Intraoperative Methadone in Next-day Discharge Outpatient Surgery: A Randomized, Double-blinded, Dose-finding Pilot Study

Abstract

Background Contemporary perioperative practice seeks to use less intraoperative opioid, diminish postoperative pain and opioid use, and enable less post-discharge opioid prescribing. For inpatient surgery, anesthesia with intraoperative methadone, compared with short-duration opioids, results in less pain, less postoperative opioid use, and greater patient satisfaction. This pilot investigation aimed to determine single-dose intraoperative methadone feasibility for next-day discharge outpatient surgery, determine an optimally analgesic and well-tolerated dose, and explore whether methadone would result in less postoperative opioid use compared with conventional short-duration opioids. Methods This double-blind, randomized, dose-escalation feasibility and pilot study in next-day discharge surgery compared intraoperative single-dose intravenous methadone (0.1 then 0.2, 0.25 and 0.3 mg/kg ideal body weight) versus as-needed short-duration opioid (fentanyl, hydromorphone) controls. Perioperative opioid use, pain, and side effects were assessed before discharge. Patients recorded pain, opioid use, and side effects for 30 days postoperatively using take-home diaries. Primary clinical outcome was in-hospital (intraoperative and postoperative) opioid use. Secondary outcomes were 30d opioid consumption, pain, opioid side effects, and left-over opioid counts. Results Median (IQR) intraoperative methadone doses were 6 (5-7), 11 (10-12), 14 (13-16), and 18 (15-19) mg in 0.1, 0.2, 0.25, and 0.3 mg/kg ideal body weight groups, respectively. Anesthesia with single-dose methadone and propofol or volatile anesthetic was effective. Total in-hospital opioid use (mg IV morphine equivalents) was 25 (20-37), 20 (13-30), 27 (18-32), and 25 (20-36) mg, respectively, in patients receiving 0.1, 0.2, 0.25 and 0.3 mg/kg methadone, compared to 46 (33-59) mg in short-duration opioid controls. Opioid-related side effects were not numerically different. Home pain and opioid use were numerically lower in patients receiving methadone. Conclusion The most effective and well-tolerated single intraoperative induction dose of methadone for next-day discharge surgery was 0.25 mg/kg ideal body weight (median 14 mg). Single-dose intraoperative methadone was analgesic and opioid-sparing in next-day discharge outpatient surgery.

Consideration of Methadone as an Analgesic Option for Short-stay Surgery

“…Kharasch et al found that there was marked interindividual variability in opioid use, with some patients not using any postoperative opioids while others used them throughout the full 30-day follow-up period. 8 Some dose-dependent differences in opioid use were seen during the inpatient period and first 7 postoperative days, and the groups were largely similar for the remainder of the 30-day course. The median duration of postoperative opioid use for the whole study cohort was 3 days.…”

“…Kharasch et al fulfilled their feasibility criteria, in that a high proportion of eligible patients were willing to consent to the study (55%), anesthesiology providers were compliant with the protocol (93%), and completion rates of in-hospital patient follow-up and assessments (96%) and patient-reported outcome surveys (72%) were high. 8 These results are very encouraging. Feasibility (pilot) trials are strongly recommended when planning a large (phase 3) clinical trial.…”

“…9 Kharasch et al also studied a broad range of pain and other clinical outcomes, most repeatedly over many weeks. 8 This long list of secondary endpoints might be criticized in a phase 3 trial because multiple testing leads to increased risk of type 1 error ("false positives"). This is not a concern in feasibility trials, for which more data offer more information-this provides them and other researchers with likely analgesic efficacy and safety data.…”

“…In this issue of the Journal, Kharasch et al explored the optimal analgesic dose of methadone for use in overnight short-stay surgery using a randomized, double-blind, dose-finding (phase 2b) trial design. 8 Their primary aim was to evaluate feasibility, because their main objective was to collect sufficient pilot data to design a definitive large-scale clinical trial. Kharasch et al enrolled adults (age 18 to 65 yr) undergoing elective surgery during general anesthesia with a planned overnight hospital stay.…”

“…Kharasch et al’s trial 8 has many strengths An appropriate range of methadone doses were evaluated, a large number of efficacy and safety endpoints were measured during the complete 30-day postoperative period, and patient diary entries and pill counts were included. There were also limitations.…”