Perioperative Methadone in Hip Fracture Patients

Perioperative Methadone for Ameliorating Postoperative Pain and Reduction in Postoperative Opioid Consumption in Hip Fracture Patients - Dosage Adjusting Pilot-study

Postoperative analgesic treatment needs to be improved. Numerous studies suggest that a single dose of Methadone given during surgery significantly ameliorates postoperative pain and reduces postoperative opioid consumption. Perioperative methadone is already used in isolated cases such as patients with chronic pain or patients with high morphine tolerance. However, it is not routinely used in the elderly and fragile, and there is insufficient reliable evidence on this treatment and population. Further investigation is highly relevant and necessary.

Study Overview

• Status: Completed
• Conditions: Pain, Postoperative; Pain, Post Operative; Analgesics, Opioid; Methadone
• Intervention / Treatment: Drug: Methadone (Dose1); Drug: Methadone (Dose 2); Drug: Methadone (Dose 3)

Detailed Description

A multimodal approach and the use of peripheral nerve blocks have improved the treatment of postoperative pain. However, supplemental opioids are predominantly necessary and often continued for months or years after surgery. In fact, continued use of opioids after surgery is an increasing challenge. Consequently, patients undergoing surgery are at risk of experiencing side effects and developing physical as well as psychological addiction to opioids. The most common opioid-related side effects include obstipation, nausea, itchy skin, dry mouth, vertigo, and sedation. The means to decrease the need for opioids in the postoperative phase are in high demand, and therefore the investigation of perioperative Methadone is highly relevant. Methadone is a lipophilic opioid agonist with a large distribution volume and a very long elimination half-life of 15 - 60 hours. It is also an N-methyl D-aspartate (NMDA) receptor antagonist, which attenuates opioid-induced tolerance and hyperalgesia. Furthermore, Methadone inhibits the reuptake of Serotonin and Noradrenalin, which could positively affect the experience of pain in the postoperative phase. Methadone is mostly excreted through the bile and can, therefore, even be used in patients with reduced kidney function. Methadone's analgesic effects occur only eight minutes after intravenous administration. In most studies, methadone is given perioperatively in dosages of 0.10-0.30 mg/kg and is commenced at the induction of anaesthesia or the initiation of surgery. Studies investigating the optimal dosage and time for administration found that patients receiving methadone after the procedure needed twice as much opioid pain medication on postoperative day one compared to patients receiving methadone at anaesthetic induction. These studies also indicate that using smaller dosages such as 5-10 mg, the analgesic duration is only 3-4 hours, whereas doses of 20 mg or more have a clinical effect closely related to the elimination half-life of 15-60 hours without any increased risk for respiratory depression. The aim of this study is to determine the optimal dose of methadone for a future randomized controlled trial (RCT). The objective is to investigate whether doses greater than 0.10 mg/kg are tolerated with no increased risk to respiratory depression, side effects, or prolonged stay in the post-anaesthesia care units (PACU).

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Aabenraa, Denmark, 6200
    • Sygehus Soenderjylland

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients diagnosed with a hip fracture on x-rays (collum femoris fractures, pertrochanteric fractures and subtrochanteric fractures).
• Patients must be able to reliably assess their level of pain using the VRS and be able to ask for supplementary analgesics if needed.
• Patients must understand the information given and be able to read and speak Danish.
• Patients must be able to give informed consent.

Exclusion Criteria:

• Polytrauma (defined as a trauma with one or more absolute indications for surgical intervention).
• Previous allergic reactions or hypersensitivity towards Methadone hydrochloride or Sodium-chloride.
• Health conditions preventing treatment, i.e. chronic obstructive pulmonary disease (Gold classification C+D), history with acute asthma attacks or atopic skin conditions, cor pulmonale, raised intracranial pressure or head injury, Pheochromocytoma, history with paralytic ileus, QT interval prolongation, myasthenia gravis, liver disorders or hypotension.
• Concurrent administration with monoamine oxidase inhibitors or within 2 weeks of suspending treatment with these medicinal products.
• Concurrent administration of sedatives, e.g. Benzodiazepines or related drugs.
• Included in other studies (e.g., SENSE-trial).
• Known cognitive disorders e.g., dementia.
• Current drug addiction e.g., opioid addiction or intravenous addiction.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Methadone (Dose 1); Methadone will be administered intravenously at the beginning of surgery, and will only be administered this one time. The gradual upward titration of Methadone will be managed using adaptive platform design. This way the number of patients in each group will be determined by the adaptive platform algorithm.	Drug: Methadone (Dose1); Dose: 0.10mg/kg; Other Names: Dose 1
Experimental: Methadone (Dose 2); Methadone will be administered intravenously at the beginning of surgery, and will only be administered this one time. The gradual upward titration of Methadone will be managed using adaptive platform design. This way the number of patients in each group will be determined by the adaptive platform algorithm.	Drug: Methadone (Dose 2); Dose: 0.15mg/kg; Other Names: Dose 2
Experimental: Methadone (Dose 3); Methadone will be administered intravenously at the beginning of surgery, and will only be administered this one time. The gradual upward titration of Methadone will be managed using adaptive platform design. This way the number of patients in each group will be determined by the adaptive platform algorithm.	Drug: Methadone (Dose 3); Dose 0.20mg/kg; Other Names: Dose 3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Respiratory depression	Occurrence of a respiratory frequency <10/min and oxygen saturation <94 % despite 4 liters of oxygen/min.	6 hours after surgery
Respiratory depression	Occurrence of a respiratory frequency <10/min and oxygen saturation <94 % despite 4 liters of oxygen/min.	24 hours after surgery
Respiratory depression	Occurrence of a respiratory frequency <10/min and oxygen saturation <94 % despite 4 liters of oxygen/min.	72 hours after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of stay at the post anaesthetic care unit	Hours	up to 12 hours after surgery
Number of times Naloxone was administered	Numerical	immediately after the surgery (6, 24, 72 hours)
Postoperative opioid consumption	mean consumption of rescue medication	immediately after the surgery (6, 24, 72 hours)
Opioid-related side-effects	Opioid-related side-effects will be registered binomial as nausea and vomiting	immediately after the surgery (6, 24 hours)
Postoperative pain	Patients will be asked to assess pain intensity at the time of arrival from the post-anaesthesia care unit using the Verbal Rating Scale (VRS) consisting of 6 categories where 0 is no pain and 5 is the highest level of pain (worst outcome).	immediately after the surgery (0, 6, 24, 72 hours)

Collaborators and Investigators

• Sponsor: University of Southern Denmark
• Investigators: Principal Investigator: Jesper Schønnemann, Hospital of Southern Denmark - Aabenraa

Study record dates

Study Major Dates

• Study Start (Actual): January 12, 2023
• Primary Completion (Actual): March 23, 2023
• Study Completion (Actual): April 4, 2023

Study Registration Dates

• First Submitted: September 15, 2022
• First Submitted That Met QC Criteria: October 13, 2022
• First Posted (Actual): October 17, 2022

Study Record Updates

• Last Update Posted (Actual): April 18, 2023
• Last Update Submitted That Met QC Criteria: April 14, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Fractures, Bone; Wounds and Injuries; Leg Injuries; Femoral Fractures; Hip Injuries; Pain, Postoperative; Hip Fractures; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Respiratory System Agents; Antitussive Agents; Methadone
• Other Study ID Numbers: SHS-An-2-2022

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
• product manufactured in and exported from the U.S.: No