Efficacy and safety of intraoperative esketamine for postoperative sleep quality: a systematic review and meta-analysis of RCTs

Abstract

To evaluate the efficacy and safety of intraoperative esketamine in improving postoperative sleep quality based on evidence from randomized controlled trials (RCTs). A systematic search was conducted in the Cochrane Central Register of Controlled Trials (CENTRAL), Medline (via Ovid), and EMBASE. Eligible studies were RCTs comparing the effects of esketamine versus placebo on postoperative sleep quality in surgical patients. Statistical analyses were performed using Cochrane Review Manager version 5.4.1. A total of 10 RCTs comprising 1,287 patients were included. Esketamine significantly improved postoperative sleep quality compared to placebo on postoperative day (POD) 1 (SMD =  − 0.52, 95% CI [− 0.69, − 0.34], P < 0.00001, I² = 61%), POD 2 (SMD =  − 0.60, 95% CI [− 1.16, − 0.03], P = 0.04, I² = 77%), POD 3 (SMD =  − 0.44, 95% CI [− 0.71, − 0.18], P = 0.001, I² = 76%), and POD 7 (SMD =  − 0.31, 95% CI [− 0.58, − 0.04], P = 0.03, I² = 0%). While the incidence of adverse events did not differ significantly between groups, elevated odds ratios indicated a potential trend toward a higher incidence with esketamine. Intraoperative esketamine may improve postoperative sleep quality. However, it is not yet possible to conclude whether this agent is suitable for clinical use in improving sleep targeting postoperative patients. Further high-quality RCTs are needed to confirm efficacy and evaluate long-term safety.

Supplementary Information

The online version contains supplementary material available at 10.1007/s41105-025-00595-8.

Introduction

Postoperative sleep disturbances are common among surgical patients and can adversely affect both recovery and prognosis [1]. These disturbances contribute to a catabolic state, which impairs postoperative healing and recovery [2, 3]. Furthermore, they are associated with delayed recovery, prolonged hospital stays, and long-term detrimental effects on patient health and overall quality of life [4, 5].

Postoperative sleep disturbances arise from multiple factors, including the type of anesthesia used, postoperative pain, environmental disruptions in the care setting, and psychological stress [6]. Effective management of sleep following surgery is essential for promoting faster recovery and enhancing patients’ quality of life.

Esketamine, the S-enantiomer of ketamine, offers several clinical advantages, including faster metabolism, fewer side effects, and enhanced pharmacological potency, making it particularly valuable in clinical practice [7, 8]. Its primary mechanism of anesthetic and analgesic action is through noncompetitive antagonism of N-methyl-D-aspartate (NMDA) receptors [7]. In addition, esketamine interacts with opioid, cholinergic, and gamma-aminobutyric acid (GABA) receptors, among others, with these non-NMDA pathways also contributing significantly to its analgesic and anesthetic effects. Esketamine further exhibits antidepressant properties through multiple mechanisms, and it has been shown to improve sleep quality in patients with depression [7, 9].

Recent studies suggest that esketamine may also improve postoperative sleep quality. Several randomized controlled trials (RCTs) have demonstrated that intraoperative administration of sub-anesthetic doses of esketamine significantly enhances nighttime sleep quality and increases the proportion of slow-wave sleep (SWS; stage 3 non-REM sleep, or stage N3) in surgical patients [10]. Poor sleep quality has been associated with heightened pain sensitivity [11–13], and enhancing postoperative sleep may also provide ancillary benefits in postoperative pain management [14, 15].

Currently, the perioperative use of esketamine is primarily focused on sedation and analgesia during short-duration procedures [7, 16], and few studies have specifically examined its effects on postoperative sleep. However, investigating the potential of esketamine to improve postoperative sleep quality holds significant clinical relevance. Enhanced sleep quality may accelerate recovery, shorten hospital stays, and reduce healthcare costs. Moreover, it may alleviate postoperative pain and psychological stress, thereby improving patient satisfaction and overall quality of life [1].

