Nonopioid Analgesics and Cholecystectomy

The Effect of Intraoperative Nefopam, Ketoprofen and Paracetamol Combination vs Ketoprofen and Paracetamol Combination on Postoperative Morphine Requirements After Laparoscopic Cholecystectomy: A Randomized, Controlled Trial

The goal of this clinical trial is to evaluate the effect of the addition of nefopam to a multimodal analgesic regimen consisting of ketoprofen and paracetamol during sevoflurane- dexmedetomidine-based anesthesia on postoperative morphine requirements in patients undergoing laparoscopic cholecystectomy.

Study Overview

• Status: Completed
• Conditions: Pain, Postoperative; Opioid Use; Cholecystectomy
• Intervention / Treatment: Drug: saline infusion, ketoprofen, paracetamol; Drug: nefopam, ketoprofen, paracetamol

Detailed Description

Nefopam is a centrally-acting anti-nociceptive compound with supraspinal and spinal sites of action. It inhibits monoamine reuptake, modulates descending serotoninergic pain, and may also interact with a dopaminergic pathway. Because its mechanism of action is distinct from that of other analgesic opioids, nefopam may well have a role in analgesic protocols. The role of nefopam in multimodal analgesia has been extensively investigated in laparoscopic cholecystectomy. However, there is general agreement that more studies are needed to determine the ideal multimodal strategy. No previous study has investigated a combination regimen of the three most commonly prescribed non-opioid analgesics (NOA) (nefopam, ketoprofen, and paracetamol) vs ketoprofen and paracetamol combination during sevoflurane-dexmedetomidine based anesthesia on pain control after laparoscopic cholecystectomy.

The aim of our study is to compare a combination regimen of three NOA (nefopam, ketoprofen, and paracetamol) vs ketoprofen and paracetamol combination during sevoflurane-dexmedetomidine based anesthesia on pain control after laparoscopic cholecystectomy. We will try to demonstrate the benefit with the addition of a third NOA, which is the nefopam, to the double-drug regimen including ketoprofen and paracetamol. Our hypothesis is that this combination regimen of three NOA is associated with less postoperative pain, less opioid consumption, shorter length of post-anesthesia care unit (PACU) stay, and fewer opioid-related adverse effects and postoperative complications compared to the double-drug regimen of ketoprofen and paracetamol.

In this prospective randomized double-blind study, 90 patients aged 18 to 64 years, with American Society of Anesthesiologists (ASA) physical status I and II, will be randomly assigned using a computer-generated random number table to one of two treatment groups. Group A will receive sevoflurane-dexmedetomidine based anesthesia with ketoprofen and paracetamol for postoperative pain control, and group B will receive sevoflurane-dexmedetomidine based anesthesia with nefopam, ketoprofen, and paracetamol for postoperative pain control. The primary outcome measure of this study is total morphine consumption in PACU. Normally distributed data will be summarized as mean ± SD and non-normally distributed data will be summarized as median [interquartile range]. This study would have an impact on our current practice and may help find out the best multimodal analgesic strategy to control postoperative pain after laparoscopic cholecystectomy.

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 3

Contacts and Locations

Study Locations

• Lebanon
  • Beirut, Lebanon
    • American University of Beirut Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• ASA physical status I-II
• Age between 18 and 64 years
• Patients able to give consent

Exclusion Criteria:

