Perioperative Methadone and Ketamine for Postoperative Pain Control in Spinal Surgical Patients

A Randomized, Double-blind, Placebo-controlled Trial

Glenn S. Murphy, M.D.; Michael J. Avram, Ph.D.; Steven B. Greenberg, M.D.; Jessica Benson, B.S.; Sara Bilimoria, B.S.; Colleen E. Maher, B.S.; Kevin Teister, B.S.; Joseph W. Szokol, M.D.


Anesthesiology. 2021;134(5):697-708. 

In This Article


Despite advances in surgical techniques and anesthetic management, patients undergoing spinal fusion surgery continue to experience moderate-to-severe postoperative pain. In recent years, clinicians have employed multimodal analgesic regimens in order to reduce postoperative pain, enhance functional recovery, and decrease hospital length of stay. Agents that are antagonists of the NMDA receptor may provide particular analgesic benefit in this patient population via an inhibition of sensitization of nociceptive pathways, prevention of opioid-related activation of pronociceptive systems, and attenuation of opioid tolerance and hyperalgesia.[17,18] In this clinical investigation, the antinociceptive effect resulting from the combination of agents acting as both NMDA antagonists and μ-opioid receptor agonists (methadone and ketamine) was assessed. We observed that patients in the methadone/ketamine group required 57% less hydromorphone on the first postoperative day than did those in the methadone group; hydromorphone use was also significantly decreased on postoperative day 2, and total hydromorphone requirements over 3 days was reduced by more than 50%. In addition, pain scores at rest, with coughing, and with movement were lower in patients in the methadone/ketamine group (at 23 of the 24 assessments). The incidences of adverse events were low in both study groups and did not differ. These findings demonstrate that the perioperative combination of methadone and ketamine is highly effective in reducing postoperative analgesic consumption and pain intensity in a patient population typically reporting severe postoperative pain.

Methadone is a unique long-acting μ-opioid receptor agonist that produces prolonged analgesia when given in larger doses (24 to 36 h at doses greater than or equal to 20 mg).[20] In addition, methadone may reduce pain by antagonizing NMDA receptors[21,22] and inhibiting reuptake of serotonin and norepinephrine in the central nervous system.[23,24] Two studies have examined the analgesic effects of a single dose of intraoperative methadone in adult patients undergoing spine surgery. Gottschalk et al. reported that opioid requirements were 50% lower at 48 h in subjects given 0.2 mg/kg of methadone, compared to those given a continuous sufentanil infusion.[14] Similar findings were observed in a trial randomizing 120 patients to receive 0.2 mg/kg of methadone at induction or 2 mg of hydromorphone at the end of spinal surgery.[13] Although both studies reported that pain scores were lower in patients given methadone, pain intensity was still described as moderate during the first 3 postoperative days in these subjects.[13,14] While methadone provides analgesic benefits in this patient population, doses of 0.2 mg/kg alone are insufficient to reduce pain to mild levels (less than or equal to 3 on a 0 to 10 scale)[25] in most subjects.

Like methadone, ketamine inhibits the NMDA receptor,[26] binds to the μ-opioid receptor,[27] and increases concentrations of serotonin and norepinephrine in the brain.[28] The use of ketamine in the setting of spinal fusion surgery has been extensively studied. In the largest randomized study enrolling 150 opioid-dependent patients, subjects given an S-ketamine infusion used 35% less morphine at 24 h than did the placebo group.[29] Patients given a ketamine infusion in a similar large trial required 30 to 37% less morphine 24 to 48 h after surgery than patients given saline.[30] However, pain scores at rest were 4 to 6 on a 0 to 10 scale in the ketamine groups in both studies, and did not differ from groups receiving placebo.[29,30] A meta-analysis of 14 randomized trials reported that patients given adjunctive ketamine for spine surgery consumed less opioid in the first 24 h, but had only slightly lower pain scores compared to control groups.[7] These investigations indicate that the use of supplemental ketamine in spinal surgical patients results in lower opioid consumption in the first 24 h, but may have only a small effect on postoperative pain scores.

A supra-additive synergy between methadone and ketamine has been demonstrated in an experimental neuropathy model.[11,12] Only one previous clinical investigation examined the analgesic benefits of combining these two medications. Pacreu et al. reported that patients given intraoperative methadone, an intraoperative ketamine infusion, and a methadone/ketamine PCA required 70 to 80% less opioid on the first 2 postoperative days, compared to a group given intraoperative methadone, a saline infusion, and a methadone PCA.[31] Similarly, we observed that hydromorphone requirements during the first 48 postoperative hours were reduced by more than 50% in patients given methadone and ketamine when compared to patients given methadone alone. Furthermore, the number of oral opioid medications needed was significantly lower in the methadone/ketamine group on postoperative days 1 and 3, and total use was 45% less in this group.

