Perioperative Methadone and Ketamine for Postoperative Pain Control in Spinal Surgical Patients: A Randomized, Double-blind, Placebo-controlled Trial

The Institutional Review Board of NorthShore University HealthSystem (Evanston, Illinois) approved this randomized, double-blind, placebo-controlled clinical trial (registry, ClinicalTrials.gov; registration number, NCT02827526; date of registration, July 1, 2016; principal investigator, Glenn Murphy). The investigation was conducted at a single tertiary medical center (NorthShore Evanston Hospital), and written informed consent was obtained from all subjects. Patients were approached by research assistants and enrolled on the day of surgery. Study staff evaluated eligibility, obtained informed consent, managed the conduct of the trial, and collected and managed the data.

A total of 130 patients, ages 18 to 80 yr, undergoing elective spinal fusion surgery of one or more sacral, lumbar, and/or thoracic levels were enrolled. Exclusion criteria included American Society of Anesthesiologists (Schaumburg, Illinois) Physical Status IV or V, preoperative renal insufficiency or failure (serum creatinine ≥ 2 mg/dl), pulmonary disease necessitating home oxygen therapy, significant liver disease (cirrhosis or hepatic failure), recent history of alcohol or opioid abuse, allergy to methadone, hydromorphone, or ketamine, poor comprehension of the English language, or inability to use a patient-controlled analgesia (PCA) pump (due to intellectual impairment, disorientation, or confusion).

Patients were assigned to one of two groups using a computer-generated randomization table (simple randomization without restrictions): a methadone group (intraoperative methadone and a dextrose 5% in water infusion) or a methadone/ketamine group (intraoperative methadone and a ketamine infusion). The allocation sequence was generated by one of the study investigators, who provided the randomization assignments to the operating room pharmacy that assigned patients to the study groups and prepared all of the study medications. Care providers, researchers, and patients were blinded to group assignment. Clinicians delivering intraoperative care were provided with a 3-ml syringe labeled “methadone” that contained 0.2 mg/kg of methadone (based on ideal body weight, up to a maximal dose of 20 mg). This dose was selected based on data establishing effectiveness and safety of methadone 0.2 mg/kg in patients undergoing spine surgery^13–15  and other procedures.¹⁶  The contents of the syringe labeled “methadone” were given to all study subjects over 5 min at induction of anesthesia. In addition, the pharmacy prepared sequentially numbered, identical-appearing 500-ml bags of dextrose 5% in water. For patients assigned to the methadone/ketamine group, 250 mg of ketamine was added to the dextrose 5% in water bag (total volume 500 ml), whereas patients assigned to the methadone group received only an infusion of dextrose 5% in water (no drug added to the 500 ml volume). The 500 ml bags were connected to a pump that was programed to deliver an infusion of ketamine dosed at ideal body weight (or an equal volume of dextrose 5% in water) at a rate of 0.3 mg · kg⁻¹ · h⁻¹ from induction of anesthesia until surgical closure, at which time the infusion was decreased to 0.1 mg · kg⁻¹ · h⁻¹. The infusion was maintained at a rate of 0.1 mg · kg⁻¹ · h⁻¹ in the postanesthesia care unit (PACU) and for the next 48 postoperative hours. Dosing of ketamine was based on recommendations in the literature^17,18  and from clinical experience at our institution.

