What can we learn from esmolol about the need to treat “pain” during general anesthesia?

Hemodynamic elevations can be managed with and without opioids leading to differences in postoperative pain scores and opioid consumption

Under general anesthesia, when we cannot ask a patient if they are experiencing pain, we are left to treat sympathetic responses, such as tachycardia and hypertension, with the assumption that these represent pain. When we refer to these disturbances as pain, we may be priming clinicians to intervene with pain medications. Heart rate and blood pressure need to be managed within appropriate ranges, but does this management need to be done with analgesics such as opioids?

To argue that one does or does not need to treat pain while under general anesthesia may be an argument over the definition of pain. If pain is subjective, maybe we should stop referring to objective measurements of heart rate and blood pressure as pain. Instead, let’s refer to them as they are—tachycardia and hypertension—and manage them with cardiovascular-specific agents.¹ As you will see below, using a non-analgesic medication instead of an opioid can actually lead to less postoperative pain.

I think the important question to ask is this: does using opioids, non-opioid analgesics, or non-analgesic medications (such as sympatholytics) offer the best postoperative pain control when used to treat elevated sympathetic responses? The opioid-sparing effects of esmolol can help us shed light on this topic.

Esmolol’s opioid-sparing effects

Higher intraoperative opioid doses lead to increased postoperative pain and postoperative opioid consumption. For this reason, minimizing intraoperative opioid use can lead to better patient outcomes.²

Multiple trials and meta-analyses have demonstrated esmolol’s opioid-sparing effects. A meta-analysis from 2018 showed that intraoperative esmolol infusions decreased intraoperative opioid use (standardized mean difference [SMD] -1.60; 95% confidence interval [CI] -2.25 to -0.96; p < 0.001) and reduced postoperative opioid use (SMD -1.21; 95% CI -1.66 to -0.77; p < 0.001). A SMD of ≥ 0.8 is considered a large effect. A more recent meta-analysis from 2025 showed that intraoperative esmolol infusions reduced intraoperative opioid use by 32% (mean difference of -12.89 IV morphine milligram equivalents [MME]; 95% CI -24.74 to -1.05; p < 0.001) and reduced postoperative opioid use by 38.6% (mean difference -3.03 IV MME; 95% CI -4.29 to -1.76; p < 0.001).

Does esmolol have analgesic properties?

The best data we have in humans suggest esmolol does not have analgesic properties. Researchers set out to test this using the cold pressor test in a randomized, placebo-controlled crossover study. Fourteen healthy, conscious volunteers each underwent three separate trials consisting of either a normal saline infusion (the control), an esmolol infusion (10 mcg/kg/min following a 0.7 mg/kg bolus), or a remifentanil infusion (0.2 mcg/kg/min following a normal saline bolus). The primary outcome was maximum perceived pain as measured by the numeric pain rating scale (NRS-max).

The mean NRS-max was similar in the esmolol and placebo groups (8.5, SD 1.4 vs. 8.4, SD 1.3; p = 0.83). When compared to placebo, the remifentanil infusion had a lower mean NRS-max of 5.4 (SD 2.1; p < 0.001). These data suggest that esmolol does not have analgesic properties. Instead, the opioid-sparing effects of esmolol are thought to be due to decreased total intraoperative opioid use, leading to less opioid-induced hyperalgesia and tolerance.

Do we need to treat pain under general anesthesia?

If patients experience better outcomes when managing hemodynamic extremes, commonly referred to as pain, without analgesics (or while minimizing analgesics), perhaps we should be more specific with our terminology. Instead of referring to pain during general anesthesia, we could talk about sympathetic responses such as tachycardia and hypertension. These perturbations can be managed effectively with multiple drug classes. Maybe this simple terminology change will push more people to use esmolol and other sympatholytic agents to minimize opioid use, leading to lower postoperative opioid requirements.

1. Of course, tachycardia and hypertension can be indicators of pain. But if we assume that our anesthetic agents prevent the brain from experiencing pain, are opioid analgesics necessary if sympathetic responses and adequate surgical conditions can be achieved without them?

2. I routinely use esmolol, rather than fentanyl, for induction of general anesthesia and intubation.