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Intraoperative Esmolol as an Adjunct for Perioperative Opioid and Postoperative Pain Reduction: A Systematic Review, Meta-analysis, and Meta-regression

Gelineau, Amanda M. MD*; King, Michael R. MD; Ladha, Karim S. MD, MSc; Burns, Sara M. MS*; Houle, Timothy PhD*; Anderson, T. Anthony MD, PhD*

doi: 10.1213/ANE.0000000000002469
Chronic Pain Medicine
Free
SDC

BACKGROUND: Esmolol is an ultrashort β-1 receptor antagonist. Recent studies suggest a role for esmolol in pain response modulation. The authors performed a meta-analysis to determine if the intraoperative use of esmolol reduces opioid consumption or pain scores.

METHODS: PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, pubget, and Google Scholar were searched. Studies were included if they were randomized, placebo- or opioid-controlled trials written in English, and performed on patients 18 years of age or older. For comparison of opioid use, included studies tracked opioid consumption intraoperatively and/or in the postanesthesia care unit. Pain score comparisons were performed during the first hour after surgery.

RESULTS: Seventy-three studies were identified, 23 were included in the systematic review, and 19 were eligible for 1 or more comparisons. In 433 patients from 7 trials, intraoperative esmolol decreased intraoperative opioid consumption (Standard Mean Difference [SMD], −1.60; 95% confidence interval [CI], −2.25 to −0.96; P ≤ .001). In 659 patients from 12 trials, intraoperative esmolol decreased postanesthesia care unit opioid consumption (SMD, −1.21; 95% CI, −1.66 to −0.77; P ≤ .001). In 688 patients from 11 trials, there was insufficient evidence of change in postoperative 1 hour pain scores (SMD, −0.60; 95% CI, −1.44 to 0.24; P = .163).

CONCLUSIONS: This meta-analysis demonstrates that intraoperative esmolol use reduces both intraoperative and postoperative opioid consumption, with no change in postoperative pain scores.

From the *Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts

Department of Pediatric Anesthesiology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University, Chicago, Illinois

Department of Anesthesia, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.

Published ahead of print October 11, 2017.

Accepted for publication August 3, 2017.

Funding: Support was provided solely from institutional and/or departmental sources of the Massachusetts General Hospital Department of Anesthesia, Critical Care and Pain Medicine, Boston, MA.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to T. Anthony Anderson, MD, PhD, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, 300 Pasteur Dr, H3590A MC5640, Stanford, CA 94305. Address e-mail to tanders0@stanford.edu.

Esmolol is an ultrashort β-1 receptor antagonist. Its current approved indications include control of ventricular rate in supraventricular tachycardias such as atrial fibrillation and atrial flutter, the reduction of heart rate (HR) in noncompensatory sinus tachycardia, and the perioperative management of tachycardia and hypertension.1–4

While traditionally not known to possess anesthetic or analgesic properties,5 recent studies suggest that esmolol may modulate the perioperative pain response6 and reduce anesthetic requirements.7 Multiple single-center randomized controlled studies over the past 15 years have investigated the antinociceptive effects of an intraoperative esmolol infusion. A 2015 meta-analysis on the effect of β-adrenergic antagonists on postoperative pain included just 10 esmolol trials and determined that β-adrenergic antagonists may decrease postoperative pain and analgesic use.8 A meta-analysis on the perioperative effect of esmolol alone on pain and opioid consumption has not been previously published, and a number of randomized controlled trials assessing the efficacy of esmolol have been published since the prior, limited analysis.

Perioperative analgesia typically includes a combination of opioid and nonopioid pharmacologic agents. However, opioids have a large number of concerning side effects9,10 and the reduction of their use perioperatively enhances recovery and decreases morbidity in adults.11,12 Thus, methods to reduce perioperative opioid use are relevant to the practice of anesthesia.

We conducted a systematic review, meta-analysis, and meta-regression evaluating the effect of intraoperative esmolol on intraoperative opioid consumption, postoperative opioid consumption, and postoperative pain.

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METHODS

This study is a systematic review, meta-analysis, and meta-regression of existing, publicly available literature. It did not involve the collection of new human or animal data and is exempt from institutional review board assessment. The systematic review was conducted using recommendations of the Cochrane Handbook for Systematic Reviews of Interventions.13

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Data Source and Search

The PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, pubget, and Google Scholar databases were searched from inception until March 2, 2016 using the following search strings: (1) “esmolol” AND “acute pain,” (2) “esmolol” AND “postoperative pain,” and (3) “esmolol” AND “pain.” The references of studies identified by the database searches and those listed as “related” by the search engine were investigated to identify further pertinent studies. The search results were screened for inclusion.

