Dexmedetomidine-esketamine Combination and Chronic Postsurgical Pain After Spinal Surgery

Effect of Perioperative Use of Dexmedetomidine-esketamine Combination on Incidence of Chronic Postsurgical 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 reduce CPSP in patients after spinal surgery.

Spinal surgery is generally 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 (CPSP). 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 hypotnsion, 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 and decrease CPSP in patients after spinal surgery.

Inclusion Criteria:

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

Exclusion Criteria:

1. Severe uncontrolled hypertension preoperatively (baseline ward blood pressure: SBP > 180 mmHg or DBP > 110 mmHg);
2. Severe bradycardia (heart rate <= 50 bpm), sick sinus syndrome, atrioventricular block of grade II or higher without pacemaker implantation, or a history of myocardial infarction within one year, severe heart failure (NYHA class >= III), or rapid ventricular arrhythmia;
3. Preoperative history of schizophrenia, epilepsy, Parkinson's disease, myasthenia gravis, or intracranial hypertension;
4. Preoperative history of hyperthyroidism or pheochromocytoma;
5. Inability to communicate preoperatively due to coma, severe dementia, or language impairment;
6. Severe cardiac insufficiency (preoperative LVEF < 30% or NYHA class IV), severe hepatic dysfunction (Child-Pugh class C), severe renal dysfunction (preoperative dialysis), or ASA physical status >= grade IV;
7. Other conditions deemed inappropriate for study participation by the investigator or attending physician.