Abstract and Introduction
Background: Despite application of multimodal pain management strategies, patients undergoing spinal fusion surgery frequently report severe postoperative pain. Methadone and ketamine, which are N-methyl-D-aspartate receptor antagonists, have been documented to facilitate postoperative pain control. This study therefore tested the primary hypothesis that patients recovering from spinal fusion surgery who are given ketamine and methadone use less hydromorphone on the first postoperative day than those give methadone alone.
Methods: In this randomized, double-blind, placebo-controlled trial, 130 spinal surgery patients were randomized to receive either methadone at 0.2 mg/kg (ideal body weight) intraoperatively and a 5% dextrose in water infusion for 48 h postoperatively (methadone group) or 0.2 mg/kg methadone intraoperatively and a ketamine infusion (0.3 mg · kg−1 · h−1 infusion [no bolus] intraoperatively and then 0.1 mg · kg−1 · h−1 for next 48 h [both medications dosed at ideal body weight]; methadone/ketamine group). Anesthetic care was standardized in all patients. Intravenous hydromorphone use on postoperative day 1 was the primary outcome. Pain scores, intravenous and oral opioid requirements, and patient satisfaction with pain management were assessed for the first 3 postoperative days.
Results: Median (interquartile range) intravenous hydromorphone requirements were lower in the methadone/ketamine group on postoperative day 1 (2.0 [1.0 to 3.0] vs. 4.6 [3.2 to 6.6] mg in the methadone group, median difference [95% CI] 2.5 [1.8 to 3.3] mg; P < 0.0001) and postoperative day 2. In addition, fewer oral opioid tablets were needed in the methadone/ketamine group on postoperative day 1 (2 [0 to 3] vs. 4 [0 to 8] in the methadone group; P = 0.001) and postoperative day 3. Pain scores at rest, with coughing, and with movement were lower in the methadone/ketamine group at 23 of the 24 assessment times. Patient-reported satisfaction scores were high in both study groups.
Conclusions: Postoperative analgesia was enhanced by the combination of methadone and ketamine, which act on both N-methyl-D-aspartate and μ-opioid receptors. The combination could be considered in patients having spine surgery.
In the United States, 80% of surgical patients reported postoperative pain, with 88% of these patients describing pain intensity as moderate to severe. Poorly controlled postoperative pain can contribute to adverse events, including morbidity, increased hospitalization costs, impaired quality of life, prolonged opioid use, and chronic postsurgical pain. Patients undergoing spinal fusion surgery are at high risk for moderate-to-severe postoperative pain and associated complications. In a study comparing pain scores in 179 surgical procedures, 3 of the 6 surgeries with a median pain score of 7 on postoperative day 1 (rating scale of 0 to 10) were major spinal procedures. Risk factors for severe postoperative pain in this patient population include significant surgical trauma, preexisting neuropathic pain, preoperative opioid use (and associated tolerance, hyperalgesia, and allodynia), and perioperative anxiety/mood disorders. Therefore, techniques to reduce postoperative pain are essential in optimizing outcomes in these patients.
Multimodal pain management regimens, which involve use of additive or synergistic combinations of analgesics, are effective in reducing postoperative pain, decreasing opioid use, and attenuating complications. Therapeutic strategies utilizing acetaminophen, nonsteroidal anti-inflammatory agents, steroids, lidocaine, and long-acting local anesthetics have been shown to improve postoperative pain outcomes and enhance recovery.[1,5] Antagonists of the N-methyl-D-aspartate (NMDA) receptor, such as ketamine and methadone, have also been used as components of multimodal anesthetic protocols. Postoperative pain scores and opioid use are significantly reduced in spinal surgical patients given ketamine[6–8] or methadone compared to control groups. Furthermore, enhanced-recovery-after-surgery protocols for spine surgery have recommended use of methadone and ketamine as part of a multimodal therapeutic approach for postoperative pain.[5,10] In an experimental neuropathy model, a supra-additive synergy between methadone and ketamine to produce antinociception has been documented.[11,12] Currently, however, there is limited evidence of the efficacy of a combination of the two agents on outcomes in this patient population.
Recent literature has supported the safety of intraoperative methadone; studies have documented that the incidences of adverse outcomes did not differ between patients given this long-acting agent and those given traditional shorter-acting opioids. In a previous investigation, we observed that patients undergoing spinal fusion surgery given intraoperative methadone required less opioid medication and had lower postoperative pain scores than those given conventional opioids, with no differences in adverse outcomes observed between groups. However, postoperative hydromorphone use remained relatively high in the methadone group (4.6 mg in the first 24 h), and moderate pain was reported in these subjects (median scores of 4 to 6 on a 0 [no pain] to 10 [worst pain imaginable] numeric rating scale). The aim of this randomized, double-blind, placebo-controlled trial in spinal surgical patients was to determine whether addition of a ketamine infusion to a methadone-based opioid regimen would further reduce opioid requirements and pain scores (to mild levels, scores of 3 or lower) after spine surgery. We therefore tested the primary superiority hypothesis that adding ketamine to methadone reduces hydromorphone requirement on the first postoperative day after spine surgery compared to methadone alone. Secondary outcome measures included hydromorphone requirements on postoperative days 2 and 3, pain scores, patient satisfaction with pain management, and any potential complications associated with methadone or ketamine administration.
Anesthesiology. 2021;134(5):697-708. © 2021 American Society of Anesthesiologists | Lippincott Williams & Wilkins