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Eligibility Criteria

Inclusion criteria were defined as follows: (1) randomized, (2) placebo, opioid, or local anesthetic controlled, (3) written in English, (4) intervention group received an intraoperative esmolol infusion, and (5) reported postoperative opioid dose, postoperative pain scores, or intraoperative opioid dose. Studies that reported only hemodynamic changes, depth of anesthesia comparisons, or intraoperative anesthetic requirements were excluded. Unpublished abstracts and reports were excluded. Trial authors were not contacted for original data.

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Study Selection

Two authors (A.M.G. and T.A.A.) independently assessed retrieved study titles and abstracts for eligibility. Any differences were settled through discussion until consensus was reached.

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Data Extraction

Information about study design, number of patients enrolled and analyzed, type of anesthesia and surgery, dose and route of administration of the study drug, choice of control intervention, intraoperative hemodynamic effects, and postprocedure outcomes regarding pain and nausea and vomiting was extracted by a single investigator (A.M.G.) and checked by another author (T.A.A.). If values were reported graphically, the computer program Plot Digitizer (available at: http://plotdigitizer.sourceforge.net/) was used to estimate mean and standard deviations.

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Risk of Bias Assessment

The risk of bias was independently assessed with the Cochrane Collaboration’s tool for assessing risk of bias14 in randomized trials by 2 authors independently (M.R.K. and T.A.A.). Each included trial was appraised for the following: (1) random sequence generation (selection bias), (2) allocation concealment (selection bias), (3) blinding of participants and personnel (performance bias), (4) blinding of outcome assessment (detection bias), (5) incomplete outcomes data (attrition bias), (6) selective reporting (reporting bias), and (7) other bias. Any differences were settled through discussion. The risk of bias for each item was rated as “low,” “unclear,” or “high” within each trial. The overall risk of bias (the “Final” score) was determined to be “low risk of bias” if all the risk of bias were appraised as “low risk” across all domains, “unclear risk of bias” if a single domain was given an “unclear risk” score, and “high risk of bias” if a single domain was given a “high risk” score.

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Analyses

Given diverse protocols in the included studies, we first performed a systematic review analyzing postoperative pain outcomes, postoperative nausea and vomiting (PONV), and intraoperative hemodynamic changes. We then examined the results in search of outcomes that could be quantitatively compared among studies. Outcomes most commonly reported among studies were the opioid dose used in the postanesthesia care unit (PACU) and visual analogue scale (VAS) pain ratings in the first hour after surgery. While opioid dose used in PACU and VAS pain ratings were defined as a priori outcomes of interest, intraoperative opioid dose was added as an outcome of interest in a post hoc analysis. These outcomes were analyzed utilizing random-effects meta-analyses with inverse variance weighting. Simple meta-regressions were performed in an attempt to account for data heterogeneity.

Based on an a priori protocol, we included all studies in the meta-analyses that reported a standardized outcome measure of interest. For the meta-regressions, variables of interest were aggregated and dichotomized based on clinically meaningful cut points. The following variables were assessed: surgery type (open/moderate–severe pain versus laparoscopic/mild pain), surgery duration (≤60 vs >60 minutes), study location (North America/Europe versus Asia), study size (<60 vs ≥60 participants), study year (≤2010 vs >2010), and average participant age (≤40 vs >40 years).

For the postoperative opioid dose meta-analysis, the primary outcome of interest was morphine equivalents (mg) used in the PACU. For the postoperative pain score meta-analysis, the primary outcome was VAS pain rating (0–10) in the first hour after surgery. For the intraoperative opioid dose meta-analysis, the primary outcome of interest was morphine equivalents (mg) used intraoperatively. Three separate univariate meta-analyses were completed using means and standard deviations from the majority of the studies. As determined a priori, because of expected heterogeneity across studies, all pooled analyses were based on random-effects models. Means and standard deviations were approximated from the median and interquartile range of the remaining studies, assuming a normal distribution (none for intraoperative opioid dose, 2 for postoperative opioid dose, and 2 for postoperative VAS scores). The Breslow-Day test was used to assess heterogeneity, and I2 values >25% were considered to have substantial inconsistency.15 Studies were stratified by the type of control used (crystalloid versus opioid) to isolate this source of variation. Meta-regression was used to assess the effects of surgery type, study year, study location, patient age, study size, intraoperative opioid type in those studies with an opioid control arm, and duration of surgery on the amount of morphine equivalents administered as well as the VAS pain rating. All analyses were performed using R Studio statistical software, version 3.2.5 (RStudio, Boston, MA, www.rstudio.com).16

For the purposes of this review, the term “significant” is used when data reached statistical significance as defined as P < .05.

