Different Dose Esketamine and Dexmedetomidine for Supplemental Analgesia and Longterm Outcomes

Sponsor

Peking University First Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06087510

Collaborator

(none)

312

Enrollment

Location

Arms

Anticipated Duration (Months)

8.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Chronic postsurgical pain (CPSP) refers to pain that occurs or increases after surgery and lasts longer than 3 months. Severe acute postoperative pain is one of the major risk factors of CPSP. Spinal correction surgery is associated with severe pain due to large trauma and long duration. Ketamine and esketamine are N-methyl-D-aspartate receptor antagonists; they have antihyperalgesic effects and may reduce CPSP. Dexmedetomidine is an alpha 2-adrenoceptor agonist with sedative, anxiolytic, and analgesic effect; it is frequently used as an adjuvant to postoperative analgesia. In a previous trial of 200 patients after scoliosis correction surgery, mini-dose esketamine-dexmedetomidine in combination with opioids significantly improved analgesia and sleep quality but did not reduce CPSP. The authors speculate that increasing esketamine dose in the combination may further improve analgesia and, therefore, reduce the occurrence of CPSP.

Condition or Disease	Intervention/Treatment	Phase
Scoliosis Correction Postoperative Analgesia Esketamine Dexmedetomidine Chronic Postsurgical Pain	Drug: Esketamine	Phase 4

Detailed Description

Chronic postsurgical pain (CPSP) refers to pain that occurs or increases after surgery and lasts longer than 3 months. Pain can be limited to the surgical area or projected to the innervated area. The incidence of CPSP is reported from 10% to 50%, with incidence of moderate-to-severe CPSP of about 11.8%. Risk factors of CPSP include severe acute postoperative pain, long duration surgery, and related nerve injury. Spinal correction surgery is associated with severe acute postoperative pain due to large trauma and long duration, with a median pain score of 7 (interquartile range, 4 to 8) on the first day after surgery. And the incidence of persistent pain is up to 75%.

Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists. Ketamine has anti-hyperalgesia effects and may reduce the occurrence of CPSP by blocking NMDA receptors. Esketamine is the S-enantiomer of racemic ketamine with stronger analgesic effect and less adverse reactions. In previous studies, opioid-dependent patients who received low-dose ketamine/esketamine infusion during the perioperative period had decreased pain scores and opioid requirement at 6 weeks, 6 months, and 1 year after surgery. However, results in patients without opioid dependence are controversial.

Dexmedetomidine is a highly selective α2 receptor agonist with sedative, anxiolytic, and analgesic effects. When used in the perioperative period, dexmedetomidine improves analgesia, reduces opioid consumption, and decreases opioid-related adverse reactions. Meanwhile, dexmedetomidine can prolong total sleep time, improve sleep efficiency, and increase subjective sleep quality, possibly by activating the endogenous sleep-promoting pathway. The sedative effect of dexmedetomidine may help to reduce the psychiatric adverse reactions of ketamine. However, data is lacking regarding the effect of dexmedetomidine on chronic postsurgical pain.

In a previous trial of 200 patients following scoliosis correction surgery, mini-dose esketamine-dexmedetomidine in combination with opioids significantly improved analgesia and sleep quality after surgery but did not reduce CPSP. The authors speculate that increasing esketamine dose in the combination may further improve analgesia and, therefore, reduce the occurrence of CPSP.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

312 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

Impact of Different Dose Esketamine and Dexmedetomidine Combination for Supplemental Analgesia on Long-term Outcomes After Scoliosis Correction Surgery: Follow-up of a Randomized Trial

Anticipated Study Start Date :

Jan 1, 2024

Anticipated Primary Completion Date :

Mar 1, 2026

Anticipated Study Completion Date :

Dec 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Low-dose group Patient-controlled analgesia is established with esketamine 50 mg, dexmedetomidine 200 microgram, and sufentanil 4 microgram/kg (maximum 250 microgram), diluted with normal saline to 200 ml, and programmed to administer 2-ml boluses with a lockout interval of 8 minutes and a background infusion rate at 1 ml/h.	Drug: Esketamine Different doses of esketamine in the esketamine-dexmedetomidine combination as a supplement to sufentanil for postoperative analgesia.
Experimental: medium-dose group Patient-controlled analgesia is established with esketamine 100 mg, dexmedetomidine 200 microgram, and sufentanil 4 microgram/kg (maximum 250 microgram), diluted with normal saline to 200 ml, and programmed to administer 2-ml boluses with a lockout interval of 8 minutes and a background infusion rate at 1 ml/h.	Drug: Esketamine Different doses of esketamine in the esketamine-dexmedetomidine combination as a supplement to sufentanil for postoperative analgesia.
Experimental: High-dose group Patient-controlled analgesia is established with esketamine 150 mg, dexmedetomidine 200 microgram, and sufentanil 4 microgram/kg (maximum 250 microgram), diluted with normal saline to 200 ml, and programmed to administer 2-ml boluses with a lockout interval of 8 minutes and a background infusion rate at 1 ml/h.	Drug: Esketamine Different doses of esketamine in the esketamine-dexmedetomidine combination as a supplement to sufentanil for postoperative analgesia.