Nonetheless, existing studies on intraoperative esketamine and postoperative sleep quality are limited by small sample sizes, short follow-up durations, and insufficient assessment of long-term safety. Inconsistencies in study outcomes further complicate the interpretation of findings. Therefore, we conducted a meta-analysis of available RCTs to more comprehensively assess the efficacy and safety of esketamine in improving postoperative sleep quality.

Materials and methods

This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines [17]. The study protocol was prospectively registered on the PROSPERO website (CRD42024560635).

Search sources and strategy

A comprehensive literature search was performed by two independent reviewers across the Cochrane Central Register of Controlled Trials (CENTRAL), Medline via Ovid, and EMBASE, from inception to July 2024. The search strategy employed the following terms: “(Sleep or Sleeping Habits or Sleep Habits or Habit, Sleep or Habits, Sleep or Sleep Habit or Sleeping Habit or Habit, Sleeping or Habits, Sleeping).af AND (Esketamine or L-Ketamine or Spravato or S-Ketamine or Kataved).af” (detailed in Supplemental File 1). Additional manual searches were conducted by screening the reference lists of relevant reviews and meta-analyses. Only studies published in English were considered. Titles and abstracts of potentially eligible studies were screened independently by two reviewers, and full-text articles were assessed for inclusion based on pre-defined eligibility criteria.

Inclusion and exclusion criteria

Studies were included if they met the following criteria: (1) RCTs; (2) adult participants (aged 18 years or older) undergoing elective surgery under general anesthesia; (3) intraoperative administration of esketamine; (4) placebo used in the control group; and (5) postoperative sleep quality-related outcomes reported. Exclusion criteria were: (1) studies in which interventions included medications other than esketamine, and (2) duplicate publications.

Data extraction and assessment of study quality

Data extraction was performed independently by two reviewers using a standardized data collection form. Discrepancies were resolved by consensus or, if necessary, by consultation with a third reviewer. When required, corresponding authors were contacted for clarification or additional information. The extracted data included author name, publication year, sample size, patient ASA status, age, type of surgery, esketamine dosing and administration details, placebo characteristics, and reported outcomes. Primary outcomes included postoperative sleep quality scores; secondary outcomes included adverse events, pain scores, and the number of patients requiring rescue analgesia.

Risk of bias assessment

The methodological quality of the included RCTs was independently assessed by two investigators using the Cochrane Risk of Bias 2.0 (RoB 2.0) tool [18]. Each study was evaluated across five domains: the randomization process, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of reported results. Each domain was classified as having low risk, some concerns, or high risk of bias. An overall risk of bias judgment was assigned to each study, and a cumulative assessment was provided for all included studies. Publication bias was assessed by visual inspection of funnel plots and statistically evaluated using Egger’s test [19].

Data synthesis and statistical analyses

Meta-analyses were conducted using Review Manager (RevMan) version 5.4.1 (The Cochrane Collaboration, London, UK). Continuous outcomes were expressed as mean differences (MDs) or standardized MDs (SMDs) with 95% confidence intervals (CIs), depending on whether the included studies used the same or different measurement scales. Dichotomous outcomes were summarized using odds ratios (ORs) with 95% CIs. A random-effects model was applied to account for variability among studies. Statistical heterogeneity was assessed using the I² statistic. Subgroup analyses and sensitivity analyses were conducted to explore potential sources of heterogeneity. If ten or more studies were included, publication bias was further evaluated using funnel plots and Egger’s test. Additional analyses were performed using Stata version 15.1 (StataCorp, College Station, TX, USA).

Results

A total of 283 studies were identified through database searches, with an additional 4 studies obtained from other sources. After removing duplicates, 234 unique records remained. Of these, 198 were excluded following title and abstract screening for failing to meet the inclusion criteria. The full texts of the remaining 36 articles were then assessed for eligibility. Nine studies were excluded due to their use of esketamine in different ways, 15 lacked relevant data, and 2 did not include a placebo control group. Ultimately, 10 RCTs [10, 14, 20–27] met the inclusion criteria and were included in the meta-analysis. These trials involved a total of 1,287 patients, comprising 700 participants in the esketamine group and 587 in the control group. The flow diagram of the study selection process is presented in Fig. 1. Detailed characteristics of the included studies are summarized in Table 1.

