Methadone Pharmacokinetics in Cardiac Surgery

Official title

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

Overview

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.

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.

Interventions

• Drug Single dose of methadone
  Single dose of methadone 0.3 mg/kg actual body weight (max 30 mg) administered at induction of anesthesia
• 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
• 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

Primary outcome measures

• Plasma methadone concentration (ng/mL) 10 min post initial dose [Time frame: 10 minutes]
• Plasma methadone concentration (ng/mL) 30 min post initial dose [Time frame: 30 minutes]
• Plasma methadone concentration (ng/mL) 60 min post initial dose [Time frame: 60 minutes]
• Plasma methadone concentration (ng/mL) 10 min post start of cardiopulmonary bypass [Time frame: 10 minutes]
• Plasma methadone concentration (ng/mL) 30 min post start of cardiopulmonary bypass [Time frame: 30 minutes]
• Plasma methadone concentration (ng/mL) 60 min post start of cardiopulmonary bypass [Time frame: 60 minutes]
• Plasma methadone concentration (ng/mL) 10 min post cardiopulmonary bypass completion [Time frame: 10 minutes]
• Plasma methadone concentration (ng/mL) 120 min post start of cardiopulmonary bypass [Time frame: 120 minutes]
• Plasma methadone concentration (ng/mL) before first analgesic request [Time frame: up to 72 hours]
• Plasma methadone concentration (ng/mL) 3 hours post Intensive Care Unit arrival [Time frame: 3 hours]

Secondary outcome measures (7)

• pain intensity score [Time frame: 2, 4, 8, 12, 24, 48, and 72 hours postoperatively and month 3]
• patient global impression of change [Time frame: 24, 48, and 72 hours after removal of the breathing tube]
• postoperative opioid consumption [Time frame: up 72 hours postop]
• duration of postoperative mechanical ventilation [Time frame: up to 72 hours postop]
• time of ambulation [Time frame: up to 48 hours postop]
• length of Intensive Care Unit stay [Time frame: up to 3 days postop]
• length of hospital length stay [Time frame: up to 7 days postop]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Wake Forest University Health Sciences — Winston-Salem

Identifiers

NCT: NCT07226245 · IRB00136746

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