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RESULTS

Study Selection

Figure 1.

Figure 1.

Two hundred fifty-four potentially relevant publications were retrieved and screened. Seventy-three randomized controlled trials were reviewed in detail. Fifty were subsequently excluded as they did not quantify intraoperative opioid use, did not evaluate esmolol’s effect on postoperative pain or opioid use, or the randomized controlled trial design description was incomplete. Ultimately, data from 23 randomized controlled trials examining the effects of intraoperative esmolol and reporting intraoperative opioid use, postoperative pain score, and/or postoperative analgesic consumption were analyzed (Figure 1).

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Risk of Bias Within Studies

All studies included are randomized and controlled. The risk of bias assessment using the Cochrane tool is summarized in Supplemental Digital Content 1 (Figure 1, http://links.lww.com/AA/C10). Of 23 studies, 2 had a low risk of bias, 13 had an unclear risk of bias, and 8 had a high risk of bias. Additionally, funnel plots did not demonstrate obvious bias for any of the meta-analyses (plots not shown).

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Characteristics of Individual Studies

Table 1.

Table 1.

A total of 1339 patients from 23 studies were included; 670 received esmolol.17–39 The number of subjects in the studies ranged from 30 to 97. Subjects within the studies underwent laparoscopic gynecologic procedures (6 trials),21,27,33,37–39 laparoscopic cholecystectomy (7),20,22,29,30,32,34,35 orthopedic procedures (3),23,26,36 hernia repair (2),24,28 septorhinoplasty (2),18,25 “lower abdominal procedures” not further described (1),17 total abdominal hysterectomy (1),19 and laparoscopic appendectomy (1).31 Individual study findings are described in Table 1.

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Opioid Dosing

Placebo-Controlled Studies.

Fifteen studies were placebo controlled; in 14, a crystalloid bolus and infusion were given to the control group.17–19,22,23,26,27,30,31,33–35,37,39 In 1 study, the control group received a remifentanil bolus (10 µg) followed by a crystalloid infusion.29 Opioids were given to patients in both arms of all placebo-controlled studies, including remifentanil infusions (5),18,27,30,31,33 an alfentanil infusion (1),34 and fixed boluses of fentanyl during general anesthesia maintenance (2).17,37 In 3 studies, the study drug infusion rate was fixed, and remifentanil was titrated in both arms to keep hemodynamics within a predetermined range.18,27,31 In 2 studies, the remifentanil was given via effect-site concentration target-controlled infusions.30,33 In 1 study, esmolol was titrated to keep HR within a predetermined range, and alfentanil was titrated in both arms to keep mean arterial pressure within 20% of baseline.34 Opioid boluses were given on general anesthesia induction in both arms of 9 studies, fentanyl (dose ranging from 1 to 3 µg·kg1) in 8 studies17,19,22,23,26,35,37,39 and alfentanil in 1 study (10 µg·kg−1).34 In both arms of 4 studies, fentanyl boluses were given as needed during surgery for HR >20% above baseline or mean arterial pressure >20% above baseline ± somatic or autonomic changes.19,22,23,29 An additional fentanyl bolus (1.5 µg·kg−1, up to 100 µg) was given in both arms at the end of surgery in 1 study.30

Three studies had third arms, data from which are not included in this systematic review and meta-analysis (lidocaine, ketamine, and esmolol/nicardipine).29,30,39

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Local Anesthesia Infiltration-Controlled Study.

In 1 study, the control group received preincisional wound infiltration with ropivacaine.28 Both arms received a fentanyl bolus on induction of general anesthesia (1 µg·kg−1).

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Opioid-Controlled Studies.