Fig. 1.

Flow diagram of literature selection

Table 1.

Characteristics of included studies

References	ASA	Surgery	Age (year)	Intervention measures		Sample size		Sleep quality scores
				E	C	E	C
Penglei Wang2023	I-II	Thyroidectomy	18–65	0.5 mg/kg IV  + 0.24 mg/kg/h IVVP	Placebo	30	30	a 4-point scale
MinZhu 2022	I-II	Modified Radical Mastectomy	32–72	E1:0.5 mg/kg IV  + 2 µg/kg/h IVVP	Placebo	E1:33 E2:33	33	NRS
				E2:0.5 mg/kg IV  + 4 µg/kg/h IVVP
RongZhou2023	I-III	Thoracoscopic surgery	18–65	0.5 mg/kg IV	Placebo	195	192	RCSQ
Di Qiu 2022	I-III	Gynecological Laparoscopy	18–65	0.3 mg/kg/h IVVP	Placebo	92	91	AIS; NRS
Xiaoyan Ma2024	I-II	Gastrointestinal tumor surgery	≥ 65	0.3 mg/kg IV + 0.3 mg/kg/h IVVP	Placebo	78	75	PSQI
Lei Sun 2023	I-III	laparoscopic radical resection for colorectal cancer	18–79	0.1 mg/kg IV + 0.1 mg/kg/h IVVP	Placebo	32	30	AIS
Tianzhuo Zhang 2023	I-II	Gynecological Abdominal Surgery Patients	18–65	0.2 mg/kg/h IVVP	Placebo	33	31	RCSQ
Yuanyi Luo2023	II-III	Thoracoscopic surgery	≥ 18	0.5 mg/kg IV  + 0.1 mg/kg/h IVVP	Placebo	47	47	RCSQ
Jianjun Yang 2024	I-II	Thoracic Surgery	18–70	E1:0.15 mg/kg/h IVVP E2:0.25 mg/kg/h IVVP	Placebo	E1:30 E2:29	23	NRS
Liyuan Ren 2024	I-II	laparoscopic renal surgery	18–65	E1:0.125 mg/kg/h IVVP E2:0.25 mg/kg/h IVVP	Placebo	E1:33 E2:35	35	NRS

E Esketamine group, C control group, IVVP intravenous pump infusion, IV intravenous injection

Quality assessment and risk of bias

The quality and risk of bias assessment for each included RCT are presented in Supplemental File 2. Three studies (Zhou Rong, 2023; Tianguo Zhang, 2023; Xiaoyan Ma, 2024) [22, 23, 25] were judged to have a high risk of bias due to substantial loss of outcome data. One study (Min Zhu, 2022) [21] provided insufficient information regarding allocation concealment, raising potential concerns about selection bias.

Postoperative sleep quality scores

All included trials reported sleep quality outcomes for POD 1 [10, 14, 20–27]. Three trials reported data for POD 2 [14, 25, 27], five extended reporting through POD 3 [10, 14, 22–24], and two reported sleep outcomes on POD 7 [23, 24]. Various assessment tools were used to measure sleep quality, including the Pittsburgh Sleep Quality Index, Richards–Campbell Sleep Questionnaire, Athens Insomnia Scale, Numerical Rating Scale (NRS), and a 4-point Likert scale (see Table 1 for details).

To enable synthesis of data across studies that used different measurement scales, outcomes were standardized. This approach involves expressing outcomes in units of standard deviation, making the results unitless and comparable across scales. Specifically, the MDs between intervention and control groups in each study was divided by the pooled standard deviation, resulting in SMDs suitable for meta-analysis [28].

Most of the sleep quality scales used in the studies were oriented such that higher scores reflected poorer sleep quality. However, several studies used scales where higher scores indicated better sleep [14, 21, 22, 25, 27]. To ensure consistency and comparability in the pooled analysis, we reoriented all scores so that higher values uniformly reflected worse sleep quality, following recommendations from the Cochrane Handbook [29].

