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.

Disclosures

Anesthesiology. 2021;134(5):697-708. 

In This Article

Results

The trial was conducted in accordance with the original protocol, and enrollment ceased when the target sample size was obtained. One hundred thirty patients were enrolled in the study and randomized to receive the study medications. Three patients in the methadone group were excluded before study participation because the pharmacy was unable to provide study drugs before the start of the procedure. Therefore, data were collected and analyzed on a total of 127 subjects (61 patients in the methadone group and 66 patients in the methadone/ketamine group). The flow of patients through the study is presented in Figure 1.

Figure 1.

Consolidate Standards of Reporting Trials (CONSORT) flow diagram for the randomized, placebo-controlled, double-blind trial of methadone (control group) and methadone/ketamine in patients undergoing spinal fusion surgery.

The two study groups were similar in preoperative characteristics including age, sex, height, weight, American Society of Anesthesiologists Physical Status, and preexisting medical conditions (Table 1). Preoperative sedation scores were similar between groups, as were the incidences of nausea, vomiting, dizziness, and itching. The use of preoperative opioid medications did not differ between groups.

Perioperative data are presented in Table 2. The two study groups did not differ in the types of surgical procedures or number of vertebrae fused. Similar amounts of fentanyl and hydromorphone were given to each study group. No differences in the times between the end of surgery and tracheal extubation, the durations of the procedures, or the times to meet PACU discharge criteria or achieve actual discharge were observed between groups.

The time until first hydromorphone rescue in the PACU was longer in the methadone/ketamine group compared to the methadone group (Table 2). The use of hydromorphone during the first 24 postoperative hours (total dose from PACU nursing staff and PCA device) was significantly reduced in patients in the methadone/ketamine group compared to those in the methadone group (primary outcome, median [interquartile range], 2.0 [1.0 to 3.0] mg vs. 4.6 [3.2 to 6.6] mg; median difference [95% CI], 2.5 [1.8 to 3.3] mg; P < 0.0001; Table 3). Similarly, the need for PCA hydromorphone was less in this group on postoperative day 2, as was total use over 3 days (2.7 [1.0 to 4.8] mg vs. 5.8 [3.9 to 9.2] mg in the methadone group; P < 0.0001; Figure 2). Patients in the methadone/ketamine group also requested fewer oral opioid tablets on postoperative days 1 and 3, and the total use over the 3 days was less in this group (11 [4.25 to 16] vs. 20 [12 to 30] in the methadone group; P < 0.0001; Figure 2).

Figure 2.

Analgesic requirements in the postanesthesia care unit (PACU), in the first, second, and third 24 h postoperatively and the total requirements from the PACU to the end of the third 24 h postoperatively. (A) Median (interquartile range) intravenous hydromorphone requirements for the patients in the methadone group and those in the methadone/ketamine group with a forest plot of the difference (99% CI) between the groups. (B) Median (interquartile range) number of hydrocodone 5 mg/acetaminophen 325 mg tablets required by the patients in the methadone group and those in the methadone/ketamine group with a forest plot of the difference (99% CI) between the groups.

Preoperative pain scores did not differ between the study groups (Table 4). Median pain scores at rest, with coughing, and with movement were all significantly less in the methadone/ketamine group, compared to the methadone group, from the time of PACU admission until the afternoon of postoperative day 3 (all P = 0.006 to P < 0.0001), with the exception of pain at rest on the morning of postoperative day 2 (P = 0.039; Table 4). Patient satisfaction with pain management, reported on a 0 to 10 numeric rating scale, was improved in patients in the methadone/ketamine group on the morning of the first postoperative day (10 [9 to 10] vs. 8 [8 to 10] in the methadone group; P = 0.008; Table 4). Thereafter, satisfaction scores in both groups were high (all median scores 9 to 10) and did not differ between groups.

Adverse events possibly related to methadone and ketamine administration are reported in Supplemental Digital Content tables 1 (https://links.lww.com/ALN/C570) and 2 (https://links.lww.com/ALN/C571). Median sedation scores were 0 (fully awake) in both study groups on postoperative days 1 through 3 and did not differ between groups. The incidences of nausea, vomiting, need for treatment of emetic episodes, and itching did not differ between groups. The percentage of patients reporting hallucinations during the first 3 postoperative days was low (0 to 6%) and similar in the study groups. No differences between groups in episodes of dizziness were noted during those days. In addition, a similar percentage of patients in both groups had hypoxemic events (0 to 6.6% of patients) and hypoventilation episodes (0 to 11.5% of patients). Hemodynamic variables in the operating room (Supplemental Digital Content table 3, https://links.lww.com/ALN/C572) and during postoperative days 1 through 3 (Supplemental Digital Content table 2, https://links.lww.com/ALN/C571) did not differ between groups.

Cardiac, respiratory, gastrointestinal, renal, neurologic, or infection complications during the hospitalization were infrequent in both the methadone group (0 to 3.3%) and the methadone/ketamine groups (0%; Table 2). The duration of hospitalization was similar in both study cohorts (Table 2).

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