Methadone Pharmacokinetics in Cardiac Surgery

Evaluating Pharmacokinetics of Three Methadone Dosing Strategies During Cardiac Surgery With Cardiopulmonary Bypass

Cardiac surgery frequently leads to significant postoperative pain, with multiple different drug regimens being utilized (both opioid and non-opioid) in an attempt to alleviate this surgical pain. Methadone is currently one of the drugs that is being utilized to help control the pain. It can be given during and/or after surgery. This study hopes to identify the optimal dose of methadone to use to treat this surgical pain.

Study Overview

• Status: Not yet recruiting
• Conditions: Postoperative Pain Management
• Intervention / Treatment: Drug: Single dose of methadone; Drug: Split dose of methadone; Drug: Balanced split dose of methadone

Detailed Description

The uncertainty regarding optimal methadone dosing and the necessity of post-cardiopulmonary bypass (CPB) supplementation provides a compelling rationale for this study. Specifically, it remains unknown whether a single higher initial dose of methadone can adequately maintain analgesic plasma concentrations throughout cardiac surgery and recovery, or if a split-dosing strategy administering a lower initial dose followed by an additional dose post-CPB might offer similar or improved analgesic outcomes with fewer side effects. This study will evaluate pharmacokinetics of methadone using three different dosing strategies in patients undergoing cardiac surgery with CPB.

• Study Type: Interventional
• Enrollment (Estimated): 69
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Lynnette Harris, BSN; Phone Number: 336-716-8791; Email: lynnette.harris@advocatehealth.org
• Study Contact Backup: Name: Ettore Crimi, MD; Phone Number: 336-716-4498; Email: ettore.crimi@advocatehealth.org

Study Locations

• United States
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
      • Contact: Lynnette Harris, BSN, RN; Phone Number: 336-306-0778; Email: Lynnette.Harris@Advocatehealth.org
      • Principal Investigator: Ettore Crimi, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Elective cardiac surgery requiring median sternotomy and cardiopulmonary bypass (CABG, valve, combined CABG/valve surgeries)
• Anticipated extubation within 12 hours postoperatively
• No prior opioid use within 30 days of surgery
• Ability to provide informed consent

Exclusion Criteria:

• Severe liver or kidney dysfunction (Child-Pugh class B/C, eGFR <30 mL/min/1.73m², creatinine >2 mg/dL, dialysis)
• Allergy to methadone or fentanyl
• Use of CYP3A4 inducers (rifampin, phenytoin, carbamazepine), CYP3A4 inhibitors (ketoconazole, erythromycin, clarithromycin, itraconazole), SSRIs (fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine)
• Body mass index >40 kg/m²
• Corrected QT interval interval >500 milliseconds
• Intubation anticipated >12 hours
• History of illicit drug use or alcohol or opioid abuse use disorder within last 12 months
• Mechanical circulatory support, heart transplant, deep hypothermic circulatory arrest procedures
• Left Ventricular Ejection Fraction <30%
• Pulmonary disease requiring oxygen therapy
• Preoperative inotropic support or intra-aortic balloon pump
• Emergency surgery
• Postoperative regional anesthesia
• Hemofiltration during cardiopulmonary bypass

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Single dose of methadone; Single dose of methadone administered at induction of anesthesia	Drug: Single dose of methadone; Single dose of methadone 0.3 mg/kg actual body weight (max 30 mg) administered at induction of anesthesia
Experimental: Split dose of methadone; Split dose of methadone post cardiopulmonary bypass	Drug: Split dose of methadone; Split dose of methadone 0.2 mg/kg actual body weight at induction and 0.1 mg/kg actual body weight post cardiopulmonary bypass
Experimental: Balanced split dose of methadone; Balanced split dose of methadone post cardiopulmonary bypass	Drug: Balanced split dose of methadone; Balanced split dose of methadone 0.15 mg/kg actual body weight at induction and 0.15 mg/kg actual body weight post cardiopulmonary bypass

