Esmolol for Nociceptive Pain

(ESMONOL Trial)

Overseen By Nadia Godin

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Ciusss de L'Est de l'Île de Montréal

Must not be taking: Opioids, Beta blockers

Disqualifiers: Hypotension, Heart failure, Asthma, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

64 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial does not specify if you need to stop taking your current medications. However, if you are using opioids or beta-blockers regularly, you cannot participate in the trial.

What data supports the idea that Esmolol for Nociceptive Pain is an effective drug?

The available research does not provide direct evidence supporting the effectiveness of Esmolol for treating nociceptive pain. Most studies focus on its use for heart-related conditions, like controlling heart rate and blood pressure during surgery or in patients with heart issues. One study did explore its role in pain modulation in rats, but there is no clear data on its effectiveness for nociceptive pain in humans. ^{1 2 3 4 5}

What safety data exists for Esmolol in treating nociceptive pain?

The provided research does not contain specific safety data for Esmolol, Brevibloc, or Esmolol Hydrochloride in the treatment of nociceptive pain. The studies focus on other medications and conditions, such as opioids and their adverse effects, but do not address Esmolol directly. ^{6 7 8 9 10}

Is the drug Esmolol a promising treatment for nociceptive pain?

Esmolol shows potential as a promising treatment for nociceptive pain because it has been found to help manage pain in studies with animals. Additionally, it is a short-acting drug that can be easily controlled, making it useful in situations where quick adjustments are needed. ^{1 2 3 4 5}

What is the purpose of this trial?

This study aims to evaluate esmolol's perfusion impact during induction and maintenance of general anesthesia, using Nociception-Level-guided control of nociception, in adult patients undergoing laparoscopic and lower abdominal surgery, on intraoperative remifentanil consumption and postoperative pain in the Post-Anesthesia Care Unit.

Research Team

Pascal Laferrière-Langlois

Principal Investigator

Ciusss de L'Est de l'Île de Montréal

Eligibility Criteria

Adults aged 18-65, with a physical status score of 1-3, undergoing specific laparoscopic abdominal surgeries expected to last less than 180 minutes. Participants must not have allergies to study medications and should consent fully. Excluded are those with certain heart conditions, severe lung diseases, renal dysfunction, chronic opioid use or beta-blocker therapy.

Inclusion Criteria

No allergy to one of the medications used in this study

I am 18-65 years old, fit for surgery, and have agreed to a specific laparoscopic procedure.

I am scheduled for a specific surgery under general anesthesia expected to last less than 3 hours.

Exclusion Criteria

I do not have conditions that react badly to esmolol.

I do not have severe mental impairment, chronic opioid use, or take β-blockers. My surgery risk is low.

I understand I'll be removed from the study if I withdraw consent or my surgery changes from laparoscopy to open surgery.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction and Maintenance of Anesthesia

Participants receive induction of general anesthesia with propofol and remifentanil, guided by the NOL Index, with esmolol or saline infusion during surgery

Intraoperative period

1 visit (in-person, during surgery)

Post-Anesthesia Care Unit (PACU)

Participants are monitored for postoperative pain, nausea, and other outcomes in the PACU

From PACU arrival until discharge

1 visit (in-person, during PACU stay)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Esmolol

Trial Overview The trial is testing the effect of esmolol hydrochloride infusion during general anesthesia on intraoperative remifentanil use and postoperative pain in patients having laparoscopic and lower abdominal surgery compared to saline (a placebo).