Postoperative sleep quality on POD 1

Compared to placebo [10, 14, 20–27], intraoperative esketamine significantly reduced postoperative sleep quality scores on POD 1 (SMD =  − 0.52, 95% CI [− 0.69, − 0.34], P < 0.00001, I² = 61%) (Fig. 2). Due to the observed heterogeneity, a subgroup analysis was conducted based on intraoperative dosing and the mode of administration.

Fig. 2.

Forest plot of sleep quality scales on POD 1

In the subgroup receiving esketamine via intravenous infusion at a dose of 0.2–0.3 mg/kg/h (Fig. 2a), heterogeneity decreased substantially (SMD =  − 0.65, 95% CI [− 0.81, − 0.50], P < 0.00001, I² = 0%). In contrast, for the subgroup that received a lower dose (≤ 0.2 mg/kg/h IV infusion combined with a 0.1–0.5 mg/kg bolus), heterogeneity was higher (Fig. 2b), and the effect size was smaller (SMD =  − 0.61, 95% CI [− 1.11, − 0.11], P = 0.02, I² = 73%). Furthermore, when esketamine was administered intraoperatively at a dose of ≤ 0.2 mg/kg/h without a bolus injection, no statistically significant difference in sleep quality was observed on POD 1 (SMD =  − 0.31, 95% CI [− 0.70, 0.07], P = 0.11, I² = 42%) (Fig. 2c). In a trial where esketamine was administered as a one-time bolus of 0.5 mg/kg, the reduction in sleep score approached significance (SMD =  − 0.20, 95% CI [− 0.40, − 0.00], P = 0.05) (Fig. 2d).

The subgroup analysis suggests that the heterogeneity observed may be attributed to the studies involving low-dose esketamine. This finding indicates that the intraoperative use of low-dose esketamine may yield inconsistent effects on postoperative sleep quality. Sensitivity analysis, performed by sequentially omitting each study, demonstrated consistent results across iterations, suggesting the findings are robust; no studies were excluded during this process (Supplemental File 3a). Furthermore, Egger’s test indicated no evidence of publication bias (P = 0.449) (Supplemental File 3c).

Postoperative sleep quality on subsequent days

Three trials reported sleep quality outcomes on POD 2 [14, 25, 27]. Patients in the esketamine group demonstrated significantly better sleep quality than those in the placebo group (SMD =  − 0.60, 95% CI [− 1.16, − 0.03], P = 0.04, I² = 77%) (Fig. 3a).

Fig. 3.

Forest plot of postoperative sleep quality on POD 2, POD 3, and POD 7

Five trials assessed sleep quality on POD 3 [10, 14, 22–24], revealing that the esketamine group continued to experience superior sleep quality relative to the placebo group (SMD =  − 0.44, 95% CI [− 0.71, − 0.18], P = 0.001, I² = 76%) (Fig. 3b).

Two trials evaluated sleep quality on POD 7 [23, 24]. The results indicated a significant benefit in the esketamine group compared to placebo (SMD =  − 0.31, 95% CI [− 0.58, − 0.04], P = 0.03, I² = 0%) (Fig. 3c).

Postoperative resuscitation

Seven trials [10, 14, 20, 22, 24, 26, 27] reported the time from the end of surgery to tracheal catheter removal. No statistically significant difference was observed between the esketamine and placebo groups (MD = 0.93, 95% CI [− 0.99, 2.85], P = 0.34, I² = 64%) (Fig. 4a). Similarly, five trials [10, 14, 22, 26, 27] assessed the duration of stay in the Post-Anesthesia Care Unit (PACU), and again, no significant difference was found between groups (MD =  − 0.91, 95% CI [− 5.98, 4.16], P = 0.72, I² = 81%) (Fig. 4b).

Fig. 4.

