Dexmedetomidine-esketamine Combination and Moderate-to-severe Pain After Spinal Surgery

Effect of Perioperative Use of Dexmedetomidine-esketamine Combination on Incidence of Moderate-to-severe Pain After Spinal Surgery: a Randomized Controlled Trial

Spinal surgery is generally followed by severe postoperative pain, and poor pain control may cause adverse outcomes such as cardiovascular events, neurocognitive disorders, and chronic postsurgical pain (CPSP). In previous studies, perioperative use of dexmedetomidine or esketamine is each associated with improved analgesia after surgery. Recent studies suggest that combined use of dexmedetomidine and esketamine may produce synergetic effects in improving analgesia. This trial is designed to test the hypothesis that perioperative combined use of dexmedetomidine and esketamine may improve analgesia and reduce moderate-to-severe pain in patients after spinal surgery.

Study Overview

• Status: Not yet recruiting
• Conditions: Dexmedetomidine; Pain Intensity; Spinal Surgery; Postoperative Analgesia; Esketamine
• Intervention / Treatment: Drug: Combined dexmedetomidine-esketamine administration; Drug: Placebo administration

Detailed Description

Spinal surgery is genrally followed by severe pain due to extensive trauma. The reported rate of moderate-to-severe pain ranged from 30% to 63%. Uncontrolled postoperative pain is associated with worse outcomes including cardiovascular events, neurocognitive complications, and chronic postsurgical pain. Opioids are the main stay of analgesia after spinal surgery. However, high dose opioids provoke side effects such as nausea and vomiting, delirium, and even respiratory depression. Multimodel analgesia is suggested for these patients.

Dexmedetomidine is a highly selective alpha 2 adrenergic receptor agonist with sedative, analgesic, and anxiolytic effects. A meta-analysis suggest that, for patients undergoing spinal surgery, intraoperative dexmedetomidine improved early postoperative analgesia, but the effect did not persist beyond 6 hours. Ketamine is a noncompetitive N-Methyl-D-aspartic acid (NMDA) receptor antagonist and has been used as an anesthetic and analgesic for decades. Esketamine is the S-enantiomer of ketamine and has an analgesic potent of approximately 2 times of that of ketamine. Small sample size studies in patients undergoing spinal surgery showed that intra- or postoperative use of subanesthetic dose esketamine improved analgesia and reduced rescue analgesics.

The analgesic effects of dexmedetomidine and esketamine are dose-dependent. However, routine dose dexmedetomidine may increase bradycardia and hypotension, and even subanethetic dose esketamine may produce neuropsychiatric symptoms. Combined use of dexmedetomdine and esketamine may augment analgesic and sedative effects while decreasing side effects. In a previous study, using low-dose dexmedetomidine (1 ug/ml) and esketamine (0.25 mg/ml) as supplements to self-controlled sufentanil analgesia improved pain relief and sleep quality after spinal surgery, but the rate of moderate-to-severe pain remained high. In a recent study, when used as a supplement to sufentanil analgesia, increasing esketamine dose to 0.5 mg/ml did not significantly improve analgesia, whereas increasing esketamine dose to 0.75 mg/ml increased nausea and vomiting.

In available studies, use of dexmedetomidine and/or esketamine were mostly limited to either intra- or postoperative period. Introperative use of the combination only improve early postoperative analgesia. Whereas postoperative use of the combination did not have effects on peak intraoperative stress. It is reasonable to hypothesize that using dexmedetomidine-esketamine combination during both the intra- and postoperative periods may provide better analgesia in patients after spinal surgery.

• Study Type: Interventional
• Enrollment (Estimated): 274
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Huai-Jin Li, MD; Email: sophie.lee.coffee@gmail.com
• Study Contact Backup: Name: Dong-Xin Wang, MD, PhD; Phone Number: 01083572784; Email: wangdongxin@hotmail.com

Study Locations

• China
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100034
      • Peking University First Hospital
      • Contact: Huai-Jin Li, MD; Phone Number: 01083572784; Email: sophie.lee.coffee@gmail.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Aged >= 40 years but < 80 years;
2. Scheduled to undergo elective posterior cervical, thoracic, or lumbar spine surgery with an expected duration >= 2 hours under general anesthesia;
3. Required patient-controlled intravenous analgesia (PCIA) after surgery.