Participant Groups

Group I: Esmolol Experimental Treatment 1 Intervention

In the Esmolol group, intravenous esmolol will be given as a bolus (0.5mg.kg-1) over 5 minutes, and will be started simultaneously to the remifentanil initiation. Once the bolus of esmolol is over, a perfusion of 20 mcg.kg-1.min-1 will be programmed and maintained until the end of the surgery and completion of skin sutures

Group II: Standard of care Placebo Group 2 Interventions

In the standard of care group, intravenous saline bolus, equivalent to an esmolol bolus (0.5mg.kg-1) will be given over 5 minutes, and will be started simultaneously to the remifentanil initiation. Once the bolus of saline is over, a saline perfusion equivalent to an esmolol infusion of 20 mcg.kg-1.min-1 will be programmed and maintained until the end of the surgery and completion of skin sutures

Esmolol is already approved in United States, European Union for the following indications:

Approved in United States as Brevibloc for:

• Supraventricular tachycardia
• Episodic atrial fibrillation or flutter
• Arrhythmia during anesthesia
• To reduce heart rate and blood pressure during and after cardiac surgery
• Early treatment of myocardial infarction

Approved in European Union as Esmolol for:

• Supraventricular tachycardia
• Episodic atrial fibrillation or flutter
• Arrhythmia during anesthesia
• To reduce heart rate and blood pressure during and after cardiac surgery
• Early treatment of myocardial infarction

Who Is Running the Clinical Trial?

Ciusss de L'Est de l'Île de Montréal

Lead Sponsor

Trials

81

Recruited

6,400+

Findings from Research

In a study involving 60 healthy adults undergoing minor surgery, esmolol hydrochloride significantly reduced heart rate, mean arterial pressure, stroke volume, and cardiac output compared to a placebo, indicating its efficacy in managing hemodynamic variables during anesthesia.

The higher dose of 200 mg of esmolol produced greater reductions in these variables than the 100 mg dose, with the maximum effects observed at 2 minutes post-injection, although recovery was still incomplete at 5 minutes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A controlled trial of the effects of esmolol on cardiac function. Alexander, R., Binns, J., Hetreed, M.[2019]

In a study of 24 patients with acute NSTEMI and heart failure, intravenous esmolol was found to be safe and well tolerated in both elderly (≥75 years) and younger patients (32-74 years), with only one elderly patient experiencing severe bradycardia at a higher infusion rate.

Both age groups showed similar haemodynamic responses to esmolol, with a significant decrease in cardiac index and an increase in pulmonary wedge pressure, indicating that esmolol effectively managed heart function without major safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous esmolol is well tolerated in elderly patients with heart failure in the early phase of non-ST elevation myocardial infarction. Koutouzis, M., Nikolidakis, S., Grigoriadis, A., et al.[2018]

Esmolol, a beta1 receptor blocker, was found to reduce pain responses in rats, particularly during the late phase of pain (Phase 2) after formalin injection, indicating its potential analgesic properties.

High doses of esmolol not only diminished pain responses but also blunted the increase in mean arterial blood pressure (MAP) associated with pain, suggesting it can help manage both pain and cardiovascular reactions during painful stimuli.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antinociceptive and cardiovascular properties of esmolol following formalin injection in rats. Davidson, EM., Doursout, MF., Szmuk, P., et al.[2015]

Esmolol is a fast-acting, short-duration beta blocker that effectively reduces heart rate in patients with conditions like supraventricular tachyarrhythmias and acute myocardial infarction, making it a safe option for managing these conditions.

With over 1200 patients studied, esmolol's rapid onset and offset of action (with effects dissipating within 30 minutes after stopping) allow for precise control of heart rate, making it particularly useful during surgery and in postoperative care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Esmolol: a titratable short-acting intravenous beta blocker for acute critical care settings. Turlapaty, P., Laddu, A., Murthy, VS., et al.[2022]

Esmolol is a fast-acting, cardioselective beta-blocker with a very short half-life of about 9.2 minutes, making it ideal for critically ill patients who need quick control of heart-related issues.

