Table 2.
Clinical Evidence for Analgesic and Sleep-Related Outcomes of Peripartum Esketamine
| Clinical Setting or Outcome | Evidence Base | Studied Regimen | Outcome Role | Main Findings | Directness | Key Limitations | Reference |
|---|---|---|---|---|---|---|---|
| Intraoperative analgesia during cesarean delivery | Randomized and dose-finding studies | Intravenous esketamine approximately 0.15–0.5 mg/kg, alone or with dexmedetomidine; single-bolus or preventive-infusion strategies | Primary or prespecified analgesic/dose-finding outcomes | Several studies reported less visceral traction pain, lower early pain scores, or reduced analgesic requirements. | Direct obstetric evidence | Regimens and cointerventions differed; most studies were single-center and focused on short-term outcomes. | [33–36,38] |
| Post-cesarean pain and opioid consumption: pooled evidence | Systematic review and meta-analysis of randomized cesarean-delivery trials | Heterogeneous intravenous or epidural esketamine regimens | Pooled analgesic and opioid-consumption outcomes | Rest pain at 24 h was lower with esketamine (SMD −0.42, 95% CI −0.69 to −0.16; P<0.00001; I2=84%), as was movement-evoked pain at 24 h (SMD −0.68, 95% CI −1.29 to −0.07; P<0.00001; I2=92%). In contrast, pooled sufentanil consumption was not significantly reduced (SMD −0.03, 95% CI −0.21 to 0.14; P=0.71; I2=0%). | Direct obstetric evidence | High heterogeneity for pain outcomes; all included trials were conducted in China; regimens and follow-up varied. | [37] |
| PCIA: mixed surgical meta-analysis | Meta-analysis of adult surgical RCTs | Esketamine plus sufentanil versus sufentanil alone in postoperative PCIA | Pooled postoperative pain and safety outcomes | Pooled VAS scores were lower at several postoperative time points; however, the meta-analysis did not provide a pooled opioid-consumption outcome. | Partly direct/mixed surgical evidence | Included mixed surgical populations rather than an exclusively obstetric population; pooled findings therefore cannot be attributed directly to post-cesarean patients. | [40] |
| Post-cesarean PCIA | Obstetric randomized trials | Esketamine combined with sufentanil, tramadol, or dexmedetomidine-containing postoperative analgesic regimens | Analgesic, opioid-related, and/or mood outcomes; role varied across trials | Individual trials reported improved early pain control, fewer PCIA activations, or lower opioid exposure in selected regimens; opioid-related findings were not uniform across the broader evidence base. | Direct obstetric evidence | Considerable heterogeneity in background analgesics, esketamine dose, and PCIA settings; combination regimens make the independent contribution of esketamine difficult to isolate. | [41–45] |
| Intrathecal or epidural analgesia for cesarean delivery | Small RCT and pilot trial | Intrathecal S-ketamine with bupivacaine or epidural esketamine with morphine | Primary or prespecified analgesic outcomes | Prolonged analgesia or improved early pain control was reported. | Direct obstetric evidence | Small samples; older intrathecal evidence; insufficient neurological and long-term maternal or neonatal follow-up. | [46,47] |
| Epidural labor analgesia: dose exploration | Prospective dose-response and sequential ED90 studies | Epidural esketamine combined with low-concentration ropivacaine | Primary dose-finding outcome | Dose–response relationships and ED90 estimates were reported. | Direct obstetric evidence | Estimates are study-specific and should not be interpreted as standardized clinical dosing recommendations; comparative and neonatal follow-up were limited. | [48–50] |
| Epidural labor analgesia: active comparison | Randomized noninferiority study | Epidural esketamine or dexmedetomidine compared with fentanyl as ropivacaine adjuncts | Primary local-anesthetic-consumption/noninferiority outcome | Esketamine was noninferior to fentanyl with respect to ropivacaine consumption. | Direct obstetric evidence | The study did not establish superiority and was not designed to determine longer-term maternal, mood, or neonatal benefit. | [51] |
| Vaginal delivery: pain and depressive symptoms | Three-arm randomized study | Esketamine 0.5 mg/kg combined with labor analgesia | Prespecified pain and EPDS outcomes | No significant between-group improvement in EPDS or VAS outcomes was observed. | Direct obstetric evidence | Open-label design, low-risk cohort, low event rate, per-protocol analysis, and retrospective registration. | [52] |
| Subjective sleep after cesarean delivery | Randomized obstetric studies using sleep-quality scales | Esketamine plus dexmedetomidine in PCIA or perioperative esketamine within multidomain protocols | Predominantly secondary sleep outcomes | Some improvement in subjective postoperative sleep scores was reported alongside changes in pain, mood, anxiety, or inflammatory markers. | Direct obstetric evidence | Sleep was generally not the primary endpoint; subjective scales, concurrent changes in other outcomes, and cointerventions prevent attribution to a direct sleep-specific effect. | [43,80] |
| Sleep and depressive symptoms in high-risk parturients | Observational cohort | Multimodal analgesic protocol containing esketamine | Observational sleep and mood outcomes | Better subjective sleep and fewer depressive symptoms were associated with the multimodal protocol. | Direct but nonrandomized obstetric evidence | Confounding by indication and other components of the protocol; the independent effect of esketamine and any causal or mediation relationship cannot be established. | [85] |
| Objective sleep architecture | Clinical ketamine study and polysomnographic gynecological-surgery RCT | Ketamine or S-ketamine administered outside the postpartum setting | Sleep-related physiological outcomes | Increased early-night slow-wave activity or slow-wave-sleep proportion was reported; subjective improvement did not consistently parallel objective changes. | Indirect non-obstetric evidence | Different populations and clinical contexts; findings cannot establish an effect on postpartum sleep architecture. | [26,27] |
| Postoperative sleep disturbance outside obstetrics | Randomized gynecological-laparoscopy and induced-abortion studies | Single or intraoperative low-dose esketamine | Prespecified postoperative sleep outcomes | Reduced postoperative sleep disturbance was reported in non-postpartum gynecological populations. | Indirect perioperative evidence | Not postpartum populations; observed effects may reflect analgesia, sedation, or surgical recovery rather than a direct sleep-specific effect. | [86,87] |
Abbreviations: CI, confidence interval; ED90, dose effective in 90% of participants; EPDS, Edinburgh Postnatal Depression Scale; PCIA, patient-controlled intravenous analgesia; RCT, randomized controlled trial; SMD, standardized mean difference; VAS, visual analogue scale.