann–Whitney U-test); the counted data was expressed by the number (percentage) and the chi-square test was analyzed by the chi-square test.

For the primary outcome (PSQ scores at postoperative days 1, 2, and 7), between-group comparisons at each time point were first performed using independent samples t-tests, with P-values adjusted for multiple comparisons using the Bonferroni method. A sensitivity analysis using two-way repeated-measures ANOVA was further conducted to confirm the robustness of the primary outcome. For repeated-measure outcomes (NRS score, HAMD-17 score, and serum factor concentration), a two-way repeated-measures analysis of variance (ANOVA) was employed to examine the effects of group, time, and group-by-time interaction. Where significant main or interaction effects were identified, post hoc comparisons between groups at individual time points were conducted using Bonferroni correction. To control for type I error inflation due to multiple comparisons, we applied false discovery rate (FDR) correction using the Benjamini-Hochberg procedure for all secondary repeated-measure outcomes. A two-sided P<0.05 was considered statistically significant.

Results

A total of 92 patients were assessed for eligibility from August 24, 2024 to May 20, 2025. Of these, 84 were enrolled and randomly assigned to either the esketamine group (n = 42) or the control group (n = 42). The high inclusion rate was primarily due to the homogeneous study population and an efficient, well-organized screening workflow with limited exclusion criteria.After exclusions (3 lost to follow-up in control Group, 1 transferred to ICU due to postoperative moderate-to-severe anemia), 80 patients were included in the final analysis (esketamine group: n = 42; control group: n = 38) (Figure 1). Baseline demographic and clinical characteristics were well balanced between the two groups (Table 1). As shown in Figure 2A, the mean (SD) preoperative PSQ total scores for the esketamine and control groups were 4.03 (1.54) and 4.17 (0.86), respectively, with no significant difference observed between the two groups (P=0.604). Notably, preoperative psychological status—assessed by HAMD-17 scale was also comparable between the two cohorts (Median [IQR]: 6.0 [4.0–8.0] vs 7.5 [5.0–10.0]; P=0.145).

Figure 1 Flow diagram of the study. CONSORT flow diagram for the study.

Figure 2 Changes in Pain Sensitivity Questionnaire (PSQ) scores during the perioperative period. (a) PSQ-total scores. Two-way repeated-measures ANOVA revealed a significant main effect of group (F(1,78) = 9.881, p= 0.002). (b) PSQ-minor scores. A significant main effect of group was found (F(1,78) = 10.035, p= 0.002). (c) PSQ-moderate scores. A significant main effect of group was found (F(1,78) = 10.334, p= 0.002). Data are presented as mean ± SEM. P values shown in graphs indicate significant between-group differences at specific time points by post hoc independent samples t-tests with Bonferroni correction. Abbreviations: Pre-op, preoperative; POD 1, postoperative day 1; POD 2, postoperative day 2; POD 7, postoperative day 7. Note: I bars represent standard errors.

Primary Outcome

A two-way repeated-measures ANOVA revealed a significant main effect of group for the PSQ-total score (F(1,78) = 9.881, P = 0.002) (Figure 2A). Post-hoc tests further confirmed significantly lower PSQ-total scores in the esketamine group on postoperative day 1 (Estimate = 0.79, 95% CI: 0.31 to 1.27, P = 0.001) and day 2 (Estimate = 0.55, 95% CI: 0.07 to 1.03, P = 0.027).

This robust beneficial effect of esketamine was also consistently observed in both subscales. For the PSQ-minor score, a significant main effect of group was found (F(1,78) = 10.035, P = 0.002) (Figure 2C), and for the PSQ-moderate score, the main effect of group was also significant (F(1,78) = 10.334, P = 0.002) (Figure 2B). These results strongly support the primary findings, indicating that perioperative esketamine significantly attenuates early postoperative pain sensitivity across different pain intensity domains. Detailed statistical results for all PSQ domains, including P-values for group, time, and interaction effects from the repeated-measures ANOVA, are summarized in Supplementary Table 1.