Patients were given 2 mg of midazolam before entering the operating room. Standard intraoperative monitoring was applied, which included an automatic blood pressure cuff, electrocardiography, capnography, pulse oximetry, and bispectral index monitoring (BIS system, Aspect Medical Systems, USA). Anesthesia was induced with propofol 1 to 2 mg/kg, lidocaine 50 mg, fentanyl 100 µg, rocuronium 0.6 mg/kg, dexamethasone 8 mg, and methadone 0.2 mg/kg. The ketamine or dextrose 5% in water infusion was initiated after induction and dosed as described above. Anesthesia was maintained with sevoflurane 1%, remifentanil 0.1 µg · kg⁻¹ · min⁻¹, and a propofol infusion titrated to 50 and 150 µg · kg⁻¹ · min⁻¹ in order to achieve bispectral index values between 40 and 60 and mean arterial pressures within 20% of baseline measures (a combination of lower concentrations of propofol and sevoflurane are used at our institution during spinal surgery in order to allow for acceptable sensory evoked potential monitoring). Redosing of rocuronium was determined based on requirements for motor evoked potential monitoring. The administration of additional fentanyl (up to a total dose of 200 µg) or hydromorphone (1 mg), was at the discretion of the anesthesia care team. Hypotension was treated with phenylephrine 80 µg, ephedrine 5 mg, or a fluid bolus, as indicated. Episodes of hypertension were managed by increasing the propofol infusion rate. Blood glucose concentrations were monitored every hour in insulin-dependent diabetic patients and every 2 to 4 h in non–insulin-dependent diabetic patients, and patients with blood glucose concentrations greater than 180 to 200 mg/dl were treated with insulin. At the conclusion of the procedure, patients were given odansetron 4 mg, and neuromuscular blockade was reversed with neostigmine 50 to 70 µg/kg (with an appropriate dose of glycopyrrolate) or sugammadex 2 to 4 mg/kg. Patients were extubated in the operating room unless concerns about airway edema were raised by the care team.

Patients were assessed for pain by nurses at PACU admission and every 15 min thereafter. Moderate pain was treated with hydromorphone 0.25 mg, and severe pain with hydromorphone 0.5 mg, with the goal of reducing pain scores to less than or equal to 3 on a 0 to 10 numeric rating scale (0, no pain; 10, worst pain imaginable). Patients were transitioned to a hydromorphone PCA device when adequate pain control was achieved (initial programming: a demand dose of 0.2 mg with a 10 min lockout interval, a 1 h limit of 1.2 mg). Discharge to the surgical wards with continuous pulse oximetry monitoring occurred when Aldrete scores of greater than or equal to 8 out of 10 were achieved.

Pain was managed on the first 3 postoperative days using the hydromorphone PCA device, which was discontinued at the discretion of the managing surgical service. Patients were transitioned to hydrocodone 5 mg and acetaminophen 325 mg tablets when able to resume oral intake. Pain was assessed and treated by surgical ward nurses per standard protocols, with the goal of maintaining pain scores less than or equal to 4 on the 0 to 10 numerical rating scale.

In the preoperative holding area, a research team member recorded preoperative levels of pain at rest, with coughing, and with movement using a 0 to 10 numeric rating scale. Preoperative sedation was measured on a 0 to 3 scale (0, fully awake; 1, mildly sedated, seldom drowsy, and easy to awaken; 2, moderately sedated, often drowsy, and easy to awaken; and 3, severely sedated, somnolent, and difficult to awaken). The presence or absence of dizziness, nausea, vomiting, or itching was noted. The use of preoperative opioids was documented.

Anesthesia team members recorded heart rate and mean arterial blood pressures preinduction and then 5, 15, 30, 45, and 60 min postinduction. In addition, the times between the end of surgery and tracheal extubation were noted, as was the use of any additional hydromorphone in the operating room. PACU nurses documented the times from PACU admission until first request for pain medication and the total dose of hydromorphone (nurse-administered and via the PCA device). Nurses also recorded the times to meet discharge criteria and to achieve actual discharge. At the time of discharge from the PACU, overall satisfaction with pain management was measured using an 11-point numeric rating scale (0, worst possible; 10, best possible).

On PACU arrival, a research team member assessed patients for pain at rest, with coughing, and with movement using a 0 to 10 numeric rating scale. Level of sedation was determined using the 0 to 3 scale described above. The presence or absence of nausea and vomiting was noted, the severity graded on a 3-point scale (1, mild; 2, moderate; 3, severe), and drugs used to treat these events were recorded. The presence or absence of episodes of itching, hypoxemia (peripheral oxygen saturation less than 90%), hypoventilation (respiratory rate less than 8), dizziness, or hallucinations was documented. The heart rate, respiratory rate, mean arterial pressure, and peripheral oxygen saturation at the time of assessment were noted. All of the outcome variables assessed at PACU arrival, with the addition of patient satisfaction with pain management scores, were again measured 1 h after PACU admission, as well as on the morning (between 8 am and 10 am) and late afternoon (between 3 pm and 4 pm) of postoperative days 1, 2, and 3. Total doses of intravenous hydromorphone and oral hydrocodone and acetaminophen tablets used during each of the first 3 postoperative days were recorded.

