Reducing Pain With Methadone and Ketamine in Liver Transplant (RELIEF-LT)

Randomized Clinical Trial of Methadone and Ketamine for Pain Management During Deceased Donor Liver Transplant

The goal of this clinical trial is to learn if using methadone and ketamine during an adult deceased donor liver transplant can help decrease pain after surgery.

The main questions it aims to answer are:

• What impact does using methadone and ketamine during a deceased donor liver transplant have on pain after surgery?
• Does the use of methadone and ketamine also have an impact on mental confusion (delirium) after surgery?

Researchers will compare the use of methadone and ketamine to standard of care to see if the two drugs work to decrease pain and impact delirium after liver transplant.

Participants will:

• Receive either methadone and ketamine or standard of care during their deceased donor liver transplant.
• Allow researchers to follow medical care throughout inpatient stay.

Study Overview

• Status: Active, not recruiting
• Conditions: Liver Transplantation
• Intervention / Treatment: Drug: Methadone; Drug: ketamine; Drug: Hydromorphone; Drug: fentanyl

Detailed Description

Pain control following liver transplantation (LT) has been the subject of interest of many research projects due to invasive nature of the procedure, significant comorbidities of recipients, effect of hepatic metabolism on many common pain medications and difficulties in performing some neuraxial and regional techniques given patient coagulopathy. Some newer regional nerve blocks such as External Oblique Intercostal (EOI) block has also been successfully utilized in pain management of patients undergoing liver resections but their utilization in perioperative setting for high-MELD patients and after-hour operations are limited. Methadone and ketamine are well-known drugs that have been recently emerged as components of new pain management pathways in many open surgeries due to their availability, cost, well-known metabolism, good safety profile and prolonged effects. Evidence has emerged that their use is associated with decreased likelihood of development of chronic pain and need for long term opioids. The combination of methadone and ketamine has been shown to be superior to opioids alone due to synergistic effect on N-methyl-d-aspartate and μ-opioid receptors. But these medications have not been extensively studied in LT recipients except for a few case reports and small studies. Current standards of care for intraoperative pain management during LT are systemic short and medium long-acting opioids such as fentanyl and hydromorphone which both have numerous concerns such as respiratory depression and opioid dependency. The aim of this study is to prospectively evaluate the effect of intraoperative methadone and ketamine administration on postoperative pain in liver transplant recipients. These drugs have been safely used during liver transplantation at LHMC and other centers and showed to be effective and safe, but the exact dosing and timing of administration requires further studies.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Burlington, Massachusetts, United States, 01805
      • Lahey Hospital and Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult patients ≥ 18 years of age at the time of LT.
• Undergoing LT from a deceased donor.
• Written informed consent obtained from subject or subject's legal representative and ability for subject to comply with the requirements of the study.

Exclusion criteria:

• Living donor liver transplantation (LDLT).
• Split liver transplantation (isolated right or left lobe).
• Acute liver failure (ALF) as the indication for LT.
• Repeat (redo) liver transplant
• Simultaneous liver and kidney transplant (SLK)
• Sedation or high vasopressor use.
• Subject is intubated and/or mechanically ventilated prior to entering the operating room for LT.
• Severe Hepatic encephalopathy
• History of psychiatric disorders such as schizophrenia or bipolar mood disorders
• History of chronic opioid use, substance abuse or opioid maintenance therapies
• Any history of allergic reaction to any of the study drugs History of Brugadda, prolonged QT syndrome or QTc in preoperative setting
• Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data
• Prisoner
• Pregnant person
• Operational Exclusion Criterion: Subjects will not be enrolled if study personnel required for protocol execution (e.g., study investigator, research staff or pharmacy staff) are unavailable at the time of transplantation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: M+K group; Participants in this arm will receive the intervention with methadone and ketamine	Drug: Methadone; Participants in this group will receive one bolus dose of intravenous Methadone and Ketamine at the start of operation; Drug: ketamine; Participants in this group will receive one bolus dose of intravenous Methadone and Ketamine at the start of operation
Active Comparator: SOC group; Participants in this arm will receive the standard of care with combination of hydromorphone and fentanyl	Drug: Hydromorphone; Participants in this group will receive standard of care for pain with either intravenous fentanyl and/or hydromorphone boluses during the procedure; Drug: fentanyl; Participants in this group will receive standard of care for pain with either intravenous fentanyl and/or hydromorphone boluses during the procedure

