Methadone in Cystectomy Patients (METAMORF)

Clinical Effectiveness and Safety of Intraoperative Methadone in Patients

The role of a single-dose intraoperative methadone on postoperative pain and opioid consumption in patients undergoing Surgeon Accuracy Robot Assistant cystectomy. A prospective double-blind, randomized controlled trial investigating the effect of a single-dose of intraoperative methadone in patients undergoing robotassisted cystectomy.

Study Overview

• Status: Completed
• Conditions: Pathologic Processes; Pain; Pain, Postoperative; Postoperative Complications; Neurologic Manifestations; Bladder Cancer; Neurologic Symptoms; Signs and Symptoms; Side Effect of Drug
• Intervention / Treatment: Drug: Methadone; Drug: Morphine

Detailed Description

During early recovery after surgery, intravenous opioids are typically administered to control the pain, either as intermittent bolus administration by nursing staff or by a patient-controlled analgesia device. Unfortunately, repeated doses or boluses of shorter-acting opioids, such as morphine, oxycodone and fentanyl, result in fluctuating blood concentrations, with the inherent risk of only relatively brief periods of adequate pain relief. Moreover, the use of shorter-acting opioids increases the risk of opioid-associated side effects, such as sedation, nausea and vomiting. An alternative approach to the postoperative use of shorter-acting opioids is therefore called for.

In this respect, methadone is an opioid with unique pharmalogical properties that may be advantageous when applied intraoperatively. A single-dose of this long acting opioid could provide a stable analgesia and potentially reduce the need for shorter-acting opioids

Method:

110 patients will be included in an investigator-initiated, prospective, randomised, double-blind, controlled trial with two arms: intervention arm (methadone 0.15 mg/kg ideal body weight). Control arm (morphine 0.15 mg/kg ideal body weight). The study will be GCP-monitored, and is approved by the Danish Health and Medicines Authority (2020041652) and the Central Denmark Region Committees on Health Research Ethics (1-10-72-275-19).

Hypothesis We hypothesize that a single-dose of intravenous intraoperative methadone is efficient and safe for the treatment of postoperative pain after cystectomy.

Objectives The primary objective is to determine whether a single-dose of intravenous methadone reduces postoperative opioid consumption when compared to morphine. The secondary objectives are to compare the effect and safety of intravenous methadone and morphine on postoperative pain, side effects, patient satisfaction and length of stay.

• Study Type: Interventional
• Enrollment (Actual): 114
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark, 8200
    • Aarhus University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 110 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

- All patients (≥18 years) scheduled for elective robot assisted cystectomy.

Exclusion Criteria:

• American Society of Anesthesiologists (ASA) physical status IV or V
• Prolonged QTc-interval assessed by electrocardiogram (> 440 milliseconds)
• Existing treatment with a high risk of QTc-interval prolongation
• Allergy to study drugs
• Preoperative daily use of opioids
• Inability to provide informed consent
• Severe respiratory insufficiency (oxygen treatment at home)
• Heart failure (ejection fraction < 30%)
• Acute abdominal pain
• Signs of severe liver dysfunction (cirrhosis, inflammation/hepatitis or liver malignancy)
• Severe kidney insufficiency (estimated Glomerular Filtration Rate < 30 ml/min)
• Treatment with rifampicin
• Phaeochromocytoma
• Treatment with MAO-inhibitor during the last 14 days
• Pregnancy
• Nursing mothers
• Intraoperative conversion to open surgery (secondary inclusion criterion)
• Epidural analgesia in relation to surgical procedure

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: 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 (0.15 mg/kg treatment weight (height (cm) - 100)). The study drug will be administered 1 hour prior to expected extubation.	Drug: Methadone; One intravenous administration of methadone (0.15 mg/kg treatment weight (height(cm)-100)) one hour prior to expected extubation.
Active Comparator: Morphine; A 10 ml syringe with 2 mg/ml of morphine will be prepared and and study drug will be administered as intravenous bolus dose (0.15 mg/kg treatment weight (height (cm) - 100)). The study drug will be administered 1 hour prior to expected extubation.	Drug: Morphine; One intravenous administration of morphine (0.15 mg/kg treatment weight (height(cm)-100)) one hour prior to expected extubation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Opioid consumption (morphine mg equivalents)	• Opioid consumption within the first 3 hours after extubation	3 hours
Opioid consumption (morphine mg equivalents)	• Opioid consumption within the first 24 hours after extubation	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain intensity	NRS (0-10) at rest and when coughing. Questionnaires answered by nurse.	within 24 hours
Opioid consumption (morphine mg equivalents)	• Opioid consumption within the first 72 hours after extubation	72 hours
PONV	• Nausea and/or vomiting (PONV) on a 4-point Likert scale (none/mild/moderate/severe). Questionnaires answered by nurse.	Within 24 hours
Level of sedation	Level of sedation (Ramsey Sedation Score) assessed by PACU nurse.	3 hours
Adverse events	Any adverse events registered.	6 hours
Patient satisfaction from 0-10.	Patient satisfaction with pain management (NRS 0-10) Questionnaires answered by nurse.	24 hours
Discharge	• Time from arrival to discharge from PACU and hospital (hours and minutes)	6 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain intensity	• Pain intensity (NRS, 0-10) at rest and coughing, questionnaires answered by nurse.	32-72 hours
PONV	• Nausea and/or vomiting (PONV) on a 4-point Likert scale (none/mild/moderate/severe). Questionnaires answered by nurse.	32-72 hours
Gastrointestinal function	Gastrointestinal function (flatus, stools) and laxatives ordained.	6-72 hours

Collaborators and Investigators

• Sponsor: University of Aarhus

Study record dates

Study Major Dates

• Study Start (Actual): July 6, 2020
• Primary Completion (Actual): August 15, 2023
• Study Completion (Actual): August 17, 2023

Study Registration Dates

• First Submitted: July 9, 2020
• First Submitted That Met QC Criteria: July 16, 2020
• First Posted (Actual): July 17, 2020

Study Record Updates

• Last Update Posted (Actual): September 13, 2023
• Last Update Submitted That Met QC Criteria: September 11, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: morphine; analgesics; methadone; opioids; effect of drugs
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Nervous System Diseases; Pain; Pain, Postoperative; Postoperative Complications; Drug-Related Side Effects and Adverse Reactions; Neurologic Manifestations; Pathologic Processes; 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: 004581; 2019-004581-18 (EudraCT Number)

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