Perioperative Methadone Compared to Placebo in Elderly Hip Fracture Patients

Study Overview
=================
Brief Summary
-----------------
Hip fractures are associated with severe pain and are sustained by the elderly population. Demand for adequate pain relief combined with a low tolerance for analgesic drugs makes the treatment of elderly hip fracture patients difficult. Perioperative methadone could improve the analgesic treatment of these patients. An earlier pilot study showed that 0.10 mg/kg was safe to use. This study further investigates the advantages of methadone. The study's objective is to investigate the analgesic effects of a single dose of methadone given during hip fracture surgery.

Detailed Description
-----------------
Studies investigating the perioperative use of methadone have shown promising analgesic properties. Our pilot study (EudraCT no.: 2022-001857-22) showed that a dosage of 0.10 mg/kg was safe to use and showed excellent analgesic properties. Sufficient management of acute postoperative pain is important in relation to morbidity, hospital costs, and mortality. About 60% of patients undergoing surgical intervention experience moderate to severe postoperative pain. Thus, sufficient analgesic treatment is crucial in the initial postoperative days, which are considered the most painful phase of recovery. Opioids have conventionally been used as an analgesic treatment in this phase. However, this treatment has been accompanied by side effects and addiction. Methadone shares these side effects, however, as methadone only needs to be administered once, the risk of side effects decreases significantly. This study will investigate the analgesic effects of a single dose of methadone given during hip fracture surgery. The first objective is to investigate the analgesic effect of perioperative methadone compared with a placebo in acute hip fracture surgery. The second objective is to investigate the long-term effects of methadone on continued opioid consumption, pain, and mobility three months after surgery. The null hypothesis is that there is no difference in postoperative pain, opioid consumption, or related side effects if a patient receives a dose of methadone or placebo during the surgery.

Official Title
-----------------
Perioperative Methadone Compared to Placebo in Elderly Hip Fracture Patients

Conditions
-----------------
Hip Fractures, Methadone

Intervention / Treatment
-----------------
* Drug: Methadone Hydrochloride
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients diagnosed with an acute hip fracture (incurred <24 hours ago) on x-rays in the emergency department (ED) at the university hospital of southern Denmark (SHS). This includes collum femoris fractures, pertrochanteric fractures, and subtrochanteric fractures. Patients must be able to read and understand Danish. Exclusion Criteria: Multiple fractures or multi-trauma patient Previous allergic reactions or hypersensitivity towards methadone hydrochloride or sodium chloride Health conditions preventing treatment: Chronic obstructive pulmonary disease with either past exacerbations or daily symptoms History of acute asthma attacks History of drug-induced eczema Pulmonary hypertension Raised intracranial pressure or recent head injury Pheochromocytoma History of paralytic ileus QT-interval prolongation on electrocardiogram (ECG) Myasthenia gravis Known liver disorder Hypotension (systolic blood pressure <100 mmHg at admission) Acute pancreatitis Severe kidney disease (GFR ≤10) Concurrent administration with MAO inhibitors or within 2 weeks of suspending treatment with these medicinal products Concurrent administration of benzodiazepines Impaired cognitive function e.g. dementia. Patients must be able to give informed consent and be able to ask for rescue analgesics if needed Current opioid addiction or intravenous addiction

