Pain and Opioid Consumption and Mobilization After Surgery

Post Hoc Analysis of Two Randomized Trials

Eva Rivas, M.D.; Barak Cohen, M.D.; Xuan Pu, M.Sc.; Li Xiang, M.D.; Wael Saasouh, M.D.; Guangmei Mao, M.Sc.; Paul Minko, B.S.; Lauretta Mosteller, B.A.; Andrew Volio, M.D.; Kamal Maheshwari, M.D.; Daniel I. Sessler, M.D.; Alparslan Turan, M.D.

Disclosures

Anesthesiology. 2022;136(1):115-126.

Materials and Methods

Study Design

We conducted a retrospective analysis of data from two randomized trials: Effect of Intravenous Acetaminophen on Postoperative Hypoxemia After Abdominal Surgery: the FACTOR Randomized Clinical Trial (NCT02156154; Alparslan Turan; registered on June 5, 2014),^[34] which evaluated the effect of intravenous acetaminophen on postoperative opioid-related complications after colorectal surgery; and Transversus Abdominis Plane Block with Liposomal Bupivacaine versus Continuous Epidural Analgesia for Major Abdominal Surgery: the EXPLANE clinical trial (NCT02996227; Alparslan Turan; registered on December 19, 2016), which compared the effect of continuous epidural analgesia and transversus abdominis plane blocks on postoperative analgesia and opioid consumption after abdominal surgery. Both trials enrolled patients who had abdominal surgery and used a continuous vital sign recording system that also captures mobilization information, and were approved by the Cleveland Clinic Institutional Review Board (IRB; Cleveland, Ohio). The current analysis was approved by the IRB with waived individual consent and was designed before completing the trial enrollment (Cleveland Clinic IRB No. 19–341; approval date March 19, 2019).

Patients were managed according to Cleveland Clinic enhanced recovery after surgery protocols. Orogastric tubes were removed before endotracheal extubation. Patients were encouraged to walk on the evening of surgery and were offered noncarbonated liquids ad libitum. On the first postoperative day, patients were encouraged to walk at least one round of the nursing floor (approximately 60 m) up to five times, to sit out of bed between walks, and to perform regular incentive spirometry. Liquids were allowed and solid food offered if tolerated. Intraoperative analgesia was provided with short-acting opioids, and intravenous patient-controlled analgesia was used during the postoperative period. Oral analgesia was started, and the Foley catheter was removed on postoperative day 1.^[35–37]

Study Population

We included adult inpatients having elective open or laparoscopic abdominal surgery scheduled to last at least 2 h with general anesthesia at the Cleveland Clinic between February 2014 and September 2019 who participated in FACTOR or EXPLANE and had continuous postoperative activity monitoring. We excluded patients who had less than 12 h of continuous activity monitoring during the initial 48 postoperative hours, along with patients who had missing pain assessments or lacked important confounding variables.

Measurements

Postoperative pain was recorded using the numerical rating scale, which is an 11-point Likert scale from 0 (no pain) to 10 (worst imaginable pain). Pain scores were recorded at least every 30 min while patients remained in the postanesthesia care unit, and at least every 4 h while hospitalized. All available pain scores during the monitoring period were collected from patients' electronic medical records, and time-weighted average pain score was calculated for each patient. Opioid consumption during the initial 48 postoperative hours was also collected from patients' electronic records and converted into milligram of intravenous morphine equivalents.^[38,39]

Our primary outcome was duration of mobilization, defined as hours per monitoring day spent sitting or standing. Position and activity were continuously monitored and recorded at 15-s intervals from postanesthesia care unit admission until the earlier of 48 postoperative hours or hospital discharge using the ViSi Mobile monitoring system (Sotera Wireless, Inc., USA), which is cleared by the U.S. Food and Drug Administration (Silver Spring, Maryland) for noninvasive continuous vital sign monitoring.^[40]

The ViSi Mobile monitoring system includes a three-axis accelerometer that characterizes patients' orientation and activity.^[41] It captures posture status as upright 90 degrees, upright 45 degrees, supine, lying on the side, walking, and fallen. We defined mobilization as standing or sitting position, with standing defined "walking" posture and sitting as "upright 90 degrees" posture. When more than one posture was detected during a 15-s interval, a combined posture was recorded. For example, if a patient walked and sat upright 45° during a single 15-s interval, the posture would be recorded as upright 45 degrees and walking. Combined postures were considered as mobilization if one of the components was eligible. Neither patients nor clinicians had access to mobilization data.

