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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Postoperative Pain

Intervention / Treatment
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* Drug: Methadone
* Drug: Morphine


Participation Criteria
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Eligibility Criteria
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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.

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

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Intravenous single-dose 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 (0.2 mg/kg) corresponding to 1 ml for every 10 kg of ideal body weight (height (cm) - 105). | Drug: Methadone<br>* One intravenous administration of methadone (0.2 mg/kg ideal body weight)<br>|
| Active Comparator: Intravenous single-dose morphine<br>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<br>* One intravenous administration of morphine (0.2 mg/kg ideal body weight)<br>|

What is the study measuring?
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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 |