Ages Eligible for Study
-----------------
Minimum Age: 60 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 |
| --- | --- |
| Experimental: Methadone<br>Methadone hydrochloride (0.10 mg/kg) administered intravenously at the induction of anaesthesia | Drug: Methadone Hydrochloride<br>* Methadone hydrochloride (0.10 mg/kg) administered intravenously at the induction of anaesthesia<br>* Other names: Methadone;|
| Placebo Comparator: Placebo<br>Standard saline solution administered intravenously at the induction of anaesthesia | Other: Placebo<br>* Saline solution<br>* Other names: Saline;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Consumption of daily morphine equivalents 3 days post operatively | All opioids (short-acting and long-acting) will be converted into daily morphine milligram equivalent doses. The amount of opioids used by the patient within the last 24 hours will be registered daily. A minimum amount of 0 mg and a maximum amount of 150 mg can be recorded. | 3 days post-surgery | 
| Consumption of daily morphine equivalents 3 months post operatively | The opioid consumption will be registered as a mean daily consumption of both long-acting opioids and rescue medication prescribed in the medication chart and reported by the patient. Different types of opioids will be converted into the daily morphine milligram equivalent dose. Minimum score will be 0 mg and the maximum will be 150 mg. | 3 months post-surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postoperative pain assessment with verbal rating scale (VRS) | Patients will be asked to assess pain intensity daily in the hip both at rest and when mobilized. Pain intensity will be evaluated using the verbal rating scale consisting of five choices - 1 (No pain), 2 (Slight pain), 3 (Moderate pain), 4 (Severe pain), and 5 (Unbearable pain). | 3 days post-surgery | 
| Time until patient first stands up post-surgery | This will be registered in hours and minutes. The minimum is 0 hours and 0 minutes and the maximum is 72 hours and 0 minutes. | up to 72 hours post-surgery | 
| Mobility assessment using the Cumulated Ambulation Score (CAS) | The cumulated ambulation score describes the patient's independence with regard to three activities. The first getting in and out of bed, the second ability to transition from sit-to-stand-to-sit from a chair, and the third is walking ability. Each of these activities is assessed on a three-point scale from 0-2 (0 = Not able to, despite human assistance and verbal cueing, 1 = Able to, with human assistance and/or verbal cueing from one or more persons, 2 = Able to safely, without human assistance or verbal cueing. A CAS score will range from zero (worst) to six (best) and will be measure daily. | 3 days post-surgery | 
| Number of patients with post operative nausea or vomiting (PONV) | Postoperative nausea or vomiting (PONV) will be registered binomial as yes or no once daily | 3 days post-surgery | 
| Number of days to discharge after surgery | The number of days from ward admission until discharge. Patients moved to another department are still considered hospitalized. The minimum is 0 days and the maximum is 14 days. | From admission to the ward to discharge, up to 14 days | 
| Number of patients requiring an antidote | Administration of an antidote will be registered binomial as yes or no. Indications for the use of an antidote include a respiratory frequency of <10/min with peripheral oxygenation of <94% despite 4 liters of oxygen/minute, clinical signs of opioid overdose e.g. disproportionate drowsiness, or if the orthopaedic resident deems it necessary. | 3 days post-surgery | 
| Number of patients with delirium assessed using the Confusion Assessment Method (CAM) | Patients will be monitored using the confusion assessment method for signs of delirium. The method is binomial so that 0 means no signs of delirium and 1 means a patient is delirious. | 3 days post-surgery | 
| Number of participants with constipation | Occurrence of constipation during admission will be registered binomial as yes or no. A patient with no bowel movements for ≥2 days is considered constipated. | 3 days post-surgery | 
| Postoperative pain assessment with verbal rating scale (VRS) | Patients will be asked to assess pain intensity daily in the hip both at rest and when mobilized. Pain intensity will be evaluated using the verbal rating scale consisting of five choices - 1 (No pain), 2 (Slight pain), 3 (Moderate pain), 4 (Severe pain), and 5 (Unbearable pain). | 3 months post-surgery | 
| Quality of life assessed using EQ-5D-5L questionnaire | The questionnaire comprises of five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state. | 3 months post-surgery | 
| Patient mobility assessed using the new mobility score (NMS) | New mobility score assesses gait; inside the home, outside the home and whilst shopping. A score of 0-3 points is given for each of these three functions, resulting in a total score between 0-9 points. | 3 months post-surgery | 
| Number of persistent side effects | The persistent presence of potential adverse reactions will be registered. This includes disproportional dizziness, vertigo, nausea, vomiting, constipation, and drowsiness. | 3 months post-surgery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hip fractures, Elderly, Fragile, methadone, perioperative, analgesic treatment, pain, verbal rating scale, morphine consumption