Forest plot of postoperative resuscitation

Pain

Postoperative pain scores were reported in eight trials; four used the Visual Analog Scale [10, 14, 22, 25], and four used the NRS [20, 21, 24, 26]. Both scales range from 0 to 10, with higher scores indicating more severe pain. Therefore, the data from these two scales were analyzed together.

Three trials [21, 24, 25] did not differentiate between resting and movement-associated pain scores. At 24 h postoperatively, there was no statistically significant difference between the esketamine and placebo groups (MD =  − 0.35, 95% CI [− 0.79, 0.08], P = 0.11, I² = 75%) (Fig. 5a). Similarly, no significant difference was observed at 48 h (MD =  − 0.13, 95% CI [− 0.38, 0.11], P = 0.27, I² = 0%) (Fig. 5b).

Fig. 5.

Forest plot of meta-analysis of postoperative pain scores

Two trials [14, 22] reported postoperative pain scores at rest and during movement at 6 h after surgery. There were no significant differences between groups in pain scores at rest (MD =  − 0.04, 95% CI [− 0.38, 0.30], P = 0.82) (Fig. 5c) or during movement (MD =  − 0.02, 95% CI [− 0.26, 0.23], P = 0.90, I² = 0%) (Fig. 5d).

Four trials [10, 14, 22, 26] assessed pain scores at rest and during movement 24 h postoperatively. Again, no significant differences were found at rest (MD =  − 0.18, 95% CI [− 0.62, 0.25], P = 0.41, I² = 82%) (Fig. 5e) or during movement (MD =  − 0.22, 95% CI [− 0.60, 0.17], P = 0.27, I² = 78%) (Fig. 5f).

Two trials [10, 14] reported pain scores at rest and during movement 48 h postoperatively. No statistically significant differences were observed in pain scores at rest (MD =  − 0.13, 95% CI [− 0.42, 0.16], P = 0.38, I² = 59%) (Fig. 5g) or during movement (MD =  − 0.17, 95% CI [− 0.46, 0.12], P = 0.25, I² = 59%) (Fig. 5h).

Five trials [14, 20, 21, 25, 27] evaluated the need for postoperative remedial analgesics. Fewer patients in the esketamine group required rescue analgesia than in the placebo group (OR = 0.36, 95% CI [0.20, 0.65], P = 0.0008, I² = 0%) (Fig. 5i).

Adverse events

Five trials reported the occurrence of postoperative nightmares [10, 20, 21, 24, 26], and four trials reported the incidence of hallucinations [20, 24, 26, 27]. In the esketamine groups, four patients experienced nightmares, and two patients exhibited psychotic symptoms. These adverse events were not reported in the placebo groups. The meta-analysis found no statistically significant difference in the occurrence of nightmares between the esketamine and placebo groups (OR = 3.35, 95% CI [0.38, 29.96], P = 0.28, I² = 0%) (Fig. 6a). Similarly, no significant difference was observed in the incidence of hallucinations between the two groups (OR = 2.04, 95% CI [0.09, 44.20], P = 0.65) (Fig. 6b).

Fig. 6.

Forest plot of meta-analysis of adverse events

Two studies reported the incidence of postoperative nausea and vomiting (PONV) within 24 h after surgery [10, 26]. The meta-analysis showed no significant difference in the occurrence of PONV between the two groups at 24 h postoperatively (OR = 1.31, 95% CI [0.78, 2.22], P = 0.31, I² = 0%) (Fig. 6c).

Although the differences did not reach statistical significance (P = 0.05), the point estimates of ORs for nightmares (3.35), hallucinations (2.04), and PONV (1.31) all favored a higher risk in the esketamine group.

Discussion

This meta-analysis of published trials aimed to assess differences in postoperative sleep, pain, adverse reactions, and the consumption of remedial analgesics between patients treated intraoperatively with esketamine and those receiving placebo.

