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β-Adrenergic blockade is an important mechanism for reducing morbidity and mortality in patients with hypertension and heart failure. Esmolol has been used widely for its chronotropic and antihypertensive effects. However, there has been recent inquiry regarding perioperative esmolol use and nociceptive modulation. Conventional postoperative analgesic treatment has relied primarily on opioids, which present their own adverse effects and pharmacoepidemiologic repercussions. Esmolol, to date, has not shown any direct analgesic or anesthetic properties; however, recent studies suggest that esmolol may have antinociceptive and postoperative opioid-sparing effects. In this Daring Discourse narrative, we describe the role of esmolol in current perioperative β-blockade guidelines (related to noncardiac surgery), briefly describe studies supporting the antinociceptive effects of esmolol, propose mechanisms for esmolol antinociception, and forecast potential routine esmolol use intraoperatively (as part of a multimodal total intravenous anesthetic) and its effects on opioid sparing. The reading audience of regional anesthesiologists and acute pain medicine physicians is uniquely positioned to take a lead role in promulgating this care advance amid (i) the unwanted effects of the opioid epidemic and (ii) the uncertain notion of whether routine general anesthesia care (with fentanyl) may indirectly be contributing to the epidemic.