Seven studies were opioid controlled.20,21,24,25,32,36,38 In 1 study, a remifentanil infusion was used in both study arms.25 In the esmolol arm, remifentanil and propofol were titrated to keep the depth of anesthesia within a predetermined depth of anesthesia range, and esmolol was titrated to keep the mean arterial pressure within a predetermined range.25 In the control arm, remifentanil and propofol were titrated to keep the mean arterial pressure and depth of anesthesia within predetermined ranges. In 4 studies, the opioid control was a remifentanil bolus and infusion.20,21,32,38 In one of these studies, a third arm received a fentanyl bolus followed by scheduled fentanyl boluses20; for statistical validity, data from only the remifentanil and esmolol arms were included in the data analysis. In the 4 remifentanil-controlled studies, remifentanil and esmolol infusions were titrated to keep the HR and/or blood pressure (BP) (MAP or systolic BP) within 15%–25% of baseline. In one of these studies, the control group also received a ketamine bolus at anesthetic induction.32 In another opioid-controlled study, the control group received a fentanyl bolus (1 µg·kg−1) on induction and an additional 50 µg every 30 minutes during surgery and anesthesia24; the fentanyl boluses and esmolol infusion were adjusted to maintain HR within 20% of baseline. In the final opioid-controlled study, the control group received an alfentanil bolus and infusion36; esmolol and alfentanil infusions were titrated to maintain a HR within 15% of baseline.

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Esmolol Dosing Regimens

In all studies, intravenous esmolol was given as a bolus followed by an infusion for the duration of surgery. One study included an additional bolus equivalent to the loading dose before extubation.31 The loading dose varied from 1.0 µg·kg−1 to 2 mg·kg−1. The loading dose was 1.0 µg·kg−1 in 1 study,24 0.5 mg·kg−1 in 11 studies,17–19,22,25–28,30,32,33 1 mg·kg−1 in 9 studies,20,21,23,29,31,34,35,37,38 2 mg·kg−1 in 1 study,36 and 50 mg in 1 study.39 Infusion rates varied from 5 to 500 µg·kg−1·minute−1. The infusion rate was 5 µg·kg−1·minute−1 in 2 studies,26,39 5–10 µg·kg−1·minute−1 in 2 studies,34,35 10 µg·kg−1·minute−1 in 2 studies,30,31 5–15 µg·kg−1·minute−1 in 5 studies,20,21,24,28,32 15 µg·kg−1·minute−1 in 1 study,23 20 µg·kg−1·minute−1 in 1 study,38 30 µg·kg−1·minute−1 in 3 studies,27,33,37 50 µg·kg−1·minute−1 in 4 studies,18,19,22,29 titrated from 100 to 300 µg·kg−1·minute−1 in 1 study,25 and 500 µg·kg−1·minute−1 in 1 study.17 One study started an infusion of 100 µg·kg−1·minute−1 after a preinduction bolus and then decreased the infusion rate to 25 µg·kg−1·minute−1·after intubation.36

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Esmolol Versus Crystalloid or Local Infiltration

Quantitative or Qualitative Pain Rating.

Nine of the 15 esmolol versus crystalloid studies,17–19,22,23,26,29–31 and the esmolol versus ropivacaine wound infiltration study,28 reported VAS scores (Table 2). One of these reported both VAS and verbal rating scale scores.18 Three studies reported numerical rating scale scores.27,33,37 Three studies did not report pain scores.34,35,39 There was heterogeneity with respect to when and for how long after surgery pain scores were checked, ranging from immediately on admission to the PACU until 72 hours postoperatively. Five studies reported time to first analgesic requirement.18,22,26,28,37 Six studies reported the number requiring rescue analgesic.18,27,33–35,39 Rescue analgesics included fentanyl,27,33,39 morphine,18 tramadol,35 and either diclofenac or tramadol, although which of these was given was not reported.34 Ten studies reported the cumulative dose of opioid required until PACU or hospital discharge.17–19,23,26,27,29,30,33,37 Three studies reported the cumulative dose of naproxen,18 diclofenac and ketorolac,30 and diclofenac.31

Table 2.

Table 2.

