Postoperative analgesia using dezocine alleviates depressive symptoms after colorectal cancer surgery: A randomized, controlled, double-blind trial.

BACKGROUND: Postoperative depression is one of the most common mental disorders in patients undergoing cancer surgery and it often delays postoperative recovery. We investigated whether dezocine, an analgesic with inhibitory effect on the serotonin and norepinephrine reuptake, could relieve postoperative depressive symptoms in patients undergoing colorectal cancer surgery.
METHODS: This randomized, controlled, single-center, double-blind trial was performed in the Second Affiliated Hospital of the Army Medical University. A total of 120 patients were randomly assigned to receive either sufentanil (1.3 μg/kg) with dezocine (1 mg/kg) (dezocine group; n = 60) or only sufentanil (2.3 μg/kg) (control group; n = 60) for patient-controlled intravenous analgesia after colorectal cancer surgery. The primary outcome was the Beck Depression Inventory score at 2 days after surgery. The secondary outcomes included the Beck Anxiety Inventory, sleep quality, and quality of recovery scores.
RESULTS: Compared with those in the control group, patients in the dezocine group had lower depression scores (7.3±3.4 vs. 9.9±3.5, mean difference 2.6, 95% CI: 1.4-3.9; P<0.001) at 2 days after surgery and better night sleep quality at the day of surgery (P = 0.010) and at 1 day after the surgery (P<0.001). No significant difference was found in other outcomes between the two groups.
CONCLUSIONS: Intravenous analgesia using dezocine can relieve postoperative depression symptoms and improve sleep quality in patients undergoing colorectal cancer surgery.

RCT Entities:   Population Interventions Outcomes

Introduction

Surgery, anesthesia, and pain are associated with the postoperative recovery of patients undergoing cancer surgery, and a growing number of studies have focused on the effect of the anesthetic or analgesic technique on these patients’ postoperative outcomes[1-3]. Psychological disorders, including depression and anxiety, almost always accompany cancer diagnosis. Depression, generally considered to be one of the most important psychological disorder in patients with cancer, has a negative effect on the quality of life and decreases treatment compliance[4,5]. Studies have reported that a pre-existing depressive disorder often delays the patients’ postoperative recovery[6,7]. However, few studies have investigated how perioperative intervention can alleviate postoperative depression symptoms in patients undergoing cancer surgery.

Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer among both men and women in the United States[8]. In China, the incidence of CRC in 2015 ranked fifth among all cancers[9]. As previous studies reported, CRC surgery may result in persistently low physical activity levels and worse bowel symptoms, leading to a high risk of postoperative adverse psychological symptoms in these patients[10,11]. Approximately one-third of survivors experience continuing psychological problems[12]; thus, postoperative depression treatment in patients undergoing CRC surgery remains challenging.

Dezocine, a known partial μ opioid receptor agonist and κ receptor agonist, is becoming one of the most widely prescribed analgesics for postoperative pain management in China in recent years[13-15]. Several recent studies have demonstrated that dezocine can also inhibit the reuptake of norepinephrine and serotonin, both of which are major targets in depression treatment[14,16]. In particular, serotonin and norepinephrine reuptake inhibitors are first-line antidepressant drugs. Moreover, several previous studies have reported that increased serum concentrations of norepinephrine and serotonin were associated with improved depressive symptoms[17-21]. Furthermore, a recent study found that postoperative patient-controlled intravenous analgesia (PCIA) using tramadol, which has serotonin and norepinephrine reuptake inhibitory effects, can significantly decrease the postoperative depression scores[22].

Based on the above information, we hypothesized that postoperative analgesia using dezocine could provide antidepressant effect. Therefore, we investigated whether dezocine use for postoperative PCIA can relieve postoperative depression symptoms in patients undergoing CRC surgery.

Methods

Ethical considerations

The study protocol was approved by the Institutional Ethics Committee of the Second Affiliated Hospital of the Army Medical University (2018–029). The trial was registered prior to patient enrollment at the Chinese Clinical Trial Registry (www.chictr.org.cn; ChiCTR1800016246). Written informed consent was obtained from all patients prior to their participation. No change was made to the protocol after the trial commenced.

Study design and patients

This was a randomized, parallel-controlled, double-blind, single-center trial performed in the Second Affiliated Hospital of the Army Medical University, Chongqing, China.

