Clinical Effectiveness and Safety of Intraoperative Methadone in Patients Undergoing Laparoscopic Hysterectomy

Clinical Effectiveness and Safety of Intraoperative Methadone in Patients Undergoing Laparoscopic Hysterectomy: a Prospective, Double-blind, Randomised Controlled Trial

The role of a single-dose of intraoperative methadone on postoperative pain and opioid consumption in patients undergoing hysterectomy remains scarcely explored. A prospective double-blind, randomised controlled trial investigating the effect of a single-dose of intraoperative methadone in patients scheduled for same day hysterectomy is therefore conducted.

Study Overview

• Status: Active, not recruiting
• Conditions: Postoperative Pain
• Intervention / Treatment: Drug: Methadone; Drug: Morphine

Detailed Description

Background with aim: Hysterectomy is the most common major gynaecological procedure in the world and hysterectomy on benign indications are increasingly being performed as same-day surgery. Therefore, perioperative anaesthesia has moved towards the use of very short-acting opioids with the incitement to speed up extubation and facilitate hospital discharge. However, the potential consequence is that more patients experience pain and discomfort.

Methadone has several desirable pharmacological features, and a single intraoperative dose of the long acting opioid could therefore theoretically expand the analgesic window and reduce postoperative opioid consumption compared to the more conventional use of short-acting opioids. The aim of this study is to investigate the effect of a single-dose of intravenous intraoperative methadone on postoperative opioid consumption, pain and side effects in patients scheduled for hysterectomy for benign indications. Our primary hypothesis is that intravenous perioperative methadone reduces opioid consumption (oral cumulative equivalent dose) by 30% during the first 24 postoperative hours compared to intravenous morphine.

Methods: 126 patients will be included in an investigator-initiated, prospective, randomised, double-blind, controlled trial with two arms: an intervention arm (methadone 0.2 mg/kg ideal body weight) and a control arm (morphine 0.2 mg/kg ideal body weight). The study will be GCP-monitored, and is approved by the Danish Health and Medicines Authority (2018-004351-20) and the Central Denmark Region Committees on Health Research Ethics (1-10-72-365-18).

Hypothesis: The results will probably be applicable to other types of surgery involving visceral pain, and thus the present study has the potential to improve the pain management for a large number of patients undergoing surgery.

• Study Type: Interventional
• Enrollment (Actual): 126
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Central Denmark Region
    • Horsens, Central Denmark Region, Denmark, 8700
      • Department of Anaesthesiology and Intensive Care, Horsens Regional Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 108 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

- Patients scheduled for elective laparoscopic hysterectomy for benign indications

Exclusion Criteria:

• American Society of Anaesthesiologists (ASA) physical status IV or V
• prolonged QT-interval assessed by electrocardiogram (> 440 milliseconds)
• Existing treatment with medications prolonging the QT-interval
• Hysterectomy due to malignancy or acute bleeding disorders
• Allergy to study drugs
• Preoperative daily use of opioids
• Severe respiratory insufficiency
• Heart failure
• Acute alcohol intoxication/delirium tremens
• Increased intracranial pressure
• Acute liver disease
• Acute abdominal pain
• Liver insufficiency
• Kidney insufficiency
• Treatment with rifampicin
• Breastfeeding
• Inability to provide informed consent.

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
Experimental: Intravenous single-dose methadone; A 10 ml syringe with 2 mg/ml of methadone will be prepared and and study drug will be administered as intravenous bolus dose (0.2 mg/kg) corresponding to 1 ml for every 10 kg of ideal body weight (height (cm) - 105).	Drug: Methadone; One intravenous administration of methadone (0.2 mg/kg ideal body weight)
Active Comparator: Intravenous single-dose morphine; A 10 ml syringe with 2 mg/ml of morphine will be prepared and study drug will be administered as intravenous bolus dose (0.2 mg/kg) corresponding to 1 ml for every 10 kg of ideal body weight (height (cm) - 105).	Drug: Morphine; One intravenous administration of morphine (0.2 mg/kg ideal body weight)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Opioid consumption at 24 hours after extubation (cumulative opioid consumption)	cumulative opioid consumption in oral morphine equivalents	24 hours
Opioid consumption at 6 hours after extubation (cumulative opioid consumption)	cumulative opioid consumption in oral morphine equivalents	6 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain intensity (NRS, 0-10) at rest and coughing	Numeric Rating Scale (NRS) ranging from 0 (no pain) to 10 (worst imaginable pain)	0-48 hours after extubation
Postoperative side effects/ adverse events (nausea and vomiting, sedation, hypoventilation, and hypoxemia)	Number of patients	0-72 hours after extubation

Collaborators and Investigators

• Sponsor: University of Aarhus
• Investigators: Principal Investigator: Kristian Friesgaard, MD, PhD, Department of Anaesthesiology and Intensive Care, Horsens Regional Hospital

Publications and helpful links

General Publications

• Gottschalk A, Durieux ME, Nemergut EC. Intraoperative methadone improves postoperative pain control in patients undergoing complex spine surgery. Anesth Analg. 2011 Jan;112(1):218-23. doi: 10.1213/ANE.0b013e3181d8a095. Epub 2010 Apr 24.
• Murphy GS, Szokol JW, Avram MJ, Greenberg SB, Marymont JH, Shear T, Parikh KN, Patel SS, Gupta DK. Intraoperative Methadone for the Prevention of Postoperative Pain: A Randomized, Double-blinded Clinical Trial in Cardiac Surgical Patients. Anesthesiology. 2015 May;122(5):1112-22. doi: 10.1097/ALN.0000000000000633.
• Murphy GS, Szokol JW, Avram MJ, Greenberg SB, Shear TD, Deshur MA, Vender JS, Benson J, Newmark RL. Clinical Effectiveness and Safety of Intraoperative Methadone in Patients Undergoing Posterior Spinal Fusion Surgery: A Randomized, Double-blinded, Controlled Trial. Anesthesiology. 2017 May;126(5):822-833. doi: 10.1097/ALN.0000000000001609.
• Richlin DM, Reuben SS. Postoperative pain control with methadone following lower abdominal surgery. J Clin Anesth. 1991 Mar-Apr;3(2):112-6. doi: 10.1016/0952-8180(91)90007-a.
• Chui PT, Gin T. A double-blind randomised trial comparing postoperative analgesia after perioperative loading doses of methadone or morphine. Anaesth Intensive Care. 1992 Feb;20(1):46-51. doi: 10.1177/0310057X9202000109.

Study record dates

Study Major Dates

• Study Start (Actual): May 6, 2019
• Primary Completion (Actual): July 8, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: April 5, 2019
• First Submitted That Met QC Criteria: April 5, 2019
• First Posted (Actual): April 9, 2019

Study Record Updates

• Last Update Posted (Actual): November 2, 2022
• Last Update Submitted That Met QC Criteria: November 1, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Respiratory System Agents; Antitussive Agents; Morphine; Methadone
• Other Study ID Numbers: 01052019

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