Nonopioid Analgesics and Cholecystectomy

Study Overview
=================
Brief Summary
-----------------
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.

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.

Official Title
-----------------
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

Conditions
-----------------
Cholecystectomy, Pain, Postoperative, Opioid Use

Intervention / Treatment
-----------------
* Drug: nefopam, ketoprofen, paracetamol
* Drug: saline infusion, ketoprofen, paracetamol


Participation Criteria
=================
Eligibility Criteria
-----------------
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

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. |