The evidence suggests that intraoperative esketamine improves postoperative sleep quality compared to placebo. However, these results should be interpreted cautiously due to the observed data heterogeneity. On POD 1, a subgroup analysis indicated that the heterogeneity may stem from studies using lower intraoperative esketamine pump doses (≤ 0.2 mg/kg/h) without a combined single intravenous dose. No differences in sleep quality between groups were found in this subgroup analysis. However, in the subgroup receiving an intraoperative esketamine infusion of 0.2–0.3 mg/kg/h, heterogeneity was minimal, and the SMD was − 0.61—lower than in other groups—suggesting that this dosage range may optimize postoperative sleep quality improvement.

In the week following surgery, the esketamine group consistently showed better sleep quality outcomes than the placebo group. We observed that the absolute value of the SMD exhibited a decreasing trend from POD 1 to POD 7, suggesting that the beneficial effect of esketamine on sleep quality diminishes over time. Unfortunately, most studies did not assess long-term sleep quality outcomes beyond this period, nor did they compare preoperative and postoperative sleep quality.

For the analysis and evaluation of sleep quality on the days following surgery, heterogeneity was also high, likely due to three factors. First, the age range of patients was broad, as the studies included patients aged 18 and older, and the response and metabolism of esketamine may vary across different age groups. Second, the patients underwent various types of surgeries, and the pain levels and psychological burdens could differ significantly between operations. Third, different sleep quality scales were used for assessment, contributing to inconsistencies in evaluation.

Intraoperative esketamine did not delay postoperative recovery. Ketamine is seldom used clinically due to its adverse effects, and thus it remains crucial to evaluate whether esketamine shares similar risks. Four patients in the esketamine group reported nightmares, while two experienced postoperative hallucinations—adverse events not documented in the placebo group. While these differences did not reach statistical significance, clinicians should remain vigilant regarding such potential complications. Future clinical applications of esketamine should monitor for potential adverse reactions.

Regarding postoperative pain, no significant differences were found between the two groups in pain scores, either at rest or during movement. However, the esketamine group had fewer patients requiring additional pain management than the placebo group. This finding is consistent with the known mechanism of action of esketamine, which can inhibit the activation of downstream signaling pathways and exert an analgesic effect by blocking NMDA receptors [7].

Several limitations may affect the generalizability of our findings. First, the scales used to assess postoperative sleep quality and pain scores were inconsistent. Due to the heterogeneity of these results, the combined effect should be interpreted with caution. Additionally, the number of studies and participants was relatively small, which may limit the power of the analysis and increase the risk of random errors [30]. Furthermore, due to insufficient available data, a more comprehensive aggregated analysis was not possible. Finally, since all included studies were conducted in China, the findings may be subject to regional bias. Esketamine was first approved in Europe in 1997, with most research focusing on its antidepressant effects, while its perioperative applications remained relatively understudied. In contrast, esketamine was only approved in China in 2019, resulting in limited clinical experience and evidence-based data. This knowledge gap likely spurred more clinical research on its use in China. Additionally, the growing emphasis on Enhanced Recovery After Surgery in the Chinese perioperative setting may have contributed to the increased number of studies investigating esketamine’s perioperative applications.

Therefore, further large-scale, high-quality RCTs across different regions and ethnic groups are needed to enhance our understanding. Future research should focus on the optimal use of esketamine, its dosing, and the monitoring of its adverse effects, as well as its impact on the quality of postoperative recovery and patient satisfaction. Moreover, long-term follow-up could clarify whether transient sleep benefits influence recovery trajectories.

Conclusion

Compared to placebo, intraoperative esketamine may improve postoperative sleep quality and reduce the need for supplemental analgesia. Although there were no significant differences in recovery time, PONV, nightmares, or hallucinations, esketamine showed a trend toward more adverse events. It is not yet possible to conclude whether this agent is suitable for clinical use in improving sleep targeting postoperative patients. Clinicians should closely monitor for potential side effects, and further research is necessary to confirm these findings.

Supplementary Information

Below is the link to the electronic supplementary material.

Authors' contributions

All authors contributed to the writing and preparation of the manuscript.

Funding

This research was funded by a grant from Chengdu Health Commission project (No. 2023393).

Declarations

Conflicts of interest

The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.