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

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

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.

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.

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.