• ASA physical status III to V
• History of chronic pain
• Use of an opioid analgesic within 12 hours prior to surgery
• Alcohol or drug abuse
• Chronic opioid intake
• Morbid obesity
• Psychiatric disorder
• Pregnancy or breast-feeding
• Intolerance to NSAIDSs
• Allergy or contraindication to nefopam (acute angle-closure glaucoma, epilepsy, coronary artery disease, prostate adenoma), to morphine or paracetamol (liver failure), to ketoprofen (increased risk of bleeding, stomach or intestinal ulcer, chronic kidney disease) or to dexmedetomidine (uncontrolled hypertension, heart block greater than first degree, or other clinically significant morbidities)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo group; Patients received sevoflurane-dexmedetomidine-based anesthesia with saline, ketoprofen and paracetamol for postoperative pain control,	Drug: saline infusion, ketoprofen, paracetamol; Patients in this group will receive one placebo infusion (saline infusion) in addition to the ketoprofen and paracetamol intraoperatively prior to the anticipated end of the surgery
Experimental: Multimodal group; patients received sevoflurane-dexmedetomidine-based anesthesia with nefopam, ketoprofen, and paracetamol for postoperative pain control.	Drug: nefopam, ketoprofen, paracetamol; Patients in this group will receive Nefopam and Ketoprofen in addition to the paracetamol intraoperatively prior to the anticipated end of the surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total morphine consumption in the post anesthesia care unit	Total morphine doses consumed after the surgery during the post anesthesia care unit stay of the patient	Throughout the patient's stay in the recovery room (average of 30 minutes after the surgery)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total fentanyl	Total fentanyl given intraoperatively.	Intraoperatively
Total morphine	Total morphine on the floor	Throughout the patient's stay on the floor
Ketoprofen consumption	Ketoprofen consumption on the floor	Throughout the patient's stay on the floor
Paracetamol consumption	Paracetamol consumption on the floor	Throughout the patient's stay on the floor
Total morphine consumption at 24 hours after surgery	Total morphine doses consumed at 24 hours after surgery	24 hours after surgery
Number of patients receiving morphine in PACU	Number of patients receiving morphine in post anesthesia care unit	Throughout the patient's stay in the recovery room (average of 30 minutes after the surgery)
Number of patients receiving morphine on the floor	Number of patients receiving morphine on the floor	Throughout the patient's stay on the floor
Number of patients receiving morphine during the first 24 hours after surgery	Number of patients receiving morphine during the first 24 hours after surgery	During the first 24 hours after surgery
Number of patients receiving ketoprofen on the floor	Number of patients receiving ketoprofen on the floor	On the floor
Number of patients receiving paracetamol on the floor	Number of patients receiving paracetamol on the floor	On the floor
NRS pain scores at rest in PACU	NRS pain scores at rest in post anesthesia care unit	Throughout the patient's stay in the recovery room (average of 30 minutes after the surgery)
NRS pain scores at 24 h after surgery	NRS pain scores at 24 hours after surgery	24 hours after surgery
sedation scores in PACU	sedation scores in post anesthesia care unit	Throughout the patient's stay in the recovery room (average of 30 minutes after the surgery)
Time to first morphine requirement	Time to first morphine requirement	From the time of arrival to PACU until discharge
Time to discharge (readiness) from PACU	Time to discharge (readiness) from post anesthesia care unit	Throughout the patient's stay in the recovery room (average of 30 minutes after the surgery)
Nausea and vomiting	Incidence and severity of nausea and vomiting	Throughout the patient's stay in the recovery room (average of 30 minutes after the surgery)
Rescue antiemetics	Need for rescue antiemetics	Throughout the patient's stay in the recovery room (average of 30 minutes after the surgery)
Pruritus	Incidence of pruritus	Throughout the patient's stay in the recovery room (average of 30 minutes after the surgery)
Respiratory depression	Incidence of respiratory depression	Throughout the patient's stay in the recovery room (average of 30 minutes after the surgery)
Urinary retention	Incidence of urinary retention	Throughout the patient's stay in the recovery room (average of 30 minutes after the surgery)
Tachycardia	Episodes of tachycardia	Intraoperatively and in PACU
Sweating	Episodes of sweating	Intraoperatively and in PACU
Quality of recovery	Quality of recovery at 24 h using the QoR-40	At 24 hours after the surgery
Overall satisfaction score	Overall satisfaction score collected one month after surgery.	One month after surgery.

Collaborators and Investigators

• Sponsor: American University of Beirut Medical Center
• Investigators: Principal Investigator: Sahar Sayyid, MD, American University of Beirut Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): April 8, 2021
• Primary Completion (Actual): October 19, 2022
• Study Completion (Actual): October 19, 2022

Study Registration Dates

• First Submitted: October 30, 2020
• First Submitted That Met QC Criteria: November 5, 2020
• First Posted (Actual): November 10, 2020

Study Record Updates

• Last Update Posted (Estimate): May 5, 2023
• Last Update Submitted That Met QC Criteria: May 3, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antipyretics; Acetaminophen; Ketoprofen; Nefopam
• Other Study ID Numbers: BIO-2020-0375

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No