A majority of the 12 studies evaluating pain scores within the first hour after surgery reported significantly lower pain scores in the esmolol group during most of those times.17,18,22,23,26–31,33,37 Of the 9 studies that recorded pain scores after the first hour postoperatively, 3 showed decreased pain scores at some or all time points,26,28,31 1 showed decreased pain until 6 hours postoperatively,29 and 3 showed no difference between the groups at any point after the first hour postoperatively.18,19,30 Two studies reported lower pain scores in the esmolol group for 24 hours postoperatively; however, P values were not reported except at time 0 hour in one of the 2 studies.22,23 The single study measuring VAS at rest and with movement from 2 to 72 hours postoperatively showed no difference in pain at any time point.19

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Number Requiring Rescue Analgesic.

Of the 6 studies reporting the number requiring rescue analgesic, 5 reported a significantly smaller percentage of patients in the esmolol group compared with the control group,18,33–35,39 and 1 study reported no differences between groups.27

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Cumulative Analgesic Dose.

Of the 10 studies reporting the cumulative dose of opioid postoperatively up to various time points, 9 reported a lower total opioid requirement in the esmolol group.17–19,23,26,27,29,33,37 One study reported a lower mean fentanyl dose in the first hour after surgery in the esmolol group, but no difference in the median tramadol in the first 6 hours postoperatively.30 Two studies reported a lower total opioid consumption in the esmolol group out to 24 hours postoperatively.23,29 There was heterogeneity between studies with regard to when the cumulative dose was calculated ranging from 1 hour to 3 days postoperatively, with a majority recording opioid used until PACU discharge. Of the 3 studies reporting the cumulative dose of nonsteroidal anti-inflammatory given postoperatively at different time points, 1 reported a lower cumulative dose in the esmolol group31 and 2 reported no difference between groups.18,30

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Esmolol Versus Opioid

Quantitative or Qualitative Pain Rating.

Four of the 7 esmolol versus opioid studies reported VAS scores (Table 3).24,25,36,38 One study reported VAS both at rest and with movement.38 One study reported VRS scores,20 1 reported verbal numeric rating scale scores,32 1 reported pain on a 4-point scale from “no pain” to “severe pain,”21 and 1 reported the time to VAS ≥4.25 Again, there was heterogeneity with respect to when and for how long after surgery pain scores were checked, ranging from immediately on admission to the PACU until 24 hours after discharge. Three studies reported the number requiring rescue analgesic (fentanyl,21 morphine,32 and unidentified “opioid”36). Five studies reported the cumulative dose of opioid required until PACU or hospital discharge.20,21,24,32,38 One study reported the cumulative doses of acetaminophen and naproxen.20

Table 3.

Table 3.

Results from 4 studies show no difference in postoperative pain scores between the esmolol and opioid control groups.20,21,24,38 In another study, the esmolol group had significantly lower pain scores at 1 and 2 hours postoperatively, though no difference was found at <1 hour or at >2 hours.32 In 1 study, the pain scores between the 2 groups were similar at all time points checked within the first hour except 1, when the control group had a lower pain score.36 One study reported the time to a VAS score ≥4 in the PACU; the time was significantly greater in the esmolol than in the opioid control (48 vs 17 minutes).25

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Number Requiring Rescue Analgesic.

Of the 3 studies reporting the number of subjects requiring rescue analgesic, 1 reported a significantly smaller percentage of patients in the esmolol group requiring rescue analgesic,32 1 reported no difference between groups,21 and 1 favored the control group.36

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Cumulative Analgesic Dose.

Five studies reported the cumulative dose of opioid postoperatively up to various time points.20,21,24,32,38 Three studies that recorded opioid consumption in the PACU reported a lower requirement in the esmolol group20,24,32; 1 study found no difference.38 One study found no difference in the total opioid consumption between groups out to 24 hours postoperatively.21 One study recorded total opioid, acetaminophen, and nonsteroidal anti-inflammatory drug consumption on the first postoperative day and found no difference between groups.20

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Meta-analysis of Intraoperative Opioid Use.

Figure 2.

Figure 2.

