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.

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.

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.

Sensitive transplant data will not be shared for patients privacy

Participants won't be aware of the study arm and treatments they receive. The statistician will be masked on the treatment group during final study analysis.