Methadone in Cystectomy Patients

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Clinical Effectiveness and Safety of Intraoperative Methadone in Patients

Conditions
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Pain, Postoperative, Postoperative Complications, Pathologic Processes, Bladder Cancer, Pain, Signs and Symptoms, Neurologic Manifestations, Neurologic Symptoms, Side Effect of Drug

Intervention / Treatment
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* Drug: Methadone
* Drug: Morphine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 110 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized controlled trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methadone<br>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<br>* One intravenous administration of methadone (0.15 mg/kg treatment weight (height(cm)-100)) one hour prior to expected extubation.<br>|
| Active Comparator: Morphine<br>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<br>* One intravenous administration of morphine (0.15 mg/kg treatment weight (height(cm)-100)) one hour prior to expected extubation.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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morphine, methadone, analgesics, opioids, effect of drugs