We performed a meta-analysis using all studies from the systematic review where opioid dose was titrated to predetermined hemodynamic goals intraoperatively in both the control and esmolol groups (n = 7). Data from 433 patients in 7 studies were included for the intraoperative opioid dose meta-analysis (table not shown). Patients randomly assigned to esmolol were administered less morphine equivalents than patients in the control groups intraoperatively (standard mean difference [SMD], −1.60; 95% confidence interval [CI], −2.25 to −0.96; P ≤ .001) (Figure 2). Evidence for this effect size is supported by the fact that in 4 studies from the systematic review, no opioid was used in the esmolol arms intraoperatively. As significant heterogeneity in intraoperative dosing (I2 = 87.9%) was observed across the included studies, we stratified by the intraoperative opioid used (remifentanil/ultrashort acting versus nonremifentanil/short acting) to accommodate the high level of variability. In the stratified meta-analysis for intraoperative drug dose, heterogeneity remained high among the 4 studies using remifentanil (I2 = 92.8%), but there was low heterogeneity among the 3 studies using nonremifentanil (I2 = 0.0%). In studies in which remifentanil was utilized intraoperatively, patients randomly assigned to esmolol were administered less morphine equivalents than patients in the control groups intraoperatively (SMD, −2.33; 95% CI, −3.62 to −1.03; P ≤ .001). In studies in which a nonremifentanil opioid (fentanyl or alfentanil) was utilized intraoperatively, patients randomized to esmolol were administered less morphine equivalents than patients in the control groups intraoperatively (SMD, −0.96; 95% CI, −1.24 to −0.68; P ≤ .001) (Supplemental Digital Content 2, Figure 2, http://links.lww.com/AA/C11).

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Meta-analysis of Postoperative Pain Outcomes.

We performed 2 meta-analyses using all studies from the systematic review that had a uniform measure of PACU opioid dose (n = 12) or VAS pain rating (n = 11). Data from 659 patients in 12 studies were included for the opioid dose meta-analysis; 688 patients from 11 studies were included for the VAS pain rating meta-analysis. Patients randomized to esmolol were administered less morphine equivalents than patients in the control groups while in the PACU (SMD, −1.21; 95% CI, −1.66 to −0.77; P ≤ .001) (Figure 3A). Patients randomized to esmolol had VAS pain ratings lower than patients in the control groups (SMD, −0.60; 95% CI, −1.44 to 0.24; P = .163) in the first hour after surgery, although these results are not statistically significant (Figure 3B).

Figure 3.

Figure 3.

Significant heterogeneity in postoperative opioid dose (I2 = 85.2%) and pain scores (I2 = 95.9%) was observed across studies. This resulted in stratification by control type and meta-regression to accommodate the high level of variability. In the stratified meta-analysis for drug dose, heterogeneity remained high among the crystalloid controls (I2 = 72.2%) and among the opioid controls (I2 = 93.7%). Patients randomized to esmolol were administered less morphine equivalents than patients in the crystalloid control groups while in the PACU (SMD, −1.23; 95% CI, −1.63 to −0.83; P ≤ .001). Patients randomized to esmolol were administered less morphine equivalents than patients in the opioid control groups while in the PACU (SMD, −1.18; 95% CI, −2.35 to −0.01; P = .048) (Supplemental Digital Content 3, Figure 3, http://links.lww.com/AA/C12). In the stratified meta-analysis for pain scores, heterogeneity also remained high among the crystalloid controls (I2 = 89.9%) and among the opioid controls (I2 = 97.2%). Patients randomized to esmolol had VAS pain scores lower than patients in the crystalloid control groups at 1 hour after surgery (SMD, −1.25; 95% CI, −1.89 to −0.62; P ≤ .001). Patients randomized to esmolol had pain scores higher than patients in the opioid control groups at 1 hour after surgery (SMD, 1.23; 95% CI, −0.68 to 3.15; P = .207), although this result is not statistically significant (Supplemental Digital Content 4, Figure 4, http://links.lww.com/AA/C13).

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Heterogeneity and Meta-regression.

Meta-regression analyses were performed in an attempt to explain the heterogeneity present in the data. Meta-regression for opioid dose showed that surgery type (P = .531), study geographic location (P = .859), surgery duration (P = .119), and study size (P = .347) did not have statistically significant impacts on morphine equivalent administration in the PACU. Subjects in studies with a mean participant age of ≤40 years received less morphine equivalents than subjects in studies with a mean participating age >40 years (SMD, −0.96; 95% CI, 1.78 to −0.14; P = .022). Subjects in studies published after 2010 received more morphine equivalents than subjects in studies published during or before 2010 (SMD, 0.95; 95% CI, 0.05–1.89; P = .049). Meta-regression for pain scores showed that surgery type (P = .195), surgery duration (P = .924), study geographic location (P = .086), study size (P = .804), study year (P = .310), and age (P = .433) did not have statistically significant impacts on VAS scores.