To further assess the robustness of the findings, an intention‑to‑treat (ITT) sensitivity analysis including all 84 randomized patients (42 in the esketamine group, 42 in the control group) was performed. Missing PSQ‑total scores at postoperative days 1, 2, and 7 due to patient dropout were handled by last observation carried forward (LOCF) imputation. A mixed‑effects model for repeated measures (MMRM) was then applied, including group, time, and their interaction as fixed effects, preoperative PSQ‑total score as a covariate, and patient ID as a random intercept, with Bonferroni adjustment for multiple comparisons. As shown in Supplementary Table 2, the esketamine group had significantly lower PSQ‑total scores than the control group on postoperative day 1 (difference = 0.68, 95% CI: 0.25 to 1.11, adjusted P = 0.002) and day 2 (difference = 0.45, 95% CI: 0.02 to 0.88, adjusted P = 0.040), but not on day 7 (difference = 0.39, 95% CI: –0.05 to 0.82, P = 0.079). The group‑by‑time interaction was not significant (F(2,164) = 0.74, P = 0.479), suggesting no evidence that the treatment effect differed across postoperative time points. These ITT results were consistent in both direction and magnitude with the primary per-protocol analysis, further supporting the robustness of the main conclusions.

Secondary Outcomes

The NRS scores during movement were significantly lower in the esketamine group than in the control group at 30 minutes, 3.0 (2.0–4.0) vs 4.0 (2.0–5.0) (95% CI, 0.57 to 2.42; P<0.001). Although dynamic NRS scores were lower in the esketamine group than in the control group at 6 hours, 2.0 (2.0–4.0) vs 4.0 (3.0–5.0) (95% CI, 0.23 to 1.65; P=0.02), this did not remain statistically significant after FDR correction (adjusted P=0.073), and no significant differences were observed between the two groups at other time points for dynamic pain or at any time points for resting pain. In terms of analgesic consumption, there was no significant difference in the number of PCA compressions between the groups (P>0.05). The proportion of patients requiring rescue analgesia was 1 of 42 (2.38%) in the esketamine group and 2 of 38 (5.26%) in the control group (95% CI, −12.5% to 6.8%; P=0.602) (Table 2). Although the median PCA demand was 0 in both groups, a small number of patients required additional rescue analgesia for breakthrough pain. There were also no meaningful differences between two groups in HAMD-17 scores on postoperative day 7 (median [IQR]) were 3.0 (2.0–4.8) in the esketamine group and 4.0 (3.0–6.0) in the control group (95% CI, −0.09 to 2.34; P=0.125) (Table 3). Nonetheless, within-group comparisons showed a significant reduction from baseline in both groups (P_time<0.01). In terms of biochemical markers, serum BDNF levels were significantly higher in the esketamine group (P_group<0.05), showing an initial postoperative decrease followed by recovery by day 2. In contrast, no significant differences were observed in PGE₂ levels between groups (P_group>0.05) (Table 4). Additionally, we conducted exploratory subgroup analyses to investigate potential factors influencing the treatment effect on POD1 PSQ-total scores, the results showed that the beneficial effect of esketamine on PSQ scores was more pronounced in patients with mild preoperative depression (HAMD-17>7), those without prior surgical history, those planning pregnancy, younger patients (<35 years), and those with higher baseline PGE2 levels (≥765 pg/mL) (Figure 3).

Table 2 Comparison of Postoperative Pain and Analgesic Effects Between the Two Groups

Table 3 Comparison of Perioperative Depression Scores Between the Two Groups

Table 4 Comparison of Perioperative Key Serum Biomarkers Between the Two Groups

Figure 3 Subgroup analysis results of influencing factors of pain sensitivity score on the first day after surgery in two groups.

Safety Outcomes

During the 2 days after surgery, the incidence of adverse events —including nausea, vomiting, dizziness, and somnolence —did not differ significantly between groups (P>0.05). No hallucinations or delirium were reported in either group (Table 5). Complete FDR-adjusted P-values for all outcome measures are provided in Supplementary Table 3.