The exploratory outcome was a composite of postoperative complications, including myocardial injury (defined as either a postoperative peak fourth-generation troponin T concentration 0.03 ng/ml or greater within the first 7 days after surgery, apparently of cardiac origin, or an International Classification of Diseases code for myocardial infarction);^[42] stroke or transient ischemic attack; venous thromboembolism; pulmonary complications; and all-cause in-hospital mortality (appendix, Table A1). Data were extracted from patients' electronic medical records, the anesthesia record-keeping system, and pharmacy records.

Statistical Methods

Gaps in activity/posture monitoring were removed and subtracted from total monitoring time, so that each patient's mobilization was calculated as hours of mobility per day by multiplying average mobilization minutes per monitoring hour by 24 h/day. Around 4% of all postures were recorded as unknown and were treated as missing and removed. Demographic and clinical characteristics of patients were summarized and presented by time-weighted average pain score category in Table 1, only for presentation purposes.

For the primary analysis, a quantile regression model was used to assess the association between time-weighted average pain score and mobilization time, in hours per day. A similar model was used to secondarily assess the association between opioid consumption during the first 48 postoperative hours and mobilization time. The associations were adjusted for all demographics and surgical variables in Table 1.

We conducted four sensitivity analyses. The first evaluated associations between time-weighted average pain scores and opioid consumption and postoperative mobilization, restricted to patients older than 65 yr. Second, we restricted the definition of mobilization to include only standing position. Third, we restricted the analysis to daytime, defined as 7 PM. For our final sensitivity analysis, we restricted the analysis to the first 24 postoperative hours.

For our exploratory analysis, the incidence of a composite of myocardial injury, stroke or transient ischemic attack, venous thromboembolism, pulmonary complications, and all-cause in-hospital mortality was summarized by quartiles of mobilization time.

We did two post hoc analyses. First, we fitted a quantile regression model with interaction between surgical approach (open or laparoscopic) and both exposures (pain and opioid consumption) with mobilization time as the outcome; and second, we explored the relationship between the mobilization time in hours per day and the composite of postoperative complications through a logistic regression model adjusting for age, sex, race, and surgery duration.

We performed a complete case analysis, as participants with missing data were excluded. Data were assumed to be missing at random. The significance level was 0.025 for each association (pain and mobilization/opioid consumption and mobilization) after Bonferroni correction for the primary and secondary analyses. All analyses were conducted using the Statistical Analysis System (SAS) statistical software package, version 9.04.01 (SAS Institute Inc., USA).

Power Consideration

We did a simulation using quantile regression to calculate the effect size we could detect. With the current sample size, we had more than 90% power for detecting a 0.2-h reduction in mobilization per day for each unit increase in pain score, or to detect a 0.13-h reduction in mobilization per day for each doubling of morphine consumption at a significance level of 0.025.

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Table 1. Demographic, Surgical, and Postoperative Characteristics of Patients, Presented According to Time-weighted Average Pain Scores during the Initial 48 Postoperative Hours
Factor	Overall (N = 673)	Pain ≤ 3 (N = 195)	3 < Pain < 6 (N = 354)	Pain ≥ 6 (N = 124)
Demographics
Age, yr	51 ± 15	55 ± 16	50 ± 15	46 ± 14
Body mass index	27 ± 5	27 ± 5	27 ± 5	27 ± 6
Female	361 (54)	76 (48)	197 (56)	70 (57)
Race, white	622 (92)	152 (95)	327 (92)	111 (90)
Surgical characteristics
ASA Physical Status
I or II	243 (36)	72 (37)	123 (35)	48 (39)
III	413 (61)	116 (60)	224 (63)	73 (59)
IV or V	17 (3)	7 (3)	7 (2)	3 (2)
Surgery type
Colorectal	601 (89)	173 (89)	317 (90)	111 (89)
Gynecological	31 (5)	10 (5)	15 (4)	6 (5)
Urological	9 (1)	1 (1)	7 (2)	1 (1)
Other	32 (5)	11 (5)	15 (4)	6 (5)
Procedure type
Open	446 (66)	131 (67)	224 (63)	91 (73)
Laparoscopic	227 (34)	64 (33)	130 (37)	33 (27)
Surgery duration, min	272 [197–365]	260 [186–355]	279 [202–375]	271 [191–329]
Estimated blood loss, cc	75 [25–200]	50 [25–150]	100 [30–200]	75 [50–200]
Intraoperative ketorolac use	10 (2)	5 (3)	4 (1)	1 (1)
Postoperative characteristics
Time-weighted average pain score	4.3 ± 1.9	2.0 ± 0.8	4.6 ± 0.8	6.9 ± 0.8
Opioid consumption (mg of IV morphine equivalents)	36 [10–97]	8 [0–50]	39 [16–101]	67 [34–171]
Any use of (%)
NSAID	430 (64)	126 (65)	226 (64)	78 (63)
Acetaminophen	230 (34)	64 (33)	123 (35)	43 (35)
Gabapentin	355 (53)	95 (49)	190 (54)	70 (57)