To further examine heterogeneity, meta-regression analyses were performed on studies that had opioid controls for the PACU opioid dose outcome (n = 6) and VAS pain scores (n = 4). The type of opioid control (remifentanil versus fentanyl or alfentanil) did not have a statistically significant impact on either opioid dose or VAS pain scores (data not shown).

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Analysis of Intraoperative HR and BP

Fifteen studies quantitatively compared and reported changes in intraoperative HR and/or BP between the esmolol and control groups.17–19,21–23,25,28–31,35–39 Five studies noted no significant difference in the HR between groups.21,28–30,39 Four studies noted significant changes in the HR within the esmolol group only at some time points intraoperatively; in 3 studies, the HR was lower compared to control at those time points,17,25,31 and in 1 study, it was higher.18 Four studies noted a lower HR in the esmolol group at most or all of the time points measured intraoperatively; the control group received a crystalloid solution in all 4 studies.19,23,35,37 Two studies noted a higher HR in the esmolol group at most or all of the time points measured intraoperatively; the control group received an opioid in both studies.36,38

Eight studies noted no significant difference in the mean BP between groups.18,19,28–30,35,36,39 Three studies noted significant changes in the BP within the esmolol group only at some time points intraoperatively; the BP was lower compared to control at those time points.17,25,31 Two studies noted a lower BP in the esmolol group at most or all of the time points measured intraoperatively; the control group received a crystalloid solution in both studies.23,37 Two studies noted a higher BP in the esmolol group at most or all the time points measured intraoperatively; the control group received an opioid in both studies.21,38 No studies reported an increased incidence of clinically significant episodes of bradycardia or hypotension in the esmolol group.

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Analysis of PONV Outcomes

Evaluation of PONV also varied between studies (Supplemental Digital Content 5, Table 1, http://links.lww.com/AA/C14). Five studies reported the incidence of PONV.20,25,27,32,33 Eleven reported the incidence of nausea,18–21,24,28,29,31,34,36,38 7 of which separately reported the incidence of vomiting.18–21,28,29,34 Four studies evaluated the severity of nausea, with 2 studies reporting ranges from none to severe31,34 and 2 using a VAS scale.36,38 Nine studies reported the need for rescue antiemetic.20,21,24,27,31,33,34,36,39 Two of these also evaluated the total dose of antiemetic required.20,34

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Incidence of PONV.

Of the 5 studies reporting PONV, there was no difference between groups in any of the studies.20,25,27,32,33 Of the 11 studies reporting nausea, there was less nausea in the esmolol group in 5 of the studies.20,21,24,31,34 There was no difference in nausea in 5 of the studies.18,19,28,29,36 In 1 study, although only presented graphically, while there did not appear to be a difference in nausea between study groups in the PACU and on discharge, there may have been a higher incidence of nausea on postoperative day one in the esmolol group.38 There was no difference in vomiting in any of the 7 studies evaluating this outcome.20,25,27,32,33

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Antiemetic Requirement.

Six of the 9 studies reporting the incidence of need for rescue antiemetic showed no difference between groups,21,27,31,33,36,39 while 3 studies reported decreased need in the esmolol group.20,24,34 Both of the 2 studies reporting cumulative antiemetic dose favored the esmolol group.20,34

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DISCUSSION

In this systematic review, meta-analysis, and meta-regression of 23 randomized controlled trials including 670 patients who received an intraoperative esmolol infusion, we assessed the effects of intraoperative esmolol on intraoperative opioid use and postoperative pain scores and opioid consumption. Intraoperative esmolol (1) decreases intraoperative opioid use compared to both remifentanil and nonremifentanil opioid controls, (2) decreases immediate postoperative pain scores compared to a crystalloid control, (3) results in equivalent immediate postoperative pain scores compared to an opioid control, (4) decreases PACU opioid consumption compared to a crystalloid control, and (5) decreases PACU opioid consumption compared to an opioid control. The effect size of intraoperative esmolol use on the reduction of postoperative opioid consumption is similar, or greater in magnitude, to that of other commonly used multimodal, opioid-sparing, analgesic agents.40–42

Qualitative results from the systematic review are similar to results of the stratified meta-analyses when postoperative pain outcomes are assessed. In the majority of studies with a crystalloid control arm, subjects in the esmolol arm had decreased immediate postoperative pain and PACU opioid consumption. In studies with an opioid control arm, subjects in the esmolol arm had similar immediate postoperative pain scores, while PACU opioid consumption was decreased. When compared with a crystalloid control, there appears to be a lower need for “rescue” analgesic in the PACU in those who received esmolol, but no difference when compared to an opioid control.