All patients were first screened in the general surgery ward and were recruited according to the inclusion and exclusion criteria 1 day before the surgery. Patients aged 18 to 70 years with an American Society of Anesthesiologists physical class II to III who were scheduled for elective laparoscopic CRC resection under general anesthesia from May 2018 to September 2018 were recruited. Patients were excluded if they met any of the following criteria: history of known psychiatric disease; history of administration of antipsychotic drugs for any reason; taking monoamine oxidase inhibitors within 2 weeks before the surgery; inability to communicate; allergy to opioids or dezocine; history of alcohol or drug abuse; or severe cardiac, hepatic, renal, or pulmonary dysfunction. One day before surgery, eligible patients who signed a written informed consent were consecutively enrolled in the study. Patients’ demographic and preoperative clinical data were recorded. Beck’s Depression Inventory (BDI) and Beck’s Anxiety Inventory (BAI) were applied to measure the patients’ preoperative depression and anxiety scores [23,24].

Randomization and masking

Randomization was taken the form of simple randomization procedure and performed using the sealed envelope method. A biostatistician, who was not included in data management and statistical analysis, generated random numbers (in a 1:1 ratio) using the SPSS 22.0 software (SPSS Inc., Chicago, IL). An independent assistant who was not involved in the study or data analysis prepared the allocation sequence and hid the random numbers in opaque, numbered, and sealed envelopes. During the study period, patients were recruited consecutively and were randomly assigned to receive either sufentanil with dezocine (dezocine group) or sufentanil without dezocine (control group) in the operating room according to the random number in the envelopes. A study nurse, who was independent from data collection and analysis, prepared the drugs according to the randomization sequence. Since both analgesic drugs are colorless and transparent, they cannot be distinguished based on their appearance from the PCIA mechanical pump box. After the intervention was performed according to the randomization number, the envelopes were sealed again and stored until the end of the study. The study investigators, healthcare team members, and patients were blinded to the treatment group allocation throughout the study period. Perioperative data collection and postoperative follow-up interviews during the hospitalization period were performed by study investigators.

Anesthesia procedures

In the operating room, all patients were continuously monitored using electrocardiography, invasive blood pressure measurement, pulse oximetry, and bispectral index monitoring. Intravenous administration of metoclopramide 10 mg and dexamethasone 5 mg to prevent intraoperative stress response and postoperative nausea and vomiting before anesthesia induction. Standard sequenced anesthesia induction was performed using midazolam 0.05 mg/kg, propofol 1.5–2 mg/kg, sufentanil 0.5 to 1 ug/kg, and rocuronium bromide 0.6 mg/kg. Subsequently, endotracheal intubation was performed and controlled respiration was applied with a tidal volume of 8–10 mL/kg, respiratory frequency of 13–15/min, and inspiratory-to-expiratory ratio of 1:2 to maintain an end-tidal carbon dioxide level of 35–45 mmHg. General anesthesia maintenance was performed using propofol 0.067–0.14 mg/kg/min, remifentanil 0.2–0.8 mg/kg/min, rocuronium bromide 0.6 mg/kg/h, and inhalation anesthesia with sevoflurane. At the time of skin closure, all patients were given sufentanil 0.1 μg/kg. After sobering in the post-anesthesia care unit, patients were extubated and transferred to the surgery ward. If patients reported pain ≥ 4 on the numerical rating scale (NRS), 5-ug boluses of sufentanil were given. After 15 min, patients’ pain intensity would be assessed again. When intensity of pain by NRS was less than 4 points and the vital signs was stable, the patient would be transferred to the surgical ward.

Analgesia interventions

Analgesia was provided to the patients at the end of surgery through PCIA using 250-mL electronic pumps. Because PCIA with sufentanil has been widely used for postoperative analgesia in China and considering that using dezocine alone might not be effective for pain control in patients undergoing CRC surgery, we used sufentanil combined with dezocine for the experimental intervention, which is a commonly used combination in clinical practice and in many previous studies[15,25-27]. According to the strategy of equivalent opioid dose, 1 ug of sufentanil equals 1 mg of dezocine[27-29]. Therefore, we set the following experimental and control interventions: patients in the dezocine group received 1.3 μg/kg sufentanil (Yichang, Hubei Fu Pharmaceutical Co. Ltd, Hubei, China) plus 1 mg/kg dezocine (Yangtze River Pharmaceutical Group Co. Ltd, Jiangsu, China) diluted in 250 mL normal saline, while those in the control group received 2.3 μg/kg sufentanil diluted in 250 mL normal saline. During the first 48 h after surgery, the PCIA pump was set at a loading dose of 2 mL with continuous background infusion speed of 4 ml/h, 1 ml each press, with a lockout interval of 15 min. If patients reported pain ≥ 4 on the NRS, clinicians provided additional intravenous injection of 50 mg flurbiprofen axetil. To minimize performance bias, additional analgesia within groups was administered by clinicians who were blinded to the group allocation.

