Objective Previous studies have confirmed the opioid-sparing and analgesic properties of perioperative esmolol, yet relevant clinical evidence specifically focusing on patients with ischemic heart disease (IHD) remains scarce, and the spinal nociceptive mechanism underlying esmolol-induced pain relief has not been fully elucidated. This study aimed to investigate the association between perioperative esmolol administration and early postoperative opioid demand in IHD patients undergoing elective non-cardiac surgery, and further explore the role of spinal 5-hydroxytryptamine (5-HT)/5-HT2B signaling in incisional pain using a female rat plantar incision model. Methods For the clinical retrospective cohort, eligible IHD patients were divided into esmolol-exposed and non-exposed groups balanced via 1:1 propensity score matching. The primary outcome was cumulative 24-h postoperative opioid consumption converted to intravenous morphine equivalents (IME); secondary endpoints included early Numeric Rating Scale (NRS) pain scores, opioid-related adverse events and perioperative cardiovascular safety indicators. In animal experiments, intrathecal esmolol or selective 5-HT2B antagonist RS127445 was delivered to the female rats with plantar incision, followed by detection of mechanical withdrawal thresholds and spinal 5-HT/5-HT2B expression. Results After matching, 52 patients were included in each group. Perioperative esmolol was associated with a 3.0 mg reduction in 24 h IME (mean difference [MD] = −3.0, 95% CI [−4.9, −1.1], P = 0.002), alongside lower post-anesthesia care unit (PACU) opioid consumption (MD = −2.3, 95% CI [−4.2, − 0.3], P = 0.022) and decreased resting NRS scores in PACU (MD = −0.8, 95% CI [−1.3, −0.2], P = 0.006) and at postoperative 6 h (MD = −0.6, 95% CI [−1.1, −0.02], P = 0.043); no intergroup difference in NRS was observed at 24 h (P = 0.379). All opioid-related adverse events showed comparable incidence between groups (all P > 0.05). Intraoperative heart rate was significantly lower in the esmolol group (MD = −4.4 beats/min, 95% CI [−7.8, −1.0], P = 0.012), while intraoperative mean arterial pressure (MAP) and major cardiovascular complications exhibited no between-group differences (all P > 0.05). In rats, the results revealed transiently elevated paw withdrawal mechanical thresholds after intrathecal esmolol (P < 0.05 at 5 and 10 min), accompanied by suppressed surgery-induced upregulation of spinal 5-HT and 5-HT2B protein (P < 0.05). Intrathecal RS127445 also significantly alleviated mechanical hypersensitivity at 1 h post-administration (P < 0.01), with loss of efficacy at 2 h (P > 0.05). Conclusions Perioperative esmolol is associated with early opioid-sparing and mild relief of acute postoperative pain in IHD patients receiving elective non-cardiac surgery, without increasing cardiovascular risks, whereas this regimen fails to reduce opioid-associated side effects. Preclinical data suggest that spinal 5-HT/5-HT2B signaling contributes to incision-induced mechanical hyperalgesia and may mediate the transient analgesic effect of esmolol.

Perioperative Esmolol Is Associated with Early Opioid Sparing in Patients with Ischemic Heart Disease: Evidence from a Retrospective Cohort and an Incisional Pain Rat Model

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发表日期：

2026年7月23日

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Yue-yang Xin,
Ning Yang,
Hao Chen,
Gao-feng Zhan,
Hui Xu

摘要

Objective

Previous studies have confirmed the opioid-sparing and analgesic properties of perioperative esmolol, yet relevant clinical evidence specifically focusing on patients with ischemic heart disease (IHD) remains scarce, and the spinal nociceptive mechanism underlying esmolol-induced pain relief has not been fully elucidated. This study aimed to investigate the association between perioperative esmolol administration and early postoperative opioid demand in IHD patients undergoing elective non-cardiac surgery, and further explore the role of spinal 5-hydroxytryptamine (5-HT)/5-HT_2B signaling in incisional pain using a female rat plantar incision model.

Methods

For the clinical retrospective cohort, eligible IHD patients were divided into esmolol-exposed and non-exposed groups balanced via 1:1 propensity score matching. The primary outcome was cumulative 24-h postoperative opioid consumption converted to intravenous morphine equivalents (IME); secondary endpoints included early Numeric Rating Scale (NRS) pain scores, opioid-related adverse events and perioperative cardiovascular safety indicators. In animal experiments, intrathecal esmolol or selective 5-HT_2B antagonist RS127445 was delivered to the female rats with plantar incision, followed by detection of mechanical withdrawal thresholds and spinal 5-HT/5-HT_2B expression.

Results

After matching, 52 patients were included in each group. Perioperative esmolol was associated with a 3.0 mg reduction in 24 h IME (mean difference [MD] = −3.0, 95% CI [−4.9, −1.1], P = 0.002), alongside lower post-anesthesia care unit (PACU) opioid consumption (MD = −2.3, 95% CI [−4.2, − 0.3], P = 0.022) and decreased resting NRS scores in PACU (MD = −0.8, 95% CI [−1.3, −0.2], P = 0.006) and at postoperative 6 h (MD = −0.6, 95% CI [−1.1, −0.02], P = 0.043); no intergroup difference in NRS was observed at 24 h (P = 0.379). All opioid-related adverse events showed comparable incidence between groups (all P > 0.05). Intraoperative heart rate was significantly lower in the esmolol group (MD = −4.4 beats/min, 95% CI [−7.8, −1.0], P = 0.012), while intraoperative mean arterial pressure (MAP) and major cardiovascular complications exhibited no between-group differences (all P > 0.05). In rats, the results revealed transiently elevated paw withdrawal mechanical thresholds after intrathecal esmolol (P < 0.05 at 5 and 10 min), accompanied by suppressed surgery-induced upregulation of spinal 5-HT and 5-HT_2B protein (P < 0.05). Intrathecal RS127445 also significantly alleviated mechanical hypersensitivity at 1 h post-administration (P < 0.01), with loss of efficacy at 2 h (P > 0.05).

Conclusions

Perioperative esmolol is associated with early opioid-sparing and mild relief of acute postoperative pain in IHD patients receiving elective non-cardiac surgery, without increasing cardiovascular risks, whereas this regimen fails to reduce opioid-associated side effects. Preclinical data suggest that spinal 5-HT/5-HT_2B signaling contributes to incision-induced mechanical hyperalgesia and may mediate the transient analgesic effect of esmolol.