Abstract
BACKGROUND: Hysteroscopy is a minimally invasive procedure that can nonetheless elicit considerable pain, especially during cervical dilation. While fentanyl is widely used for analgesia, its application is limited by side effects such as respiratory depression. Esketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has emerged as a promising alternative due to its potent analgesic effects and safer profile. This study aimed to determine and compare the effective dose 90 (ED90) of these drugs for preventing physical movements and to evaluate their efficacy and safety. METHODS: This two-part, prospective, randomized, double-blind trial enrolled patients scheduled for hysteroscopy. In Part 1, the ED90 of intravenous fentanyl (0.25-2.00 μg/kg) and esketamine (0.15-0.50 mg/kg) was determined using a sequential allocation biased-coin design (SABCD). The SABCD was implemented independently for each drug, with a targeted enrollment of 60 participants per group; ultimately, 56 participants per group were included in this dose-finding phase. In Part 2, clinical outcomes and adverse events were compared in an additional set of 56 patients per group, all of whom received the predetermined ED90 of their assigned drug. RESULTS: The ED90 of fentanyl was 1.424 μg/kg (95% confidence interval [CI]: 1.322-1.618 μg/kg), compared to 0.423 mg/kg (95% CI: 0.368-0.569 mg/kg) for esketamine. The two groups exhibited comparable efficacy in physical movements inhibition and total propofol consumption. However, the esketamine group demonstrated a markedly improved safety and recovery profile. Specifically, patients receiving esketamine reported significantly less propofol injection pain (fentanyl group vs esketamine group, 25% vs 7.1%; relative risk [RR], 0.4; 95% CI: 0.2-0.8; P = 0.019), experienced significantly faster emergence from anesthesia (7.0 [5.0, 9.5] vs 6.0 [5.0, 8.0]; median difference [MD], -1.0; 95% CI: -2.0-0; P = 0.029), and maintained better hemodynamic stability. Crucially, the incidence of respiratory depression was significantly lower in the esketamine group (26.8% vs 3.6%; RR, 0.2; 95% CI: 0.06-0.6; P = 0.001). Furthermore, the esketamine group showed a significantly greater reduction in Hospital Anxiety and Depression Scale (HADS) scores at the one-month follow-up than the fentanyl group (4.0 [3.0, 4.0] vs 2.0 [1.0, 2.0]; MD, -2.0; 95% CI: -2.0--2.0; P < 0.001). CONCLUSION: At equipotent ED90 doses, esketamine provides analgesia equivalent to fentanyl during hysteroscopy, while conferring additional advantages, such as reduced injection pain, faster emergence, superior cardiorespiratory stability, and potential psychological benefits. REGISTRATION: Chinese Clinical Trial Registry ChiCTR2500106429.