Table 5 Adverse Events in the Study Participants

Discussion

In this randomized clinical trial, we demonstrated that perioperative administration of subanesthetic-dose esketamine was associated with a modest reduction in patient-reported postoperative pain sensitivity during the early postoperative period in patients undergoing laparoscopic salpingectomy for ectopic pregnancy. Notably, this early analgesic benefit was accompanied by significantly higher serum BDNF concentrations in the esketamine group than in the control group at all perioperative time points. This intergroup difference in BDNF levels suggests that neuroplastic and neuroprotective mechanisms may underlie the observed effects. Importantly, the modest changes in HAMD-17 scores imply that the attenuation of postoperative pain sensitivity is unlikely to be fully explained by esketamine’s antidepressant actions alone. Furthermore, post hoc exploratory analyses indicated that the treatment effect might vary across specific patient subgroups—such as younger age or presence of mild depressive symptoms—though these observations are exploratory and require further validation in future well-powered studies.

Postoperative hyperalgesia (POH) is an experimentally measured clinical phenomenon,²⁴ often attributed to central sensitization mediated by N-methyl-D-aspartate (NMDA) receptor overactivation,²⁵ dysfunction of descending modulatory circuits, and proinflammatory mediators such as prostaglandins.²⁶ Given esketamine’s role as a non-competitive NMDA receptor antagonist, its potential to counteract these pathophysiological processes has attracted increasing clinical interest.²⁷ Our study found that perioperative administration of subanesthetic doses of esketamine in patients undergoing laparoscopic salpingectomy was associated with a modest reduction in early postoperative pain sensitivity. Although this finding is generally consistent with previous reports suggesting a potential beneficial effect of esketamine on postoperative pain-related outcomes in thoracic and gynecologic surgery,²⁸ the magnitude of the between-group difference in our study was relatively modest, and its clinical relevance should therefore be interpreted with caution. In addition, contrasting evidence from pediatric scoliosis surgery further highlights the complexity and context-dependence of the clinical effects of perioperative esketamine.²⁹ Nevertheless, our study adds preliminary evidence for the potential perioperative use of esketamine in gynecologic laparoscopic surgery for ectopic pregnancy. Of note, in our study, the postoperative sufentanil dose was set lower in the esketamine group and higher in the control group in order to partially account for the anticipated analgesic contribution of esketamine and to maintain adequate postoperative analgesia in both groups. Similar opioid-adjusted designs have been adopted in previous perioperative esketamine studies, particularly in PCIA-based regimens, where the esketamine-containing arm was combined with a lower opioid exposure or compared with a conventional opioid-based regimen.^30–32 This strategy was intended to preserve clinically acceptable analgesia while accounting for the expected opioid-sparing effect of esketamine; however, a potential confounding influence of differential opioid exposure cannot be fully excluded.

Less opioid was administered in the esketamine group without any increase in postoperative pain scores. Notably, it exerted a mild and transient significant beneficial effect on dynamic pain during the first 6 hours after surgery. This selective effect—improving movement-evoked but not resting pain—which has also been observed in other surgical cohorts and may be particularly relevant for facilitating early mobilization and enhancing functional recovery.^32–34 Mechanistically, BDNF—capable of crossing the blood–brain barrier and modulating synaptic plasticity—likely plays a potential pivotal role.²³ Preclinical evidence indicates that esketamine exerts its neuroprotective effects in the acute postoperative period precisely through modulation of BDNF release.³⁵ Our findings show that serum BDNF levels were significantly higher in the esketamine group at all perioperative time points, with both groups exhibiting an acute postoperative decrease followed by recovery to near-baseline levels by day 2. This suggests that the beneficial effect of esketamine on early postoperative pain sensitivity may, at least in part, be attributable to its modulation of BDNF expression and recovery, which aligns with clinical observations in patients undergoing gynecologic procedures.³⁶ However, current data do not establish a cause-and-effect relationship. Peripheral BDNF levels may not fully reflect central nervous system plasticity, and further studies, including mediation analysis or central biomarker assessment, are needed to determine whether BDNF signaling mechanistically contributes to the analgesic effects of esketamine. By contrast, serum PGE₂ levels did not differ between groups in our trial. While PGE₂ is recognized as a critical mediator of central sensitization,²² our results diverge from animal studies reporting reductions in cortical PGE₂ following repeated esketamine administration.³⁷ Differences in species, tissue specificity (systemic vs cortical levels), and anesthetic protocols may account for these inconsistencies.

