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.

Abstract and Introduction

Abstract

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.

Introduction

In the United States, 80% of surgical patients reported postoperative pain, with 88% of these patients describing pain intensity as moderate to severe.^[1] 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.^[1] 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.^[2] 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),^[3] and perioperative anxiety/mood disorders.^[4] 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^[9] 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.^[9] 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.^[13] 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).^[13] 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.

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Table 1. Patient Characteristics
Characteristics	Methadone Group	Methadone/Ketamine Group	Absolute Standardized Difference
Patients, No.	61	66
Sex, female	34 (56%)	34 (52%)	0.08
Age, yr	66 (58 to 72)	61.5 (47.3 to 69)	0.47
Actual body weight, kg	90 ± 21	84 ± 20	0.29
Ideal body weight, kg	62 ± 11	64 ± 11	0.18
Height, cm	169 ± 10	171 ± 10	0.20
American Society of Anesthesiologists Physical Status	2 (2 to 3)	2 (2 to 2)	0.36
Preoperative opioids	38 (62%)	33 (50%)	0.25
No. of opioid tablets per day	2 (0 to 3)*	0 (0 to 2.5)†	0.21
History
Smoking	9 (15%)	8 (12%)	0.08
Drinking	4 (7%)	7 (11%)	0.14
Steroids	6 (10%)	6 (9%)	0.02
Myocardial infarction	2 (3%)	2 (3%)	0.02
Congestive heart failure	1 (2%)	0 (0%)	0.18
Atrial fibrillation	3 (5%)	2 (3%)	0.10
Hypertension	33 (54%)	36 (55%)	0.01
Chronic obstructive pulmonary disease/emphysema	3 (5%)	2 (3%)	0.10
Obstructive sleep apnea	12 (20%)	8 (12%)	0.21
Liver disease	1 (2%)	0 (0%)	0.18
Renal disease	6 (10%)	3 (5%)	0.21
Thyroid disease	9 (15%)	6 (9%)	0.18
Non–insulin-dependent diabetes mellitus	10 (16%)	6 (9%)	0.22
Insulin-dependent diabetes mellitus	1 (2%)	1 (2%)	0.01
Cerebrovascular accident	3 (5%)	1 (2%)	0.19
Transient ischemic attack	2 (3%)	1 (2%)	0.12
Peripheral vascular disease	0 (0%)	0 (0%)
Preoperative assessment
Sedation	0 (0%)	1 (2%)	0.17
Nausea	6 (10%)	10 (15%)	0.16
Vomiting	4 (7%)	3 (5%)	0.09
Itching	13 (21%)	10 (15%)	0.16
Dizziness	9 (15%)	9 (14%)	0.03
Heart rate, beats/min	76 ± 13‡	77 ± 12	0.08
Mean blood pressure, mmHg	95 ± 10‡	95 ± 11	0

The data are mean ± SD, median (interquartile range), or number of patients (%). Drinking history indicates alcohol consumption of more than two drinks per day.
*n = 57. †n = 63. ‡n = 60.