Exclusion Criteria:

1. Uncontrolled preoperative hypertension (ward systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg);
2. Severe bradycardia (heart rate <= 50 bpm), sick sinus syndrome, atrioventricular block of grade II or higher without pacemaker implantation, a history of myocardial infarction within one year, or presence of rapid ventricular arrhythmia;
3. History of schizophrenia, epilepsy, Parkinson's disease, or myasthenia gravis, or prresence of intracranial hypertension;
4. Uncontrolled hyperthyroidism or pheochromocytoma;
5. Inability to communicate due to coma, severe dementia, or language barrier;
6. Severe cardiac insufficiency (preoperative left ventricular ejection fraction < 30% or New York Heart Association Functional classification IV), severe hepatic dysfunction (Child-Pugh class C), severe renal dysfunction (preoperative dialysis), or American Society of Anesthesiologists physical status >= IV;
7. Other conditions that are considered unsuitable for study participation.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Combined dexmedetomidine-esketamine group; During anesthesia, a loading dose (0.2 ml/kg) of dexmedetomidine-esketamine (DEX-ESK) combination (DEX 2 ug/ml; ESK 1 mg/ml) will be infused after anesthesia induction (DEX 0.4 ug/kg; ESK 0.2 mg/kg), followed by a continuous infusion at 0.1 ml/kg/h (DEX 0.2 ug/kg/h; ESK 0.1 mg/kg/h) until 1 hour before the expected end of surgery. After surgery, patient-controlled intravenous analgesia will be established with dexmedetomidine (DEX 1.5 ug/ml), esketamine (ESK 0.5 mg/ml), and sufentanil (1.25 ug/ml), programmed to deliver 2-ml boluses (DEX 3.0 ug, ESK 1 mg, and sufentanil 2.5 ug) with a 8-10-minute lockout interval and a 1-ml/h (DEX 1.5 ug/h, ESK 0.5 mg/h, and sufentanil 1.25 ug/h) background infusion, and used for up to 48 hours.	Drug: Combined dexmedetomidine-esketamine administration; During anesthesia, a loading dose (0.2 ml/kg) of dexmedetomidine-esketamine (DEX-ESK) combination (DEX 2 ug/ml; ESK 1 mg/ml) will be infused after anesthesia induction (DEX 0.4 ug/kg; ESK 0.2 mg/kg), followed by a continuous infusion at 0.1 ml/kg/h (DEX 0.2 ug/kg/h; ESK 0.1 mg/kg/h) until 1 hour before the expected end of surgery. After surgery, patient-controlled intravenous analgesia will be established with dexmedetomidine (DEX 1.5 ug/ml), esketamine (ESK 0.5 mg/ml), and sufentanil (1.25 ug/ml), programmed to deliver 2-ml boluses (DEX 3.0 ug, ESK 1 mg, and sufentanil 2.5 ug) with a 8-10-minute lockout interval and a 1-ml/h (DEX 1.5 ug/h, ESK 0.5 mg/h, and sufentanil 1.25 ug/h) background infusion, and used for up to 48 hours.; Other Names: Dexmedetomidine and esketamine
Placebo Comparator: Placebo group; During anesthesia, a loading dose (0.2 ml/kg) of normal saline will be infused after anesthesia induction, followed by a continuous infusion at 0.1 ml/kg/h until 1 hour before the expected end of surgery. After surgery, patient-controlled intravenous analgesia will be established with sufentanil (1.25 ug/ml), programmed to deliver 2-ml boluses (sufentanil 2.5 ug) with a 8-10-minute lockout interval and a 1-ml/h (sufentanil 1.25 ug/h) background infusion, and used for up to 48 hours.	Drug: Placebo administration; During anesthesia, a loading dose (0.2 ml/kg) of normal saline will be infused after anesthesia induction, followed by a continuous infusion at 0.1 ml/kg/h until 1 hour before the expected end of surgery. After surgery, patient-controlled intravenous analgesia will be established with sufentanil (1.25 ug/ml), programmed to deliver 2-ml boluses (sufentanil 2.5 ug) with a 8-10-minute lockout interval and a 1-ml/h (sufentanil 1.25 ug/h) background infusion, and used for up to 48 hours.; Other Names: Placebo (normal saline)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of moderate-to-severe pain within 72 hours after surgery	Pain intensity will be assessed at 1 and 6 hours, and then twice daily (8:00-10:00, 18:00-20:00) until 72 hours after surgery, using the Numerical Rating Scale (NRS; an 11-point scale where 0=no pain and 10=the worst pain) both at rest and with movement (e.g., bed turning, walking). NRS pain scores 1-3 points indicate mild pain, 4-6 points indicate moderate pain, and 7-10 points indicate severe pain.	Up to 72 hours after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of delayed neurocognitive recovery at postoperative day 5	Cognitive function will be assessed with the Montreal Cognitive Assessment (MoCA; scores range from 0 to 30, with higher scores indicating better function) at baseline and on the 5th day or before hospital discharge after surgery. Delayed neurocognitive recovery is defined as a decline of MoCA score of >= 1 stndard deviation (SD) from baseline.	Up to 5 days after surgery