Outcome measurement

The primary outcome of the study was the BDI score at 2 days after surgery. According to the standardized process, the BDI and BAI tests were administered to patients by a study investigator at the general surgery ward. In order to minimize detection bias, the tests were administered by the same investigator who had been trained by psychology experts. The BDI is a 21-item self-report inventory that measures characteristic attitudes and symptoms of depression with items being rated on a 4-point Likert scale (range 0–3)[23,30,31]. Higher scores indicate higher depression levels.

The secondary outcomes included the BAI score at 2 days after surgery, night sleep quality at the day of surgery and 1 day after surgery, and quality of postoperative recovery at 7±2 days after surgery. The BAI consists of 21 questions with a four-point response scale (range 0–3), with higher scores indicating higher anxiety levels[24]. The Chinese versions of both the BDI and BAI have been validated in previous studies[32,33]. Sleep quality was subjectively assessed by patients as good, average, or poor. Quality of recovery was assessed using the Quality of recovery-15 items (Qor-15) test, which is a validated, self-report measure of the early postoperative health status of patients. Each item is rated on an 11-point (0−10) NRS (for positive items, 0 = “none of the time” and 10 = “all the time”; for negative items, the scoring was reversed; maximum score 150), with higher scores representing better functioning[34].

Other outcomes included the pain scores at rest and movement, which were evaluated using an 11-point NRS (where 0 indicated no pain and 10 indicated the worst possible pain) at 6, 12, 24, and 48 h after surgery. The side-effects of analgesic consumption (nausea and vomiting) and additional analgesia requirement at 48 h after surgery were also recorded. In addition, postoperative major complications and hospital stay were recorded. Hospital discharge was decided by the attending surgeons. Major complications were defined as any adverse event that occurred after the surgery and required additional intervention.

Furthermore, peripheral blood samples were collected from all patients for validation of the potential biological effects of dezocine in depression symptom improvement. Blood sampling was performed at three time points in both groups: before anesthesia induction, 24 h after surgery, and 48 h after surgery. At each time point, 2 mL of peripheral blood was collected using a vacuum tube with heparin (for anticoagulation), and the levels of serum serotonin and norepinephrine were tested using an ELISA-kit.

Sample size calculation

Based on our pilot investigation (n = 10), the mean BDI score 2 days after CRC surgery was 10.2 (standard deviation [SD], 4.2). Comparison of the two means of parallel variables was performed as the main analysis. The minimum clinically important difference between the experimental and control groups was set as 0.5SD, e.g., 2.1[35]. And the test statistic was based on two sample T-Test (difference). Here because the SD in experimental group is unknown, we assumed it as 3.0. Thus the sample size was calculated based on 10.2±4.2 in control group and assumed 8.1±3.0 in experimental group. With significance set at 0.05 and power set at 80%, the sample size required to detect the assumed differences was about 50 patients, calculated by using PASS 11.0 software (NCSS, LLC. Kaysville, Utah, USA). Taking into account a lost-to-follow-up rate of about 20%, we aimed to include a total of 120 patients.

Statistical analysis

Data were analyzed according to the intention-to-treat principle and following a pre-established analysis plan. According to the original allocation, all patients who were randomized in this study for the validity of the statistical calculations. In the current study, no interim analysis was performed.

Standard descriptive statistics, such as the mean (SD) and number of patients (frequency), were used to summarize the variables. The primary outcomes, i.e., postoperative BDI scores, were compared between the groups using homogeneous variances. Mean differences with 95% CI were calculated. Pre- and intraoperative data, including age, height, weight, surgery duration, and blood loss, as well as other postoperative outcomes, including the BAI scores, PCIA consumption, early walking time, Qor-15 scores, and intensive care unit and hospital stays, were compared between the two groups using the independent-sample t test for normally distributed data. The pain scores were compared between the groups using a two independent samples nonparametric test (the Mann-Whitney test). Categorical data, including education level, sex, and sleep quality, were analyzed using the chi-square test or Fisher’s exact test. Two-way repeated ANOVA with LSD multiply comparisons was applied to compare the level of serotonin and norepinephrine at different time points between the two groups. Statistical analysis was performed using SPSS version 22.0. A two-tailed P-value less than 0.05 was considered statistically significant.

