Determining the effective dose of esketamine for mitigating pain during propofol injection by Dixon’s up-and-down method: a double-blind, prospective clinical study of drug dose response
Authors: Tan Meiyun , Zhang Chunyuan , Zeng Wei , Chen Maofang , Huang Zehui , Huang Ding 
Published: December 2022

Abstract
Background
Propofol is an intravenous (IV) anesthetic medication widely used for procedural sedation, operative anesthesia, and in intensive care unit (ICU), but the incidence of pain during IV infusion can reach 28–90%. Ketamine can attenuate pain associated with IV propofol injection through local and central analgesic effects. Ketamine is gradually being transitioned to its S-enantiomer, esketamine, which has a similar mechanism of action. The purpose of our study is to determine the half effective dose (ED50), 95% effective dose (ED95), and 99% effective dose (ED99) of esketamine for attenuating propofol injection pain using Dixon’s up-and-down method to provide a reference for optimal dose selection for surgeries and procedures.

Methods
Thirty gynecological patients undergoing hysteroscopic surgery were enrolled in a sequential method to determine the effective dose of esticketamine for analgesic propofol injection in order of operation. This study was based on the sequential allocation up-and-down rule designed by Dixon, and each patient was induced by esticketamine combined with propofol. During induction, the target dose of esketamine was first given via venous access in the left hand of the patient, and 30 s later, a fixed dose of 2 mg/kg (1 ml/s) of propofol was given. Patient perception of pain was scored with the verbal rating scale (VRS) every 5 s after the start of the propofol infusion, and the evaluation was stopped once the patient became unresponsive. The dosage of esketamine was increased or decreased up or down according to the patient’s pain response. The initial dose of esketamine was 0.2 mg/kg, and the gradient of adjacent dose was 0.02 mg/kg. If the pain response assessment of the upper patient was positive (+), the dose of esselketamine in the next patient was increased by 0.02 mg/kg; if the pain response assessment of the upper patient was negative (−), the dose of esselketamine in the next patient was decreased by 0.02 mg/kg. The tests were carried out sequentially, with the pain response changing from positive to negative or from negative to positive, and the tests were stopped after at least 6 crossover points, and the effective dose of esticketamine was calculated using probit probability regression analysis.

Results
The ineffective group comprised patients with a positive pain response and the effective group comprised patients with a negative pain response. The 95% CI was set as the confidence interval of effective dose ED value，and we found esketamine’s ED50 = 0.143 mg/kg (0.120, 0.162 mg/kg), ED95 = 0.176 mg/kg (0.159, 0.320 mg/kg), and ED99 = 0.189 mg/kg (0.167, 0.394 mg/kg). The esketamine dose and VRS score during propofol injection were significantly different between the two groups (P < 0.05), whereas surgical duration, emergence time, visual analogue scale (VAS) score of postoperative uterine contraction pain, and Riker sedation/anxiety scale (SAS) score were not significantly different. Bradycardia occurred in only one patient during anesthesia induction, while hemodynamics was stable in the rest of the patients without obvious adverse reactions.

Conclusion
Small doses of esketamine combined with propofol can be safely and effectively used for hysteroscopic surgery. We recommended a dose of 0.2 mg/kg IV esketamine before induction of anesthesia to reduce the pain of propofol injection.

Trial registration
Chinese Clinical Trial Registry ChiCTR2100048951. Date of registration: July 19, 2021.