Incidence of cardiovascular events within 30 days after surgery	Cardiovascular events include myocardial injury after non-cardiac surgery (MINS; including myocardial infarction), non-fatal cardiac arrest, stroke, and all-cause mortality. The diagnosis of MINS will strictly follow the consensus of the American Heart Association (AHA).	Up to 30 days after surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of hospital stay after surgery	Length of hospital stay after surgery.	Up to 30 days after surgery
Area under curve of pain intensity within 72 hours postoperatively	Pain intensity will be assessed at 1 and 6 hours, and then twice daily (8:00-10:00, 18:00-20:00) until 72 hours after surgery, using the Numerical Rating Scale (NRS; an 11-point scale where 0=no pain and 10=the worst pain) both at rest and with movement (e.g., bed turning, walking).	Up to 72 hours after surgery
Consumption of sufentanil-equivalent dose within 72 hours postoperatively	Opioid consumption within 72 hours after surgery will be converted to a sufentanil-equivalent dose.	Up to 72 hours after surgery
Quality of recovery score at 24 and 72 hours postoperatively	Quality of recovery will be assessed at 24 and 72 hours after surgery, using the 15-item quality of recovery scale (QoR-15; scores range from 0 to 150 points, with higher scores indicating better recovery).	Up to 72 hours after surgery
Severity of depressive symptoms at postoperative day 5	Severity of depressive symptoms will be assessed on the 5th day or before hospital discharge after surgery, using the Patient Health Questionnaire-9 (PHQ-9; scores range from 0 to 27 with higher scores indicating more severe depressive symptoms).	Up to 5 days after surgery
Incidence of postoperative neurocognitive disorder at 30 days	Cognitive function will be assessed with the Telephone Montreal Cognitive Assessment (T-MoCA; scores range from 0 to 22, with higher scores indicating better function) at baseline and on the 30th day after surgery. Postoperative neurocognitive disorder is defined as a decline of T-MoCA score of >= 1 SD from baseline.	At 30 days after surgery
Incidence of postoperative complications within 30 days	Postoperative complications are defined as new-onset condition that are deemed harmful and required therateutic intervention, i.e., class II or higher on the Clavien-Dindo classification.	Up to 30 days after surgery
Subjective sleep quality during the first three postoperative nights	Subjective sleep quality will be assessed once daily (8:00-10:00) during the first 3 days after surgery, using the Numeric Rating Scale (NRS; scores range from 0 to 10 with 0=the best sleep quality and 10=the worst sleep quality).	Up to 72 hours after surgery

Collaborators and Investigators

• Sponsor: Peking University First Hospital
• Investigators: Principal Investigator: Dong-Xin Wang, Peking University First Hospital

Publications and helpful links

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Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: April 4, 2026
• First Submitted That Met QC Criteria: April 4, 2026
• First Posted (Actual): April 13, 2026

Study Record Updates

• Last Update Posted (Actual): April 14, 2026
• Last Update Submitted That Met QC Criteria: April 9, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Dexmedetomidine; Esketamine; Postoperative analgesia; Pain intensity; Spinal surgery
• Additional Relevant MeSH Terms: Neurologic Manifestations; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Pain; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pharmaceutical Preparations; Azoles; Imidazoles; Crystalloid Solutions; Isotonic Solutions; Solutions; Esketamine; Dexmedetomidine; Saline Solution
• Other Study ID Numbers: 2026-0136

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
• product manufactured in and exported from the U.S.: No