Table 2. Perioperative and Postoperative Data
	Methadone Group	Methadone/Ketamine Group	Difference (99% CI)	P Value
Operative sites
Thoracic	1 (2%)	5 (8%)	−6% (−19 to 6%)	0.210*
Lumbar	61 (100%)	66 (100%)
Sacral	21 (34%)	33 (50%)	−16% (−37 to 7%)	0.111
Number of levels	1 (1 to 2)	1.5 (1 to 2)	0 (0 to 0)	0.392
Anesthesia time, min	321 ± 117	319 ± 111	2 (−50 to 55)	0.903
Methadone dose, mg	12.5 ± 2.1	12.9 ± 2.2	−0.4 (−1.4 to 0.6)	0.324
Fentanyl dose, μg†	152 ± 96	143 ± 89	9 (−34 to 51)	0.606
IV acetaminophen (1,000 mg)	11 (18%)	15 (23%)	−5% (−23 to 14%)	0.664
Extra hydromorphone in operating room	6 (10%)	5 (8%)	2% (−12 to 18%)	0.891
Extra hydromorphone in operating room dose, mg	0.6 ± 0.3‡	0.6 ± 0.2§	0 (−0.5 to 0.6)	0.853
Fluid volume, ml	2,468 ± 1,040	2,529 ± 975	−61 (−528 to 407)	0.735
Urine output, ml	250 (170 to 500)	350 (213 to 563)	−50 (−150 to 70)	0.311
Estimated blood loss, ml	466 ± 402\|\|	418 ± 328	48 (−122 to 219)	0.458
Time of tracheal extubation, min	12 (9 to 17)	11 (8 to 17)#	1 (−2 to 4)	0.386
Time (min) from PACU admission to:
First hydromorphone request	20 (12 to 29)**	30 (17 to 43)††	−10 (−19 to −2)	0.003
Meeting discharge criteria	95 ± 26	94 ± 27	1 (−12 to 12)	0.994
Actual discharge	114 ± 36	113 ± 33	1 (−15 to 17)	0.889
Duration of hospitalization, days	3.5 (3.0 to 4.75)	3.0 (3.0 to 4.0)	0.25 (0 to 1)	0.043
Postoperative complications during hospitalization
Respiratory	2 (3%)	0 (0%)	3% (−6 to 15%)	0.457*
Gastrointestinal	1 (2%)	0 (0%)	2% (−8 to 13%)	0.961*
Cardiac	2 (3%)	0 (0%)	3% (−6 to 15%)	0.457*
Renal	1 (2%)	0 (0%)	2% (−8 to 13%)	0.961*
Neurologic	1 (2%)	0 (0%)	2% (−8 to 13%)	0.961*
Infection	0 (0%)	0 (0%)

The data are means ± SD, median (interquartile range), or number of patients (%). The data reported as mean ± SD were compared with the unpaired t test, the data reported as median (interquartile range) were compared using the Mann–Whitney U test, and the data reported as the number of patients (%) were compared using the Pearson chi-square test or, when at least one of the cells of the contingency table had an expected n < 5, the Fisher exact probability test. n = 61 in the methadone group, and n = 66 in the methadone/ketamine group, except where indicated.
*Fisher exact probability test. †The fentanyl dose includes the 100 μg allowed by the protocol. ‡n = 6. §n = 5. ||n = 60. #n = 65. **n = 50. ††n = 45.
IV, intravenous; PACU, postanesthesia care unit.

Table 3. Primary Outcome: Intravenous Hydromorphone Requirements in the First 24 h Postoperatively
	Methadone Group	Methadone/Ketamine Group	Difference (95% CI)	P Value
Intravenous hydromorphone, mg first 24 h	4.6 (3.2 to 6.6)	2.0 (1.0 to 3.0)	2.5 (1.8 to 3.3)	< 0.0001

The data are reported as median (interquartile range) and were compared between groups using the Mann–Whitney U test. These data are also reported in Figure 2A with the difference (99% CI) for the sake of completeness and consistency. n = 61 in the methadone group, and n = 66 in the methadone/ketamine group.