Results

A total of 313 patients were screened for study participation. Of these, 120 patients were enrolled in the study and randomly assigned to the dezocine (n = 60) or control group (n = 60) (Fig 1). The final visit of the last randomized patient was completed on September 24, 2018. During the study period, there were no lapses in the blinding. No participant was lost to follow-up, and all patients were included in the final intention-to-treat analyses (Fig 1). The patients’ demographic, historical, and intraoperative data are summarized in Table 1. And in the study no patient was observed to report pain NRS ≥4 in the post-anesthesia care unit.

Fig 1

CONSORT flow chart of the study.

Table 1

Patients’ demographic characteristics and pre- and intraoperative data.

	Dezocine group(n = 60)	Control group (n = 60)
Male	37(61.7%)	31(51.7%)
Education level
<9 years	17(28.3%)	20(33.3%)
9 to 12 years	31(51.7%)	34(56.7%)
> 12 years	12(20.0%)	6(10.0%)
Age; year	56.7(11.1)	56.0(10.9)
Height; cm	160.6(9.1)	159.9(8.3)
Weight; kg	60.9(9.6)	59.8(9.7)
BMI Smoking	23.6(3.3)	23.3(2.9)
No	38(63.3%)	41(68.3%)
Quit	7(11.7%)	5(8.3%)
Yes	15(25.0%)	14(23.3%)
Drinking
No	43(71.7%)	50(83.3%)
Quit	3(5.0%)	4(6.7%)
Yes	14(23.3%)	6(10.0%)
Time to confirmed diagnosis; month	3.9(3.8)	4.6(4.7)
BDI score	5.6(3.4)	5.3(3.1)
BAI score	2.7(2.1)	3.2(2.6)
ASA
II	38(63.3%)	34(56.7%)
III	22(36.7%)	26(43.3%)
Diagnosis
Colon cancer	23(38.3%)	23(38.3%)
Rectal cancer	37(61.7%)	37(61.7%)
Operative time; min	222 (59)	218 (51)
Fluid infusion volume; mL	1791 (605)	1958 (546)
Bleeding volume; mL	199 (147)	223 (169)
Urine volume; mL	422 (364)	416 (242)

Values are presented as mean (SD) or number (proportion). BDI, Beck Depression Inventory; BAI, Beck Anxiety Inventory; ASA, American Society of Anesthesiologists.

The mean postoperative BDI score in the dezocine group was significantly lower than that in the control group (7.32±3.38 vs. 9.92±3.52, P<0.001, Table 2). The mean difference between the two groups was 2.6 (95% CI, 1.3−3.8). No significant difference was found between the two groups in the mean postoperative BAI scores (4.6±3.0 vs. 5.5±2.7, P = 0.110, Table 2) or Qor-15 scores (130.9±6.5 vs. 129.2±5.4, P = 0.138, Table 2). In addition, as shown in Fig 2, the night sleep quality was better in the dezocine group than in the control group both at the day of surgery (good 34 [56.7%], average 16 [26.7%], poor 10 [16.6%] vs. 20 [33.3%], 26 [43.3%], 14 [23.4%]; P = 0.035) and 1 day after the surgery (44 [73.3%], 11 [18.3%], 5 [8.4%] vs. 23 [38.3%], 28 [46.7%], 9 [15.0%]; P<0.001). In the dezocine group, the odds rate of good sleep at the day of surgery was 1.70 (95% CI, 1.11−2.59, P = 0.010) and that at 1 day after surgery was 1.91 (95% CI, 1.34−2.73, P<0.001).

Table 2

Postoperative outcomes.

