Intraoperative Methadone is Associated with Decreased Perioperative Opioid Use Without Adverse Events: A Case-Matched Cohort Study

Robinson JD, Caruso TJ, Wu M, Kleiman ZI, Kwiatkowski DM 

Journal of Cardiothoracic and Vascular Anesthesia 2020; 34: 335-341
DOI:  10.1053/j.jvca.2019.09.033
PMID:  31699597

Take Home Points

  • Intraoperative methadone was associated with a decrease of total opioid exposure during the early postoperative period with comparable analgesic efficacy and no increase in adverse events compared to the control group.
  • Corrected QTc prolongation was not increased in the methadone group when compared to the control group.

Commentary by Destiny F. Chau, MD
Pediatric Cardiac Anesthesiologist at Arkansas Children’s Hospital in Little Rock, Arkansas

Opioids have a critical role in the pain management of pediatric patients undergoing congenital heart surgery. The advantages of perioperative opioids are eclipsed by their associated risks of short-term and long-term adverse events, including concerns for persistent opioid use and undue exposure in the setting of the current opioid crisis. Efforts continue in the search for effective opioid-sparing strategies for perioperative pain management, and also for maximizing the benefits of the chosen opioids while minimizing their side effects.  The available literature, mostly from adult studies, suggest that the intraoperative use of long-acting opioids such as methadone, may decrease total perioperative opioid exposure without an increase in complications.  

The authors of this single-center retrospective, case-matched cohort study primarily aimed to evaluate the association of intraoperative methadone use on total perioperative opioid exposure in children undergoing congenital heart surgery. Secondary outcomes included the association of intraoperative methadone with adverse events, clinical outcomes and dose-dependent effect on total opioid use.  Pediatric patients receiving intraoperative methadone during congenital heart surgery from November 2017 to July 2018 were retrospectively identified via a pharmaceutical electronic database. Each of them was matched according to age and surgical procedure with a control who did not receive methadone. Patients were excluded if they received opioids the day before the surgery, had postoperative nerve blocks, had delayed sternal closure, required additional procedures during the first postoperative 24 hours or had not found a matched control. A total of 37 patients were matched 1:1 with a control patient. The intraoperative use and dosing of methadone was at the discretion of the attending anesthesiologist.  Anesthetic managements were not standardized, including use of other opioids and sedatives. Postoperatively, analgesic control followed the cardiac intensive care units (ICU) multimodal pain management protocols. For analysis purposes, all intravenous and enteral opioids were converted to morphine equivalents per kilogram and were compared in 12-hour blocks until 36 hours postoperatively.  Also, patients in the methadone group were divided into low-dose (N = 22; 0.2 mg/kg or less) and high-dose (N = 15; over 0.2 mg/kg) to study dose-dependent effects.

Both cohorts were similar in demographics and surgical bypass times. Median age and weight were 8.9 years and 22.9 kg for the methadone and 7.4 years and 26.3 kg for the control groups. Surgical procedures had a median complexity category of 3 and interquartile range of two to four per the Society of Thoracic Surgeons-European Association of Cardio-Thoracic Surgery (STAT) system. Cardiopulmonary bypass (CPB) was used in 33 patients (89%). Methadone dosages ranged from 0.1 to 0.4 mg/kg with a maximum of 30 mg, with the majority of the overall dose given during the earlier parts of the case and administered prior to commencement of CPB. Use of nonopioid sedatives and anesthetics, including inhaled agents were comparable between cohorts. Two patients in each group were extubated in the operating room. More patients in the methadone group received intraoperative morphine, while none received benzodiazepines in the ICU period as compared to the control group.

Primary outcome results showed decreased total opioid dose in the methadone group versus the control group intraoperatively (2.51 v 4.39 mg morphine equivalent/kg), during the initial 12 hours postoperatively (0.43 v 1.28 mg morphine equivalent/kg), and cumulatively during the entire postoperative 36 hours (0.83 v 1.91 morphine equivalents/kg). No difference was found during the second and third 12-hour time blocks.  For secondary outcomes, intraoperative methadone was not associated with time to extubation, postoperative pain scores, postoperative nausea and vomiting, ICU length of stay, rate of extubation failure or in-hospital mortality. Corrected QTc prolongation was not increased in the methadone group when compared to the control group. No difference was observed in total opioid exposure based on high or low methadone dosing.

What does this mean for us?
Retrospective study limitations aside, the authors are commended for studying the use of intraoperative methadone in this patient population in the quest of achieving adequate analgesia with lower opioid exposure and minimal adverse effects. 

Although the results report a total opioid exposure reduction during the first postoperative 12-hour period that was not sustained through the second and third 12-hour blocks, the total cumulative dose (intraoperatively through the postoperative 36 hours) were reduced with comparable analgesic effectiveness and without an observed increase in complications. This is promising data for methadone’s role as part of the armamentarium to improve safe effective care for all patients while combating the opioid epidemic and navigating through different periodic opioid shortages. 

Methadone is a synthetic μ-opioid agonist with N -methyl-D-aspartate receptor antagonism properties, whose pharmacokinetics and pharmacodynamics in children are not well studied. Methadone is described to have a rapid onset and long elimination half-life, which would clinically suggest a relatively fast onset of action with prolonged effect and less frequent redosing.  Sharma and his group found that the pharmacokinetics of methadone in adolescents undergoing non-cardiac surgery were comparable to those in adults. The Society for Pediatric Anesthesia, providing guidance for perioperative opioid use in children, reports that “methadone pharmacodynamics effects are prolonged compared to morphine and the pharmacokinetic profile appears to be consistent across pediatric age ranges”. In this study, an important factor to highlight is that most of the methadone dosing occurred prior to starting CPB; CPB would alter methadone’s pharmacokinetics due to the added volume of distribution from the prime and exposure to the bypass circuit surfaces. As a speculation, dosing methadone after CPB separation has the potential to confer a longer postoperative opioid-sparing time period.

In conclusion, this single-center retrospective cohort-matched study explored the opioid-sparing effect of intraoperative methadone use on pediatric patients undergoing congenital cardiac surgery. The results showed that intraoperative methadone was associated with a decrease of total opioid exposure during the early postoperative period with comparable analgesic efficacy and no increase in adverse events compared to the control group. This promising concept should be further investigated with prospective trials including larger number of patients and expanded age range to better characterize methadone’s role during congenital cardiac surgery.

References:

  1. Robinson JD, Caruso TJ, Wu M, Kleiman ZI, Kwiatkowski DM. Intraoperative Methadone Is Associated with Decreased Perioperative Opioid Use Without Adverse Events: A Case-Matched Cohort Study. J Cardiothorac Vasc Anesth. 2020; 34(2): 335–341.
  2. Sharma A, Tallchief D, Blood J, Kim T, London A, Kharasch ED. Perioperative Pharmacokinetics of Methadone in Adolescents.  Anesthesiology 2011; 115(6): 1153-1161.
  3. Cravero JP, Agarwal R, Berde C, et al. The Society for Pediatric Anesthesia Recommendations for the Use of Opioids in Children During the Perioperative Period. Paediatr Anaesth. 2019; 29(6): 547–571.
  4. Valencia E, Nasr VG. Is Methadone an Opioid Sparing Strategy?J Cardiothorac Vasc Anesth. 2020 Feb; 34(2):342-343. Nov 16.

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