Table 4. Levels of Pain at Rest, with Coughing, and with Movement, and Overall Satisfaction with Pain Management
	Methadone Group	Methadone/Ketamine Group	Difference (99% CI)	P Value
Level of pain at rest
Preoperative	5 (2 to 7)	4 (2 to 6)*	1 (−1 to 2)	0.329
At PACU admission	6 (3 to 8)†	3.5 (0 to 5)‡	2 (0 to 4)	0.002
1 h after admission	5 (3 to 6)§	3 (2 to 4)\|\|	2 (1 to 3)	< 0.0001
Postoperative day 1 – AM	4 (3 to 6)#	3 (2 to 3)	2 (1 to 2)	< 0.0001
Postoperative day 1 – PM	4 (3 to 5)	3 (2 to 3)	1 (1 to 2)	< 0.0001
Postoperative day 2 – AM	3 (2 to 4.5)§	3 (2 to 3)\|\|	1 (0 to 1)	0.039
Postoperative day 2 – PM	4 (2 to 5)#	3 (2 to 3)**	1 (0 to 2)	< 0.001
Postoperative day 3 – AM	4 (3 to 5)††	3 (2 to 3)†	1 (1 to 2)	< 0.0001
Postoperative day 3 – PM	3 (2 to 4)‡‡	2 (2 to 3)§§	1 (0 to 2)	< 0.0001
Level of pain with coughing
Preoperative	6 (4 to 9)	4 (2 to 7)*	2 (0 to 3)	0.016
At PACU admission	6 (4 to 8)†	4 (0 to 5.75)‡	2 (0 to 4)	0.005
1 h after admission	5 (4 to 7)§	4 (2 to 4)\|\|	2 (1 to 3)	< 0.0001
Postoperative day 1 – AM	5 (3.75 to 6)#	3 (2 to 4)	2 (1 to 3)	< 0.0001
Postoperative day 1 – PM	4 (3 to 6)#	3 (2 to 4)	1 (1 to 2)	< 0.0001
Postoperative day 2 – AM	4 (3 to 5)§	3 (2 to 4)\|\|	1 (1 to 2)	< 0.0001
Postoperative day 2 – PM	5 (3 to 6)#	3 (2 to 4)**	2 (1 to 3)	< 0.0001
Postoperative day 3 – AM	4 (3 to 6)††	3 (3 to 4)\|\|\|\|	1 (0 to 2)	< 0.0001
Postoperative day 3 – PM	4 (3 to 5)##	3 (2 to 3)***	1 (1 to 2)	< 0.0001
Level of pain with movement
Preoperative	9 (7 to 9)	8 (6 to 10)*	0 (0 to 1)	0.212
At PACU admission	6 (4 to 8.25)†	4 (0.5 to 6)‡	2 (0 to 4)	0.006
1 h after admission	6 (4 to 7)§	4 (2 to 5)\|\|	2 (1 to 3)	< 0.001
Postoperative day 1 – AM	5.5 (4 to 7)†††	4 (3 to 5)§	2 (1 to 3)	< 0.0001
Postoperative day 1 – PM	5 (4 to 7)§	4 (3 to 5)‡‡‡	1 (0 to 2)	< 0.0001
Postoperative day 2 – AM	5 (4 to 6)§	4 (3 to 5)**	2 (1 to 2)	< 0.0001
Postoperative day 2 – PM	5.5 (4 to 6)#	4 (3 to 5)**	2 (1 to 2)	< 0.0001
Postoperative day 3 – AM	5 (4 to 6)††	4 (3 to 5)†	1 (0 to 2)	< 0.001
Postoperative day 3 – PM	4 (3 to 5)‡‡	3 (3 to 4)§§	1 (0 to 2)	< 0.001
Overall satisfaction with pain management
At PACU discharge	6 (5 to 8)‡‡‡	7 (5 to 8)§§§	−1 (−2 to 0)	0.099
Postoperative day 1 – AM	8 (8 to 10)	10 (9 to 10)	0 (−1 to 0)	0.008
Postoperative day 1 – PM	9 (8 to 10)	10 (9 to 10)	0 (−1 to 0)	0.011
Postoperative day 2 – AM	9 (8 to 10)§	9 (9 to 10)\|\|	0 (−1 to 0)	0.037
Postoperative day 2 – PM	9 (8 to 10)#	9 (8 to 10)**	0 (−1 to 0)	0.087
Postoperative day 3 – AM	9 (8 to 10)\|\|\|\|	9.5 (9 to 10)†	0 (−1 to 0)	0.076
Postoperative day 3 – PM	9 (8 to 10)\|\|\|\|\|\|	9 (8 to 10)###	0 (−1 to 0)	0.216

The data are reported as median (interquartile range) and were compared between groups at the various times using the Mann–Whitney U test. No within-group (i.e., across time) comparisons have been made. Level of pain scores on a 0 to 10 scale: 0 = no pain to 10 = worst pain imaginable. Overall satisfaction with pain management on a 0 to 10 scale: 0 = worst possible to 10 = best possible. N = 61 in the methadone group, and n = 66 in the methadone/ketamine group, except where indicated.
*n = 65. †n = 56. ‡n = 62. §n = 59. ||n = 64. #n = 60. **n = 63. ††n = 58. ‡‡n = 49. §§n = 33. ||||n = 55. ##n = 48. ***n = 32. †††n = 54. ‡‡‡n =57. §§§n = 61. ||||||n = 44. ###n = 29.
PACU, postanesthesia care unit.