Intraoperative intravenous methadone dose and postoperative pain outcomes in CABG patients: a retrospective cohort study

Technical Summary: Intraoperative Intravenous Methadone Dose and Postoperative Pain Outcomes in CABG Patients

Problem Statement
Coronary artery bypass grafting (CABG) is a major cardiac surgery associated with significant postoperative pain due to sternotomy, rib retraction, and chest tube placement. Effective pain management is critical to prevent complications such as respiratory depression, myocardial ischemia, and chronic pain syndrome. While intraoperative methadone is increasingly utilized for its long half-life and NMDA receptor antagonism, the optimal dosing strategy for CABG patients remains unclear. Existing literature supports perioperative methadone use, but it is uncertain whether higher intraoperative doses (≥20 mg) provide superior analgesia or reduced opioid consumption compared to lower doses (<20 mg) in this specific population.

Methodology
This study was a single-center, retrospective cohort study conducted at the University of California, San Diego, reviewing patients who underwent CABG between January 1, 2021, and September 30, 2024.

• Cohort: 41 opioid-naïve adult patients were included after exclusions for prolonged intubation (>12 hours), illicit drug history, subsequent surgery within 72 hours, missing QTc data, or intraoperative extubation.
• Grouping: Patients were stratified into two groups based on the intraoperative intravenous methadone dose received:
  • Low-dose group: <20 mg (n=20).
  • High-dose group: ≥20 mg (n=21).
• Primary Outcome: Total postoperative opioid consumption during the first 72 hours, converted to oral morphine milligram equivalents (MME).
• Secondary Outcomes: Postoperative pain scores (Numeric Rating Scale, NRS) on postoperative days (POD) 1–3, ICU length of stay, time to extubation, incidence of QTc interval prolongation (>500 ms), and naloxone use.
• Statistical Analysis: Continuous variables were compared using Student's t-tests or Mann-Whitney U tests, while categorical variables were analyzed using chi-square or Fisher's exact tests. A p-value <0.05 was considered statistically significant.

Key Results

• Baseline Characteristics: The high-dose group had significantly higher median weight (95.6 kg vs. 74.2 kg) and BMI (33 vs. 28) compared to the low-dose group (p < 0.001). All patients were opioid-naïve.
• Opioid Consumption: There was no statistically significant difference in total 72-hour postoperative opioid consumption between the low-dose and high-dose groups (86.1 ± 75.7 MME vs. 150.1 ± 153.6 MME; p = 0.098). While the low-dose group showed numerically lower consumption on POD 1, 2, and 3, these differences did not reach statistical significance.
• Pain Scores: Mean pain scores were numerically lower in the low-dose group across all three postoperative days, but no statistically significant differences were observed (e.g., POD 1: 3.3 vs. 3.9; p = 0.374).
• Safety and Recovery: No significant differences were found in ICU length of stay (median 2.0 days for both groups), time to extubation, or the incidence of QTc prolongation (>500 ms), although the high-dose group had a higher numerical incidence of QTc prolongation (24% vs. 10%; p = 0.24). No patients required naloxone.

Key Contributions
This study is the first to evaluate the impact of two distinct intraoperative methadone dosing strategies (low-dose vs. high-dose) specifically on postoperative pain control and opioid requirements in CABG patients. Unlike previous studies that compared methadone to non-methadone regimens, this research isolates the variable of methadone dosage magnitude. The findings suggest that within the evaluated ranges, lower intraoperative methadone doses may provide analgesia comparable to higher doses without increasing postoperative opioid requirements.

Significance and Claims
The authors conclude that there are no statistically significant differences in postoperative opioid consumption, pain scores, or key safety endpoints (ICU stay, extubation time, QTc prolongation) between CABG patients receiving low-dose (<20 mg) versus high-dose (≥20 mg) intraoperative methadone.

The paper modestly suggests that lower doses may offer comparable analgesia to higher doses in this context. However, the authors explicitly note limitations, including the small sample size, the retrospective nature of the study, and the confounding factor that the high-dose group had significantly higher body weights. They posit that the lack of observed differences might reflect appropriate dose selection based on patient body habitus rather than true equivalence between dosing strategies. Consequently, the authors state that larger prospective studies are required to confirm these results and to better characterize patient-specific factors for individualized dosing.