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative Pain	postoperative opioid consumption (measured as morphine milligram equivalents ((MME)) 48 hours after surgery	8, 16, 24, 32, 40 and 48hours post-surgery finish
Postoperative Pain	Subjective postoperative pain scores measured as 0-10 (10 being the worst pain)	8, 16, 24, 32, 40 and 48hours post-surgery finish

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of stay in intensive care unit	Duration of length of stay in intensive care unit in hours	Post surgery finish until discharge from intensive care unit, or date of death from any cause, whichever came first, assessed up to 30 days
Delirium	Incidence of postoperative delirium measured by standard CAM-ICU scores, ICD-10 diagnosis of delirium, any use of anti-agitation medication such as haloperidol, dexmedetomidine or seroquel	Post surgery finish until discharge from intensive care unit, or date of death from any cause, whichever came first, assessed up to 30 days
Respiratory complications	Any significant respiratory complications such as re-intubation, need for invasive ventilation such as BIPAP or CPAP	Post surgery finish until discharge from intensive care unit, or date of death from any cause, whichever came first, assessed up to 30 days
Narcotics reversal agent	Any need for narcotics reversal agents such as Naloxone after administration of study drugs	Post surgery finish until discharge from intensive care unit, or date of death from any cause, whichever came first, assessed up to 30 days
Postoperative adjunct pain modalities	Incidence of usage of any additional pain modalities such as nerve blocks, neuraxial anesthesia, non-narcotic pain medications such as additional ketamine dose, ketorolac, methocarbamol, ketorolac, etc	Post surgery finish until discharge from intensive care unit, or date of death from any cause, whichever came first, assessed up to 30 days
Length of stay in hospital	Duration of length of stay in the hospital in days	Post surgery finish until discharge from hospital, or date of death from any cause, whichever came first, assessed up to 30 days
Correlation Between Study Drug Exposure and Early Post-Transplant Laboratory Markers of Liver Dysfunction	Unit of measure: Correlation coefficient (r) describing the association between study drug exposure and postoperative laboratory markers of liver dysfunction during the first 24hrs post surgery. Independent variables (study drug exposure): Randomized study drug assignment (e.g., ketamine vs methadone vs standard of care); Total intraoperative dose of each study drug (total mg) Dependent variables (markers of postoperative liver dysfunction): Correlation coefficients will be calculated between study drug exposure and the following laboratory values measured during first postoperative days : Peak alanine aminotransferase (ALT), IU/L; Peak aspartate aminotransferase (AST), IU/L; Peak total bilirubin, mg/dL; Peak international normalized ratio (INR)	Immediate to 24hrs post surgery finish
Correlation Between Donor and Surgical Factors and Postoperative Opioid Use (MME)	Unit of measure: Correlation coefficient (r) describing the association between each donor/surgical factor and total postoperative opioid consumption (MME) during postoperative days 0-2. Total MME will be calculated by converting all administered opioids into morphine milligram equivalents using standard conversion factors. Factors assessed (independent variables): Donor age (years); Donation type (donation after brain death vs donation after circulatory death); Use of normothermic machine perfusion (yes/no); Cold ischemia time (hours); Warm ischemia time (minutes); Surgical technique characteristics (e.g., piggyback vs caval replacement approach, vascular anastomosis techniques, use of veno-venous bypass), coded as categorical variables	From the end of surgery through 48hr post surgery

Collaborators and Investigators

• Sponsor: Lahey Clinic
• Investigators: Principal Investigator: Ryan Nazemian, MD, PhD, Lahey Hospital and Medical Center, Department of Anesthesiology, Perioperative and Pain Medicine

Study record dates

Study Major Dates

• Study Start (Actual): June 30, 2025
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: March 1, 2025
• First Submitted That Met QC Criteria: March 7, 2025
• First Posted (Actual): March 11, 2025

Study Record Updates

• Last Update Posted (Actual): April 7, 2026
• Last Update Submitted That Met QC Criteria: April 5, 2026
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Postoperative Pain; Ketamine; Methadone; Opioids; Acute Pain; Liver Transplantation; Anesthesiology; Perioperative Analgesia; Deceased Donor Liver Transplant; Transplant Surgery
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Pain, Postoperative; Acute Pain; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Hydrocarbons; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Alkaloids; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Piperidines; Heterocyclic Compounds, 4 or More Rings; Morphinans; Opiate Alkaloids; Heterocyclic Compounds, Bridged-Ring; Phenanthrenes; Morphine Derivatives; Ketones; Ketamine; Fentanyl; Hydromorphone; Methadone
• Other Study ID Numbers: 20243140

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Sensitive transplant data will not be shared for patients privacy

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No