NSAIDs include ketorolac, ibuprofen, and celecoxib. Summary statistics presented as No. (%) of patients, mean ± SD, or median [quartile 1–quartile 3] for factors, symmetric continuous variables, and skewed continuous variables, respectively (N = 673).
ASA, American Society of Anesthesiologists; IV, intravenous; NSAID, nonsteroidal anti-inflammatory drug.

Table 2. Associations of Time-weighted Average Postoperative Pain Score or Opioid Administration and Postoperative Mobilization Hours per Day
	Pain Score (97.5% CI)*	P Value†	Opioid Consumption (97.5% CI)*	P Value†
Primary analysis
Mobilization, h/day	Unadjusted −0.16 (–0.24 to −0.04)	0.004	Unadjusted 0.04 (–0.12 to 0.08)	0.586
	Adjusted* −0.12 (–0.24 to −0.02)	0.009	Adjusted* −0.04 (–0.12 to 0.08)	0.508
Sensitivity analysis‡
Mobilization, h/day (> 65 yr old)	Adjusted* −0.03 (–0.36 to 0.28)	0.805	Adjusted* 0.12 (–0.12 to 0.36)	0.227
Mobilization, h/day (only standing position)	Adjusted* −0.01 (–0.01 to 0.0001)	0.028	Adjusted* −0.01 (–0.01 to −0.004)	<0.001
Mobilization, h/day (daytime only)	Adjusted* −0.40 (–0.72 to −0.08)	0.003	Adjusted* −0.32 (–0.56 to −0.08)	0.007
Mobilization, h/day (initial postoperative 24 h)	Adjusted* −0.04 (–0.08 to 0.0002)	0.026	Adjusted* −0.02 (–0.04 to 0.01)	0.077
Post hoc subgroup analysis§
Open surgery	Adjusted* −0.17 (–0.06 to −0.28)	<0.001	Adjusted* −0.03 (–0.12 to 0.07)	0.540
Laparoscopic approach	Adjusted* 0.05 (–0.15 to 0.25)	0.628	Adjusted* 0.02 (–0.15 to 0.18)	0.816

*The association was estimated using a quantile regression model adjusted for confounders in table 1. The associated mobilization change estimates were based on unit increase of postoperative time-weighted average pain score or a twofold increase in morphine equivalent opioid consumption.
†The significance level for each association test was 0.025 (i.e., 0.05/2, Bonferroni correction).
‡For the first sensitivity analysis, 169 patients were analyzed (age greater than 65 yr). For the second sensitivity analysis (only standing position), 673 patients were analyzed. For the third sensitivity analysis (daytime), 413 patients were analyzed since people whose actual daytime monitoring duration was less than 6 h were excluded. For the last sensitivity analysis (only first postoperative 24 h), 216 patients were analyzed since people whose actual postoperative 24 h monitoring duration was less than 6 h were excluded.
§The post hoc subgroup analysis was completed through a quantile regression model with interaction between procedure type (open vs. laparoscopic) and corresponding exposure (pain score or morphine usage) adjusting for confounders in primary analysis.

Table 3. Summary of Composite Outcomes by Mobilization Hours per Monitoring Day
Time of Mobilization, % (h/day)	Total	0–2.8 (0–0.7)	2.8–6.8 (0.7–1.6)	6.8–13 (1.6–3.1)	> 13 (3.1–13.2)
Time of Mobilization, % (h/day)	(N = 673)	(N = 168)	(N = 168)	(N = 169)	(N = 168)
Composite outcome	17 (2.5)	10 (6.0)	7 (4.2)	0 (0.0)	0 (0.0)
Composite of pulmonary complications	9 (1.3)	5 (3.0)	4 (2.4)	0 (0.0)	0 (0.0)
Myocardial injury after noncardiac surgery	3 (0.5)	2 (1.2)	1 (0.6)	0 (0.0)	0 (0.0)
Stroke/transitional intravascular accident	1 (0.2)	1 (0.6)	0 (0.0)	0 (0.0)	0 (0.0)
Venous thromboembolism	4 (0.6)	2 (1.2)	2 (1.2)	0 (0.0)	0 (0.0)
All-cause in-hospital mortality	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Post hoc summary
Preoperative ASA Physical Status
I or II	243 (36)	46 (27)	62 (37)	65 (38)	70 (41)
III	413 (61)	117 (70)	101 (60)	98 (58)	97 (58)
IV or V	17 (3)	5 (3)	5 (3)	6 (4)	1 (1)
ICU admission	27 (4)	15 (9)	6 (4)	3 (2)	3 (2)
Length of stay, days	4 [3–7]	6 [4–8]	5 [3–7]	4 [3–6]	4 [2–5]
Surgery procedure
Open	446 (66)	119 (71)	114 (68)	110 (65)	103 (61)
Laparoscopic	227 (34)	49 (29)	54 (32)	59 (35)	65 (39)
Surgery duration, min	272 [197–365]	321 [237–445]	286 [196–388]	254 [191–325]	234 [185–315]

