Mini-dose Esketamine-dexmedetomidine Supplemented Analgesia and Long-term Outcomes

Sponsor

Peking University First Hospital (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT05718544

Collaborator

(none)

199

Enrollment

Location

Arms

Anticipated Duration (Months)

9.9

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 postoperative acute pain is one of the major risk factors of CPSP. Spine surgery brings severe postoperative pain due to large trauma and long duration. Ketamine and esketamine are N-methyl-D-aspartate receptor antagonists; they have anti-hyperalgesic 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 the investigators, 200 patients following scoliosis correction surgery were randomzied to receive opioid analgsia supplemented with either mini-dose esketamine-dexmedetomidine combination or placebo. The results showed that esketamine-dexmedetomidine supplement analgesia significantly improved analgesia and sleep quality after surgery. This study is designed to test the hypothesis that mini-dose esketamine-dexmedetomidine supplemented analgesia may reduce CPSP at 2 years after scoliosis correction surgery.

Condition or Disease	Intervention/Treatment	Phase
Scoliosis Correction Postoperative Analgesia Esketamine Dexmedetomidine Chronic Postsurgical Pain	Drug: Esketamine Drug: Dexmedetomidine Drug: Sufentanil	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 about 10-50%, and the incidence of moderate to severe CPSP is as high as 11.8%. The risk factors of CPSP include severe postoperative acute pain, long duration surgery, and related nerve injury. Spine surgery brings severe lesion and postoperative pain due to large trauma and long duration, with a median pain score of 7 (interquaritle range, 4 to 8) on the first day after surgery. And the incidence of persistent pain is as high as 75%.

Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists. NMDA receptors are located in the brain and spinal cord of the central nervous system, responsible for the afferent of noxious stimuli. After nerve injury, the continuous activity and transmission of nociceptive signals up-regulates NMDA receptors in the dorsal horn of the spinal cord, amplify the pain signal to the brain, which may be related to the pathogenesis of CPSP. 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 lower incidence of 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 of patients without opioid dependence are controversial. In addition, ketamine/esketamine are approved for refractory depression. There is a significant correlation between anxiety/depression and chronic pain. This may also be one of the mechanisms in preventing CPSP.

Dexmedetomidine is a highly selective α2 receptor agonist with sedative, anxiolytic, and analgesic effects. It can improve analgesic effect, reduce opioid consumption, and reduce opioid-related adverse reactions when used in the perioperative period. Meanwhile, dexmedetomidine can prolong total sleep time, improve sleep efficiency, and increase subjective sleep quality, possibly by activating the endogenous sleep 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 the investigators, 200 patients following scoliosis correction surgery were randomzied to receive opioid analgsia supplemented with either mini-dose esketamine-dexmedetomidine combination or placebo. The results showed that esketamine-dexmedetomidine supplement analgesia significantly reduced the incidence of moderate and severe pain and improved the quality of sleep during the perioperative period; adverse reactions were not significantly increased (unpublished data). This study is designed to test the hypothesis that mini-dose esketamine-dexmedetomidine supplemented analgesia may reduce CPSP at 2 years after scoliosis correction surgery.

Study Design

Study Type:

Interventional

Actual Enrollment :

199 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

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

Primary Purpose:

Prevention

Official Title:

Effect of Mini-dose Esketamine-dexmedetomidine Supplemented Analgesia on Long-term Outcomes Following Scoliosis Correction Surgery: 2-year Follow-up of a Randomized Controlled Trial

Actual Study Start Date :

Jan 30, 2023

Anticipated Primary Completion Date :

Sep 1, 2024

Anticipated Study Completion Date :

Oct 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Combined supplement 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 Esketamine 50 mg is included in the mixture for patient-controlled analgesia. Drug: Dexmedetomidine Dexmedetomidine 200 microgram is included in the mixture for patient-controlled analgesia. Drug: Sufentanil Sufentanil 4 microgram/kg (maximum 250 microgram) is included in the mixture for patient-controlled analgesia.
Placebo Comparator: Placebo Patient-controlled analgesia is established with sufentanil 4 microgram/kg (maximum 250 microgram), diluted with normal saline to 200 ml, and programmed to administer 2-ml boluses with a lock-out interval of 8 minutes and a background infusion rate at 1 ml/h.	Drug: Sufentanil Sufentanil 4 microgram/kg (maximum 250 microgram) is included in the mixture for patient-controlled analgesia.

Arm

Intervention/Treatment

Experimental: Combined supplement

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

Esketamine 50 mg is included in the mixture for patient-controlled analgesia.

Drug: Dexmedetomidine

Dexmedetomidine 200 microgram is included in the mixture for patient-controlled analgesia.

Drug: Sufentanil

Sufentanil 4 microgram/kg (maximum 250 microgram) is included in the mixture for patient-controlled analgesia.

Placebo Comparator: Placebo

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

Drug: Sufentanil

Sufentanil 4 microgram/kg (maximum 250 microgram) is included in the mixture for patient-controlled analgesia.

Outcome Measures

Primary Outcome Measures

Incidence of chronic postsurgical pain at 2 years after surgery [At 2 years 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

Severity of chronic pain at 2 years after surgery [At 2 years 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.
Interference of chronic pain at 2 years after surgery [At 2 years after surgery]
Interference 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 interference score corresponds to the item on pain interference. The seven subitems are rated from 0, does not interfere, to 10, completely interferes, and contributes with the same weight to the final score, ranging from 0 to 70.
Proportion of chronic analgesic use after surgery [Up to 2 years after surgery]
Chronic analgesic use is defined as consecutive use of analgesics for more than 3 months.
Proportion of analgesic use at 2 years after surgery [At 2 years after surgery]
Proportion of analgesic use at 2 years after surgery (consecutive use of analgesics for more than 1 week within 3 months).
Subjective sleep quality at 2 years after surgery [At 2 years after surgery]
Subjective sleep quality at 2 years is assessed with the Pittsburgh Sleep Quality Index (PSQI). 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.
Depression severity at 2 years after surgery [At 2 years 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 2 years after surgery [At 2 years 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.
Event-free survival [Up to 2 years 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;
Scheduled for scoliosis correction surgery;
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;
Obstructive sleep apnea syndrome, or a STOP-Bang score ≥3 in combination with a serum bicarbonate level ≥28 mmol/L;
Comorbid hyperthyroidism or pheochromocytoma;
History of schizophrenia, epilepsy, myasthenia gravis;
Preoperative delirium or communication barrier;
Severe liver dysfunction (Child-Pugh grade C), severe renal dysfunction (preoperative dialysis), or American Society of Anaesthesiologists grade ≥IV;
Body weight <40 kg;
Enrolled in other clinical studies;
Loss to follow-up;
Other conditions that were considered unsuitable for study participation.