In contrast to the findings of Pacreu et al., we observed that patients given both methadone and ketamine had lower pain scores after surgery compared to those given methadone alone. Median pain scores at rest, with coughing, and with movement were significantly lower in the methadone/ketamine group from the time of PACU arrival until the late afternoon of postoperative day 3, with the exception of the assessment on the morning of postoperative day 2. In addition, median pain at rest and with coughing was reduced to mild levels (less than or equal to 3 on a 0 to 10 scale) in the methadone/ketamine group from the morning of the first postoperative day through the late afternoon of postoperative day 3. These findings are in contrast to other studies using either methadone or ketamine alone for spinal surgery, in which postoperative pain scores were moderate (mean/median scores of 4 to 6 on a 0 to 10 scale) in patients given these agents.[13,29,30]

Primary goals of enhanced recovery after surgery protocols are to reduce hospital length of stay and to enhance patient recovery. Although we observed a greater analgesic benefit in the methadone/ketamine group for up to 72 h after surgery, these benefits did not translate into a shorter PACU or hospital length of stay. When implementing enhanced recovery after surgery protocols, it is also necessary to document that interventions result in improvements in subjective outcomes that are important to patients, such as overall satisfaction.[32] Previous studies have shown that surgical patients given adjunctive methadone[13] or ketamine[33] reported higher satisfaction scores in the early recovery period. In the current investigation, we observed that patient satisfaction with pain management was better in the methadone/ketamine patients on the morning of the first postoperative day. Thereafter, median satisfaction scores were 9 on scale of 0 to 10 in the methadone group, which did not significantly differ from the scores of the methadone/ketamine group. These results, and findings from previous trials,[34] suggest that patient satisfaction with pain management is high when methadone is used, and that there is little incremental benefit of adding ketamine on this outcome measure.

There are a number of adverse events that may be associated with the use of either methadone or ketamine in the perioperative setting, which include nausea/vomiting, respiratory depression, sedation, itching, tachycardia/hypertension, and hallucinations/vivid dreams.[6–9] Reviews and meta-analyses have reported that the incidences of these adverse outcomes are no higher in patients given either methadone[9,34] or ketamine[6–8] than in control group patients managed with standard care. The risks of using methadone and ketamine together in the perioperative period, however, have not been defined. In this trial, the percentage of patients developing adverse events involving the respiratory system (hypoxemia, hypoventilation), central nervous system (sedation, hallucinations, dizziness), and gastrointestinal system (nausea, vomiting) was low, and no differences between groups were observed. Similarly, the overall incidences of complications during the entire hospitalization (cardiac, respiratory, gastrointestinal, neurologic, infection, and renal) did not differ between the two groups. Although we observed an additive analgesic effect of combining methadone and ketamine, the use of both agents together did not appear to increase the risk of postoperative complications.

There are several limitations to this investigation. First, ideal dosing regimens for methadone and ketamine (when used alone or in combination) are unknown;[9,17] further studies are needed to identify the optimal dose of methadone and ketamine when combined. Second, intraoperative fentanyl and hydromorphone could be given, in addition to the baseline remifentanil infusion, at the discretion of the anesthesia care team (a standard practice at our institution). Quantification of intraoperative opioid requirements would have been simplified if a single opioid had been given. Furthermore, dosing of opioids was at the discretion of the anesthesia care team and was not based on standard criteria such as hemodynamic responses or on data provided from nociception monitors. Third, an intraoperative remifentanil infusion was used in all patients, as is standard practice in major spine surgery at our institution. Remifentanil may produce opioid-induced hyperalgesia, and after methadone administration at anesthetic induction, the additional analgesia provided by the infusion was likely not required. Furthermore, total remifentanil doses were not recorded. However, the doses calculated from actual patient body weights, the durations of anesthesia, and remifentanil infusion rates were similar between groups (3.0 ± 1.5 mg in the methadone group and 2.7 ± 1.2 mg in the methadone/ketamine group).

Postoperative pain is often difficult to manage in patients undergoing spinal fusion surgery. In this clinical trial, spinal surgical patients randomized to receive intraoperative methadone with a perioperative ketamine infusion required significantly less opioid pain medication and reported lower pain scores during the first 3 postoperative days, compared to those given methadone alone. Postoperative analgesia can be significantly enhanced in this patient population by using a combination of agents that act on both the NMDA and μ-opioid receptors.