Arm

Intervention/Treatment

Active Comparator: Low-dose group

Patient-controlled analgesia is established with esketamine 50 mg, dexmedetomidine 200 microgram, and sufentanil 4 microgram/kg (maximum 250 microgram), diluted with normal saline to 200 ml, and programmed to administer 2-ml boluses with a lockout interval of 8 minutes and a background infusion rate at 1 ml/h.

Drug: Esketamine

Different doses of esketamine in the esketamine-dexmedetomidine combination as a supplement to sufentanil for postoperative analgesia.

Experimental: medium-dose group

Patient-controlled analgesia is established with esketamine 100 mg, dexmedetomidine 200 microgram, and sufentanil 4 microgram/kg (maximum 250 microgram), diluted with normal saline to 200 ml, and programmed to administer 2-ml boluses with a lockout interval of 8 minutes and a background infusion rate at 1 ml/h.

Drug: Esketamine

Different doses of esketamine in the esketamine-dexmedetomidine combination as a supplement to sufentanil for postoperative analgesia.

Experimental: High-dose group

Patient-controlled analgesia is established with esketamine 150 mg, dexmedetomidine 200 microgram, and sufentanil 4 microgram/kg (maximum 250 microgram), diluted with normal saline to 200 ml, and programmed to administer 2-ml boluses with a lockout interval of 8 minutes and a background infusion rate at 1 ml/h.

Drug: Esketamine

Different doses of esketamine in the esketamine-dexmedetomidine combination as a supplement to sufentanil for postoperative analgesia.

Outcome Measures

Primary Outcome Measures

Incidence of chronic postsurgical pain at 3 months after surgery. [At 3 months after surgery.]
Chronic postsurgical pain (CPSP) is defined as pain persisted for at least three months after surgery, that is not present before surgery or that has different characteristics, and other possible causes of the pain are excluded (e.g., cancer recurrence, infection).

Secondary Outcome Measures

Incidence of chronic postsurgical pain at 6 or 12 months after surgery. [At 6 or 12 months after surgery.]
Chronic postsurgical pain (CPSP) is defined as pain persisted for at least three months after surgery, that is not present before surgery or that has different characteristics, and other possible causes of the pain are excluded (e.g., cancer recurrence, infection).
Severity of chronic pain at 3, 6, and 12 months after surgery. [At 3, 6, and 12 months after surgery.]
Severity of chronic pain is assessed with the Brief Pain Inventory (BPI). The BPI gives two main scores: a pain severity score and a pain interference score. The pain severity score is calculated from the four items about pain intensity. Each item is rated from 0, no pain, to 10, pain as bad as you can imagine, and contributes with the same weight to the final score, ranging from 0 to 40.
Proportion of chronic analgesic use after surgery. [At 3, 6, and 12 months after surgery.]
Chronic analgesic use is defined as consecutive use of analgesics for more than 3 months.
Subjective sleep quality at 3, 6, and 12 months after surgery. [At 3, 6, and 12 months after surgery.]
Subjective sleep quality is assessed with the Pittsburgh Sleep Quality Index (PSQI). The PSQI is a 7-item questionnaire consisting 19 self-rated questions that assesses sleep quality over the last month, each weighted equally on a 0-3 scale; higher scores indicate worse sleep quality.
Severity of depression at 3, 6, and 12 months after surgery. [At 3, 6, and 12 months after surgery.]
Depression is assessed with the Patient Health Questionnaire-9 (PHQ-9). The PHQ-9 includes 9-item requiring responses of 0 (not at all) to 3 (nearly every day) to assess the occurrence of depressive symptoms over the last two weeks. It has 8 items on depressive symptoms and 1 focused on suicidal ideation. Total scores range from 0 to 27, with higher score indicating more severe symptoms.
Quality of life at 3, 6, and 12 months after surgery. [At 3, 6, and 12 months after surgery.]
Quality of life is assessed using the Scoliosis Research Society-22 (SRS-22) patient questionnaire, which consists of five domains: function, pain, mental health, self-image, and satisfaction with management. Each domain has five questions except the last, which has two. The total score for each item ranges from 1 to 5, with 5 being the best. Each domain has a total sum score ranging from 5 to 25, except for the satisfaction domain, which ranges from 2 to 10. Results are expressed as the mean (total sum of the domain divided by the number of items answered) for each domain.
Event-free survival. [Up to 12 months after surgery.]
Event indicates any condition that requires hospitalization and clinical treatment for unexpected reasons.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients aged ≥18 years and body weight≥40 kg;
Scheduled to undergo scoliosis correction with pedicle screw fixation;
Required patient-controlled intravenous analgesia (PCIA) after surgery.

Exclusion Criteria:

Preoperative sick sinus syndrome, severe sinus bradycardia (heart rate <50 beats per minute), atrioventricular block grade II or above without pacemaker, congenital heart disease, arrhythmia, or other serious cardiovascular diseases with a New York Heart Association class ≥III;
Patients with moderate or severe obstructive sleep apnea diagnosed preoperatively or according to the STOP-Bang score;
History of hyperthyroidism or pheochromocytoma;
History of schizophrenia, epilepsy, myasthenia gravis;
Severe liver dysfunction (Child-Pugh grade C), severe renal dysfunction (preoperative dialysis), or American Society of Anaesthesiologists grade ≥IV;
Barrier in communication;
Other conditions that were considered unsuitable for study participation.