Clinical evidence supports the safety and efficacy of esmolol in treating acute myocardial ischemia, allowing for rapid management of hemodynamic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Esmolol: a short-acting titratable beta-blocker in acute myocardial ischemia. Viray, R., Turlapaty, P., Laddu, A.[2012]

In a phase 2 study involving 254 patients with opioid-induced constipation (OIC), linaclotide significantly increased the frequency of spontaneous bowel movements (SBMs) compared to placebo, with mean increases of 2.9 and 3.5 SBMs/week for the 145 µg and 290 µg doses, respectively (P < 0.01).

Linaclotide was well tolerated, with diarrhea being the most common adverse event, but it was generally mild and led to discontinuation in only a small percentage of patients (1.1% for 145 µg and 5.7% for 290 µg), and no serious adverse events related to diarrhea were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of linaclotide for opioid-induced constipation in patients with chronic noncancer pain syndromes from a phase 2 randomized study. Brenner, DM., Argoff, CE., Fox, SM., et al.[2022]

Children require careful consideration when managing acute pain due to differences in how their bodies process medications compared to adults, making them more vulnerable to safety issues.

The review emphasizes the importance of individualized treatment and proper dosing of analgesics like acetaminophen, NSAIDs, and opioids to ensure effective pain relief while minimizing the risk of adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Issues of Pharmacological Acute Pain Treatment in Children. Rodieux, F., Piguet, V., Desmeules, J., et al.[2020]

A comprehensive analysis of 12,819,518 reports in the FDA Adverse Event Reporting System revealed that opioids like morphine and fentanyl are associated with known adverse events such as bradycardia and respiratory depression, confirming their risks during use.

The study also identified unexpected acute adverse drug reactions, including toxic leukoencephalopathy and coma, highlighting the need for ongoing safety evaluations of opioids beyond their established risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Strong opioids-induced cardiac, neurologic, and respiratory disorders: a real-world study from 2004 to 2023 based on FAERS. Dai, M., Dou, X., Chen, M., et al.[2023]

A systematic review of 34 trials involving 5,546 patients found that oral opioids used for non-cancer pain resulted in higher rates of adverse events compared to placebo, with common issues including dry mouth (25%), nausea (21%), and constipation (15%).

Approximately 22% of patients discontinued opioid treatment due to adverse events, highlighting the potential safety concerns associated with opioid use in non-cancer pain management, especially since most trials lasted less than four weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevalence of opioid adverse events in chronic non-malignant pain: systematic review of randomised trials of oral opioids. Moore, RA., McQuay, HJ.[2022]

Naloxegol, an oral therapy for opioid-induced constipation, was found to be generally safe and well tolerated in a study involving 32 healthy volunteers, with no serious adverse events leading to discontinuation.

The study demonstrated that naloxegol was rapidly absorbed and showed dose proportionality, indicating its potential effectiveness in managing constipation without significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, tolerability, and pharmacokinetics of multiple ascending doses of naloxegol. Eldon, MA., Kugler, AR., Medve, RA., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

A controlled trial of the effects of esmolol on cardiac function. [2019]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Intravenous esmolol is well tolerated in elderly patients with heart failure in the early phase of non-ST elevation myocardial infarction. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Antinociceptive and cardiovascular properties of esmolol following formalin injection in rats. [2015]

4. United States pubmed.ncbi.nlm.nih.gov

Esmolol: a titratable short-acting intravenous beta blocker for acute critical care settings. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

Esmolol: a short-acting titratable beta-blocker in acute myocardial ischemia. [2012]

6. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of linaclotide for opioid-induced constipation in patients with chronic noncancer pain syndromes from a phase 2 randomized study. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Safety Issues of Pharmacological Acute Pain Treatment in Children. [2020]

8. Germany pubmed.ncbi.nlm.nih.gov

Strong opioids-induced cardiac, neurologic, and respiratory disorders: a real-world study from 2004 to 2023 based on FAERS. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Prevalence of opioid adverse events in chronic non-malignant pain: systematic review of randomised trials of oral opioids. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Safety, tolerability, and pharmacokinetics of multiple ascending doses of naloxegol. [2018]