Data collected from the electronic anesthesia record included anesthesia duration, total volume of crystalloid solutions, blood loss, urine output, and total dose of fentanyl. The electronic medical record was reviewed for any cardiac, respiratory, gastrointestinal, renal, neurologic, or infection complications during the hospitalization. The duration of hospitalization was obtained from the electronic medical record.

The primary endpoint of this investigation was hydromorphone use on postoperative day 1. In a study of patients undergoing spinal fusion surgery using a standard anesthetic, the average ± SD intravenous hydromorphone dose in the first 24 postoperative hours was 27 ± 10 mg in patients given standard postoperative pain management and 18.5 ± 14 mg in patients given ketamine as an adjunct to that management.¹⁹  We anticipated hydromorphone consumption in the methadone group in the current study would be 19 mg and hypothesized it would be reduced by 40% in the methadone/ketamine group. Because expected group SDs of 14 mg were large relative to the means, sample size was estimated for two-sided Mann–Whitney test using the standard t test formulations with a simple adjustment to the sample sizes based on the assumption that data distribution is logistic. Using this approach, group sample sizes of 51 and 51 achieve 81% power to detect a difference of 7.6 mg between the null hypothesis that both group means are 19.0 mg and the alternative hypothesis that the mean of group 2 is 11.4 mg with a significance level (alpha) of 0.05 (PASS 2008 Number Cruncher Statistical System, USA). One hundred thirty patients were enrolled to ensure complete collection of data.

Data for the primary outcome variable, milligrams of intravenous hydromorphone in the first 24 h after the operation, are reported as the median (interquartile range) for both the methadone group and the methadone/ketamine group. These data were compared between groups using the Mann–Whiney U test (StatsDirect, United Kingdom). The median difference and its 95% CI were estimated using the Hodges–Lehmann estimator. The criterion for rejection of the null hypothesis was a two-tailed P < 0.05.

All other data, including secondary outcome data, are reported as mean ± SD, median (interquartile range), or number (percentage) of patients. Continuous data were checked for equality of variances; those data that did not meet the assumption of equal variances were reduced to ordinal data and are reported as median (interquartile range). Absolute standardized differences of the baseline characteristics of the patients in the two groups were determined to identify any possible imbalance between the groups. Other data reported as mean ± SD were compared with the unpaired, two-sample t test, data reported as the median (interquartile range) were compared with the Mann–Whitney U test, and data reported as the number of patients (%) were compared using the chi-square test (with Yates correction) unless at least one expected frequency was often less than 5, in which case the Fisher exact probability test was used. Because there was no interest in the change in the variables across time, primary and secondary outcome data were only compared between groups at each time. Given the large number of secondary comparisons, mean differences, median differences, and differences in proportions are reported with their 99% CIs. Median differences and their 99% CIs were estimated using the Hodges–Lehmann estimator. The robust approximation of Miettinen and Nurminen was used to construct the CIs for risk differences. The criterion for rejection of the null hypothesis was a two-tailed P < 0.01 throughout. All statistical analyses except calculation of absolute standardized differences were conducted with StatsDirect (United Kingdom).

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.

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; fig. 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; fig. 2).

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).

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 methadone¹³  or ketamine³³  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.

Supported by the Department of Anesthesiology, NorthShore University HealthSystem, Evanston, Illinois.

Dr. Murphy has served as a speaker for Merck, Kenilworth, New Jersey. Dr. Avram is the assistant editor-in-chief of Anesthesiology. Dr. Greenberg is editor of the Anesthesia Patient Safety Foundation Newsletter, Rochester, Minnesota, and a speaker for the American Association of Nurse Anesthetists, Park Ridge, Illinois. The other authors declare no competing interests.