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.

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.