Effect of Esketamine on Postoperative Sleep in Postmenopausal Women

The prevalence of sleep disturbance among postmenopausal women has been reported to reach 51.6%. Epidemiological studies consistently show that the incidence of sleep disorders increases with age and menopausal transition. Compared with premenopausal women, postmenopausal women demonstrate reduced circadian rhythm stability and a higher prevalence of sleep disturbance. In this population, levels of melatonin, total sleep time, sleep latency, N3 stage sleep, and the circadian amplitude of alertness are all diminished. Sleep disturbance can adversely affect both the mental and physical health of women and significantly impair their social functioning. Poor sleep is associated with decreased cognitive performance and heightened emotional distress, contributing to diminished quality of life.

Circadian rhythms are endogenous physiological and behavioral cycles that oscillate over approximately 24 hours, governing critical processes such as sleep-wake cycles, hormonal fluctuations (e.g., cortisol and melatonin). These rhythms are regulated by the suprachiasmatic nucleus (SCN). Disruptions in circadian rhythms have been associated with sleep disturbances.

Esketamine is the S (+) enantiomer of ketamine and has a higher affinity for the NMDA receptor than the R-enantiomer. Previous studies have demonstrated that intraoperative administration of esketamine can improve postoperative sleep quality and reduce the incidence of postoperative sleep disturbances, through its antidepressant efficacy, anti-inflammatory properties, analgesic efficacy, neurocognitive and anxiolytic effects. However, few studies have investigated whether esketamine can regulate perioperative circadian rhythms and subsequently affect sleep, especially in postmenopausal women.

The objective of this multi-center, prospective, randomized controlled clinical trial is to investigate the effects of esketamine on postoperative sleep in postmenopausal women.

Study Overview

• Status: Not yet recruiting
• Conditions: Circadian Rhythm; Postoperative Sleep Disturbance
• Intervention / Treatment: Drug: Esketamine; Drug: Normal Saline

• Study Type: Interventional
• Enrollment (Estimated): 164
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Zhuan Zhang, MD; Phone Number: +86-15062791355; Email: zhangzhuancg@163.com

Study Locations

• China
  • Jiangsu
    • Jingjiang, Jiangsu, China, 214500
      • Jingjiang People's Hospital Affiliated to Yangzhou University, Yangzhou University
      • Contact: Xiang Pu, Master Degree; Phone Number: +86-18951150271
    • Yangzhou, Jiangsu, China, 225012
      • the Affiliated Hospital of Yangzhou University, Yangzhou University
      • Contact: Zhuan Zhang, MD; Phone Number: +86-15062791355; Email: zhangzhuancg@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. American Society of Anesthesiologists (ASA) physical status I-III.
2. Aged ≥ 45 years.
3. Women with natural menopause (aged ≥ 45 years and postmenopause for more than 12 months without surgical or medical intervention) .
4. Scheduled to undergo elective lower-limb fracture surgery with an expected duration of more than 60 min under general anesthesia.
5. Body Mass Index (BMI) between 18 and 28 kg/m².

Exclusion Criteria:

1. Presence of preoperative sleep-related disorders, such as obstructive sleep apnea or restless legs syndrome.
2. History of drug or alcohol abuse or dependence.
3. Known contraindications or allergies to esketamine or other anesthetic agents.
4. Use of psychotropic medications or sex hormones within the past 3 months.
5. Shift work or taking medications affecting melatonin.
6. Severe comorbid conditions, including but not limited to uncontrolled hypertension, coronary artery disease, cardiac insufficiency, pulmonary hypertension, intracranial hypertension or elevated intraocular pressure, hyperthyroidism, severe hepatic or renal dysfunction.
7. History of cerebral infarction, intracerebral hemorrhage, or residual central nervous system deficits.
8. Impairments of language, hearing, vision, or cognitive function that would prevent completion of questionnaires or cooperation with sleep monitoring.
9. Active oral pathologies.
10. Transfer to ICU postoperatively.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Esketamine Group (Group E)	Drug: Esketamine; Participants in Group E are administered esketamine with an infusion dose of 0.1 ml·kg-¹·h-¹ (0.2 mg·kg-¹·h-¹, diluted with 0.9% sodium chloride in a 2 mg/mL.
Placebo Comparator: Control Group (Group C)	Drug: Normal Saline; In Group C, 0.9% sodium chloride with a maintenance dose of 0.1 ml·kg-¹·h-¹ are administered intravenously.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The incidence of postoperative sleep disturbance (PSD) on postoperative day 1.	The primary outcome is the incidence of PSD, evaluated using the Numeric Rating Scale (NRS) and the Athens Insomnia Scale (AIS) on postoperative day 1. PSD is defined as an NRS score of 6 or higher or an AIS score of 6 or higher.	Postoperative day 1.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frontal electroencephalography	Electroencephalogram (EEG) data is collected using the ConView Anesthesia Depth Monitoring System (ConView YY-105, Zhejiang Puke Medical Technology Co., Ltd., China). The analysis includes the power spectrum of EEG energy across various frequency bands, the peak frequencies in the α-β band, and key electrocorticogram indices such as the left α-index (Aileft), right α-index (Airight), electromyographic index (EMG), and burst suppression ratio (BSR).	From entering the operating room to surgery ending.
Inflammatory markers	Inflammatory biomarkers including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and IL-10 are measured.	From preoperative day 1 to postoperative day 3.
Objective sleep parameters recorded by actigraphy	Objective sleep parameters are recorded using actigraphy.The parameters include total sleep time (TST), sleep onset latency (SOL), wake after sleep onset (WASO), proportion of WASO (WASO%), and sleep efficiency (SE%).	From preoperative night 1 to postoperative night 3.
Subjective sleep quality	The Pittsburgh Sleep Quality Index (PSQI) is assessed on the day before surgery and 30 days postoperatively. Self-rated sleep quality is evaluated using the NRS and the AIS on the day before surgery and on postoperative days 2 and 3.	From preoperative day 1 to postoperative day 30.
Anxiety and Depression assessments	Anxiety and depression are measured using the Hospital Anxiety and Depression Scale (HADS). It comprises two subscales: the Anxiety subscale (HADS-A) and the Depression subscale (HADS-D). For each item, respondents select the degree of severity, ranging from 0 to 3, representing none, mild, moderate, and severe. The total score for each subscale ranges from 0 to 21, with higher scores indicating more severe anxiety or depression symptoms. Scores of 0-7 are considered normal, 8-10 suggest the possibility of mild anxiety or depression, 11-14 indicate the possibility of moderate anxiety or depression, and 15-21 signify the possibility of severe anxiety or depression.	From preoperative day 1 to postoperative day 3.
Postoperative cognitive function and biomarkers	Delirium assessments is conducted twice daily on postoperative days 1, 2, and 3 with at least 6 hours interval between evaluations, using the Chinese version of the 3-Minute Diagnostic Confusion Assessment Method (3D-CAM). Brain-derived neurotrophic factor (BDNF) and S100-β are measured from blood samples collected on preoperative day 1, postoperative day 1 and postoperative day 3.	From preoperative day 1 to postoperative day 3.
Postoperative pain assessment	Pain levels, including both rest and exercise pain, are measured using the Visual Analogue Scale (VAS) at 24 hours, 48 hours, and 72 hours postoperatively. Data on the use of the Patient-Controlled Analgesia (PCIA) device, including trigger times for bolus doses within the first 24 hours post-surgery, the total number of bolus presses, and the use of the rescue analgesic flurbiprofen, are documented.	From postoperative day 1 to day 3.
Biological rhythm detection	Melatonin and cortisol rhythm profiles are analyzed using saliva samples every 6 h for 48 h: at 10:00 PM on the night of surgery; 4:00 AM, 10:00 AM, 4:00 PM, and 10:00 PM on postoperative day 1; and 4:00 AM and 10:00 AM on postoperative day 2. Expression of core circadian clock genes, serum melatonin and cortisol concentrations are assessed on preoperative day 1, postoperative day 1 and postoperative day 3.	From preoperative day 1 to postoperative day 3.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Possible adverse reactions		From esketamine infusion to postoperative day 3.
Quality of postoperative recovery	The QoR-15 score is used to assess the quality of recovery. The QoR-15 includes five dimensions: physical comfort, physical independence, emotional state, pain, and psychological support, with a total of 15 questions. Each question is scored from 0 to 10, with a higher score indicating better recovery quality.	From postoperative day 1 to day 3.
The length of hospital stay		From the date of hospital admission to the date of discharge.

Collaborators and Investigators

• Sponsor: Zhuan Zhang

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2026
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: December 4, 2025
• First Submitted That Met QC Criteria: December 31, 2025
• First Posted (Actual): January 2, 2026

Study Record Updates

• Last Update Posted (Actual): March 17, 2026
• Last Update Submitted That Met QC Criteria: March 13, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Melatonin; Circadian Rhythm; Postmenopause; Esketamine; Postoperative Sleep Disturbance
• Additional Relevant MeSH Terms: Pharmaceutical Preparations; Crystalloid Solutions; Isotonic Solutions; Solutions; Esketamine; Saline Solution
• Other Study ID Numbers: 20251115

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No