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma methadone concentration (ng/mL) 10 min post initial dose	Plasma methadone concentration will be measured 10 minutes post initial methadone dose	10 minutes
Plasma methadone concentration (ng/mL) 30 min post initial dose	Plasma methadone concentration will be measured 30 minutes post initial methadone dose pre cardiopulmonary bypass	30 minutes
Plasma methadone concentration (ng/mL) 60 min post initial dose	Plasma methadone concentration will be measured 60 minutes post initial methadone dose pre cardiopulmonary bypass	60 minutes
Plasma methadone concentration (ng/mL) 10 min post start of cardiopulmonary bypass	Plasma methadone concentration will be measured 10 minutes after cardiopulmonary bypass started	10 minutes
Plasma methadone concentration (ng/mL) 30 min post start of cardiopulmonary bypass	Plasma methadone concentration will be measured 30 minutes after cardiopulmonary bypass started	30 minutes
Plasma methadone concentration (ng/mL) 60 min post start of cardiopulmonary bypass	Plasma methadone concentration will be measured 60 minutes after cardiopulmonary bypass started	60 minutes
Plasma methadone concentration (ng/mL) 10 min post cardiopulmonary bypass completion	Plasma methadone concentration will be measured 10 minutes after cardiopulmonary bypass ended	10 minutes
Plasma methadone concentration (ng/mL) 120 min post start of cardiopulmonary bypass	Plasma methadone concentration will be measured 120 minutes after cardiopulmonary bypass started	120 minutes
Plasma methadone concentration (ng/mL) before first analgesic request	Plasma methadone concentration will be measured at the time of first analgesic request by participant	up to 72 hours
Plasma methadone concentration (ng/mL) 3 hours post Intensive Care Unit arrival	Plasma methadone concentration will be measured 3 hours post Intensive Care Unit arrival	3 hours
Plasma methadone concentration (ng/mL) 12 hours post Intensive Care Unit arrival	Plasma methadone concentration will be measured 12 hours post Intensive Care Unit arrival	12 hours
Plasma methadone concentration (ng/mL) 24 hours post Intensive Care Unit arrival	Plasma methadone concentration will be measured 24 hours post Intensive Care Unit arrival	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pain intensity score	Pain intensity score will be measured using the visual analog scale. Scores will be measured on a scale of 0-10, with 0=no pain and 10=most severe pain	2, 4, 8, 12, 24, 48, and 72 hours postoperatively and month 3
patient global impression of change	Patient Global Impression of Change will be used to assess patient-perceived analgesic effectiveness and overall postoperative recovery. Total score range is 1-7 with a higher score indicating considerable improvement with treatment.	24, 48, and 72 hours after removal of the breathing tube
postoperative opioid consumption	total postoperative opioid consumption in morphine milligram equivalents	up 72 hours postop
duration of postoperative mechanical ventilation	number of minutes with postoperative mechanical ventilation	up to 72 hours postop
time of ambulation	number of minutes until patient first ambulates after surgery	up to 48 hours postop
length of Intensive Care Unit stay	number of hours spent in Intensive Care Unit	up to 3 days postop
length of hospital length stay	number of days spent in hospital	up to 7 days postop

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Investigators: Principal Investigator: Ettore Crimi, MD, Wake Forest University Health Sciences

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: November 4, 2025
• First Submitted That Met QC Criteria: November 6, 2025
• First Posted (Actual): November 10, 2025

Study Record Updates

• Last Update Posted (Actual): May 26, 2026
• Last Update Submitted That Met QC Criteria: May 22, 2026
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: cardiac surgery; methadone; pain management; methadone pharmacokinetics; cardiac surgery recovery
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Neurobehavioral Manifestations; Perceptual Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Agnosia; Organic Chemicals; Ketones; Methadone
• Other Study ID Numbers: IRB00136746

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: study results will be shared instead of individual patient data

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