The summary statistics are presented as N (%) or median [quartile 1–quartile 3] by overall percentage of mobilization time (hour per day) The association estimate between pain score and complications was obtained through a logistic regression model with postoperative complications as the outcome and mobilization in minutes per hour as exposure of interest, adjusting for age, sex, race, and surgery duration. The adjusted odds ratio was 0.34 (95% CI, 0.16 to 0.72) associated with each hour increase in mobilization time per day.
ASA, American Society of Anesthesiologists; ICU, intensive care unit.

Table A1. Composite of Postoperative Complications
Component of the Composite Outcome	ICD9/ICD10 Code or Definition
Pulmonary complications
Respiratory complications	997.31/J95851
	997.32/J9589
	997.39/J95859, J9588, J9589
Pulmonary infection, pneumonia	481/J13, J181
	482/J150
	483/J157, J160, J168
	484/B250
	485/J180
	486/J189
Respiratory failure and distress	518.3/J82
	518.51/J95821, J9600
	518.52/J952, J953
	518.53/J95822, J9620
	518.81/J9600, J9690
	518.84/J9620
Tracheitis and bronchitis	466/J209
	464/J040
Hypoxemia	799.02/R0902
	Or one of the following:
	•Saturation < 90%
	•Use of face mask with > 6 l O2 flow
	•Nonrebreather mask/Venturi mask
	•Continuous positive airway pressure/bilevel positive airway pressure use
Pleural effusion	511.9/J918
Atelectasis	518.0/J9811, J9819
ARDS	518.5/J80
	518.82/J80
Acute COPD exacerbation, acute asthma exacerbation	491.21/J441
	493.92/J45901
Other continuous invasive mechanical ventilation	Z99.1/Z99.11
Reintubation	Defined by: reintubation surrogate search
	•Intubation note
	•Propofol bolus >100 mg
	•Etomidate
	•Muscle relaxant
Transfusion-related acute lung injury	518.7/J9584
Pulmonary embolism, respiratory acidosis	415.1/I2699
	276.2/E872
Myocardial injury after noncardiac surgery	410
	I21–I23
	Or postoperative peak troponin T concentration ≥ 0.03 ng/ml within the first 7 days after surgery, apparently of cardiac origin
Stroke or transitional intravascular accident	430–435
	I60–I66
Venous thromboembolism	4534
	I824
All-cause mortality	Defined as any death before discharge, regardless of the cause

ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmonary disease; ICD9, International Classification of Diseases, Ninth Revision; ICD10, International Classification of Diseases, Tenth Revision.

Table A2. Most-used Opioids and Conversion Doses
Name	Route	Units	Equivalent Dose	Name	Route	Units	Equivalent Dose
Morphine	IV	Milligrams	10	Codeine	Oral	Milligrams	200
Morphine	Oral	Milligrams	30	Propoxyphene	Oral	Tablets	1
Fentanyl	IV	Milligrams	0.1	Percocet 5/325	Oral	Tablets	6
Fentanyl	Epidural	Milligrams	0.1	Hydrocodone	Oral	Milligrams	30
Fentanyl	Oral	Milligrams	0.229	Vicodin 5/500	Oral	Tablets	6
Remifentanil	IV	Milligrams	0.1	Vicodin 7.5/500	Oral	Tablets	4
Methadone	Oral	Milligrams	20	Tramadol	Oral	Milligrams	150
Hydromorphone	IV	Milligrams	1.5	Meperidine	IV	Milligrams	75
Hydromorphone	Oral	Milligrams	7	Meperidine	Oral	Milligrams	333
Alfentanil	IV	Milligrams	0.67