Intraoperative hemodynamic changes and PONV were secondary outcomes, and included studies were not powered to detect a difference between groups. However, qualitative assessment of the studies included here suggests that esmolol does not increase, and may even decrease the risk of PONV. While bradycardia and hypotension are potential side effects of esmolol, our findings suggest that esmolol, at the doses used in these studies, does not result in clinically significant hemodynamic changes. Nevertheless, further adequately powered studies are required to draw conclusions on the relative risks of intraoperative hemodynamic changes, PONV, sedation, pruritus, and time to PACU discharge with intraoperative esmolol use.

The mechanism by which esmolol modulates the pain response is unclear. β-Adrenergic antagonist regulation of voltage-gated Ca2+ channels that stimulate inhibitory G proteins in the cell membrane may control the release of neurotransmitters leading to a state of central analgesia similar to the mechanism thought to underlie the analgesic properties of clonidine.43,44 Another proposed mechanism involves blocking hippocampal activation by adrenergic pathways that may then attenuate the perception of pain. Hippocampal activation is thought to play a role in nociception via N-methyl-D-aspartate subtype glutamate receptors.45

This study suggests potential benefits of esmolol as a component of a balanced anesthetic. Poorly controlled postoperative pain and nausea and vomiting are among the most common causes of prolonged hospital stay or unanticipated hospital admission in patients who undergo ambulatory surgery.46–49 Despite the beneficial effects of opioids in the management of perioperative pain, the negative effects including respiratory depression, increased nausea and vomiting, ileus, and opioid-induced hyperalgesia contribute to prolonged PACU and hospital stays.49–52 Other opioid-sparing analgesic agents used for acute perioperative pain decrease the risk of these side effects.53–55 The intraoperative use of esmolol may prove beneficial for fast-track outpatient surgeries, patients at risk of postoperative respiratory compromise, and patients at risk of moderate to severe postoperative pain. Furthermore, there exist additional reasons to minimize the intraoperative dose of opioids. Multiple steps in the enhanced recovery after surgery pathways include the use of opioid-sparing agents perioperatively to reduce sedation, PONV, and ileus while decreasing recovery time.56,57 While opioids are commonly used intraoperative opioid analgesics, side effects from their use, especially remifentanil, include the development of hyperalgesia and acute opioid tolerance.10,58,59 Additionally, intraoperative remifentanil is associated with an increased risk of chronic postoperative pain.60,61 Esmolol may prove an effective alternative to the intraoperative use of remifentanil and other opioids in some clinical situations.

Our analysis has several limitations. First, significant trial heterogeneity was found regarding esmolol dose, surgery type, study size, timing and length of follow-up, pain score system used, and the quantitation of side effects. Publication bias and an analysis based on small and low-quality trials may result in an overestimation of the treatment effects. Additionally, the use of hemodynamic variables to guide infusion rates will naturally result in less opioid use when esmolol is given intraoperatively.

Data here show a reduction in intraoperative and PACU opioid use with equivalent or improved pain scores within 1 hour postoperatively. Both qualitative and quantitative analyses demonstrate potential benefits and minimal side effects of intraoperative esmolol, warranting further investigation. Future studies should include the dose–response relationship between esmolol and postoperative pain outcomes, the length of postoperative effect of intraoperative esmolol use on these outcomes, and greater investigation of esmolol’s potential side effects.

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DISCLOSURES

Name: Amanda M. Gelineau, MD.

Contribution: This author helped write and revise the manuscript and approve the final manuscript.

Name: Michael R. King, MD.

Contribution: This author helped write and revise the manuscript and approve the final manuscript.

Name: Karim S. Ladha, MD, MSc.

Contribution: This author helped write and revise the manuscript and approve the final manuscript.

Name: Sara M. Burns, MS.

Contribution: This author helped write and revise the manuscript and approve the final manuscript.

Name: Timothy Houle, PhD.

Contribution: This author helped write and revise the manuscript and approve the final manuscript.

Name: T. Anthony Anderson, PhD, MD.

Contribution: This author helped write and revise the manuscript and approve the final manuscript.

This manuscript was handled by: Honorio T. Benzon, MD.

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