Contrary to expectations, the esketamine regimen employed here did not confer significant antidepressant effects.^38,39 This may be related to the baseline levels of depressive symptoms in the two groups. Previous studies, including our preliminary work,^40,41 consistently suggest that esketamine exerts a pronounced antidepressant effect in patients who exhibit depressive symptoms preoperatively, whereas such an effect is not evident in individuals without preoperative depressive symptoms. The absence of a significant antidepressant effect might be partially attributable to the subanesthetic dose of esketamine used in the present study;⁴² however, this remains speculative, as no formal dose–response assessment or dedicated psychiatric endpoints were included. It is noteworthy that both PSQ and HAMD-17 scores showed a downward trend after surgery in both groups. Although this was not a primary focus of the present study, one possible explanation is that the resolution of the acute ectopic pregnancy event, relief of postoperative pain, and gradual reduction in perioperative psychological distress and uncertainty may together have contributed to an overall improvement in both perceived pain sensitivity and mood-related symptoms over time.⁴³ Because this pattern was observed in both groups, it is more likely to reflect a general recovery-related phenomenon rather than a treatment-specific effect. These findings underscore the importance of tailoring esketamine dosing to distinct therapeutic goals—analgesia versus antidepressant efficacy—and highlight the necessity of considering patient-specific factors, including baseline psychological status.

Our exploratory subgroup analyses yielded an intriguing observation: patients with mild preoperative depressive symptoms derived greater analgesic benefit from esketamine compared with their non-depressed counterparts. This may reflect the interplay between mood disorders and pain modulation, as both share overlapping glutamatergic and monoaminergic pathways.^44,45 By antagonizing NMDA receptors and modulating monoamine transmission, esketamine may restore maladaptive neural circuits in this susceptible subgroup.⁴⁶ Although promising, these subgroup findings are exploratory and hypothesis-generating rather than definitive, and must be interpreted with extreme caution given the absence of adjustment for multiple comparisons and the study’s relatively small sample size. Future confirmatory trials are needed to validate this potential interaction between psychological state and analgesic response.

Moreover, the relatively modest effects observed in the present study may also be related to the dosing strategy used and to the characteristics of the enrolled population. Previous studies suggest that the analgesic and anti-hyperalgesic effects of perioperative esketamine may vary according to dose, and more pronounced effects might potentially be observed with higher doses of esketamine regimens.⁴⁷ In addition, because the baseline pain sensitivity of our study population was not markedly elevated, and the enrolled patients represented a relatively homogeneous and generally low-risk surgical cohort, larger effects might be more readily detected in future studies involving patients with higher baseline pain sensitivity or other risk factors for heightened postoperative pain responses. However, this possibility remains speculative and requires direct confirmation in appropriately designed trials.

Limitations

Several limitations of this study should be acknowledged. First, we only evaluated patient pain sensitivity and depression one week after surgery, and the impact of esketamine on patients’ long-term pain sensitivity and depression warrants further investigation; second, our sample size may not be enough to detect rare statistically significant differences in esketamine-related psychotropic drug adverse reactions between groups, which may underestimate these risks. Third, blood levels of reproductive hormones such as testosterone and progesterone may have an impact on postoperative mood, and further measurement of postoperative hormone levels is needed to correct differences in order to achieve universal applicability of the study results. Fourth, the primary outcome was evaluated using PSQ, a subjective but clinically relevant patient-reported measure, without additional objective quantitative sensory testing. Accordingly, our findings primarily reflect changes in perceived postoperative pain sensitivity rather than objectively measured sensory thresholds. Furthermore, because the PSQ was administered repeatedly after surgery, postoperative scores may have been influenced to some extent by recent pain experience and emotional state. Fifth, four participants were excluded after randomization, all from the control group. Although the ITT sensitivity analysis supported the robustness of the main findings, this unequal post-randomization depletion remains a methodological consideration.

Conclusions

In patients with ectopic pregnancy undergoing salpingectomy, perioperative esketamine administration (0.25 mg/kg at induction and 1 mg/kg added to postoperative intravenous analgesia) was associated with reduced self-perceived pain sensitivity in the early postoperative period. Serum BDNF levels were significantly higher in the esketamine group throughout the perioperative period, with both groups demonstrating an acute postoperative decline followed by recovery. Future research should include large-scale, multi-center trials to verify these findings, establish optimal dosing strategies, assess results for specific patient subgroups, assess long-term safety and economic impact, and clarify potential mechanisms for improving rehabilitation.