	Dezocine group(n = 60)	Control group (n = 60)	P value
NRS for pain at rest; score
6 h after surgery	1.0(1.0)	1.3(1.3)	0.214
12 h after surgery	1.0(0.9)	1.2(1.1)	0.426
24 h after surgery	0.9(0.9)	1.2(1.1)	0.127
48 h after surgery	0.8(0.8)	1.0 (0.8)	0.284
NRS for pain at movement; score
6 h after surgery	1.9(1.4)	2.2(1.5)	0.143
12 h after surgery	2.1(1.1)	2.2(1.3)	0.259
24 h after surgery	2.1(1.3)	2.4(1.3)	0.221
48 h after surgery	1.8(1.0)	2.1(1.1)	0.139
Ramsay sedation scores; score
6 h after surgery	2.0(0.3)	2.0(0.2)	0.703
12 h after surgery	2.0(0.0)	2.0(0.2)	0.560
24 h after surgery	2.0(0.0)	2.0(0.2)	1.000
48 h after surgery	2.0(0.2)	2.0(0.2)	0.084
Nausea and vomiting	2(3.3%)	3(5.0%)	0.648
Total consumption of PCA; ml	175(10)	176(7)	0.518
Additional analgesia requirement	1(1.7%)	5(8.3%)	0.094
BDI; score	7.3(3.4)	9.9(3.5)	<0.001
BAI; score	4.6(3.0)	5.5(2.7)	0.110
Time to walk; hour	78.9(32.6)	78.2(50.8)	0.922
Time to resume gastrointestinal recovery; hour	85.0(44.4)	84.4(67.2)	0.954
Qor-15; score	130.9 (6.5)	129.2(5.4)	0.138
Length of hospital stay; day	13.8(3.9)	14.4(5.9)	0.471
Complications	16(26.7%)	21(35%)	0.323

Values are presented as mean (SD) or number (proportion). BDI, Beck Depression Inventory; BAI, Beck Anxiety Inventory; NRS, numeric rating scale; PCA, patient controlled analgesia; Qor-15, quality of recovery-15 items.

Fig 2

Distribution of patients’ self-reported night sleep quality at the day of surgery (A) and 1 day after surgery (B).

There was no significant difference in the pain score between the two groups at 6 (rest: P = 0.214; movement: P = 0.143), 12 (rest: P = 0.426; movement: P = 0.259), 24 (rest: P = 0.127; movement: P = 0.211) or 48 h after surgery (rest: P = 0.284; movement: P = 0.139; Table 2). No significant difference was found in the total PCIA consumption or incidence of additional analgesia requirement between the two groups (P = 0.518 and P = 0.094, respectively; Table 2). In addition, there was no significant difference with respect to the incidence of nausea and vomiting, time to walking, time to resume gastrointestinal functional, length of hospital stay, or incidence of postoperative major complications during hospitalization between the two groups. (P = 0.648, 0.922, 0.954, 0.471, 0.323, respectively; Table 2).

Two-way repeated ANOVA revealed a significant group effect both for the serum serotonin concentration (P = 0.039) and the serum norepinephrine concentration (P = 0.048) at different time points. As showed in Fig 3, there was no significant difference between the dezocine and control groups in the preoperative serum serotonin (535±138 vs. 535±149 ng/L, P = 0.997) or norepinephrine levels (189±48 vs. 192±48 ng/L, P = 0.751). Both the serum serotonin (535±142 vs. 470±139 ng/L, P = 0.013) and norepinephrine levels (199±40 vs. 174±49 ng/L, P = 0.002) at 1 day after surgery were higher in the dezocine than in the control group. Similarly, at 2 days after surgery, both the serum serotonin (532±147 vs. 473±127 ng/L, P = 0.022) and norepinephrine levels (205±46 vs. 183±41 ng/L, P = 0.008) were higher in the dezocine than in the control group.

Fig 3

Serum serotonin (A) and norepinephrine (B) concentrations at different time points for the patients of the two groups.

Discussion

Through this randomized controlled trial, we found that postoperative intravenous analgesia using sufentanil combined with dezocine can significantly lower the depression scores compared to those in the control group at 2 days after CRC surgery. The results also showed that dezocine significantly improved the night sleep quality at the day of surgery and 1 day after surgery. Both the serum serotonin and norepinephrine levels at 1 and 2 days after surgery in the dezocine group were higher than those in the control group. No significant difference was found in the other outcomes, including postoperative anxiety, Qor-15, and pain scores between the two groups.

Dezocine is a partial μ opioid receptor agonist[27,36,37]that is theoretically approximately equipotent with morphine. Clinical studies have also proved it has the same analgesic effect as morphine[38-40]. Dezocine is becoming one of the most popular postoperative analgesics in China and is often used in combination with opioids, such as sufentanil[15,27]. In the present study, we found no significant difference in the pain scores both at rest and movement between the dezocine and control groups. The mean pain score at movement during the 48-h analgesia was less than 3 in both groups. In addition, no difference was found in the PCIA consumption or additional analgesia requirement during the 48-h follow-up. These results indicated that sufentanil combined with dezocine can provide effective postoperative analgesia in patients undergoing CRC surgery.

Our findings showed that, compared to the preoperative psychological assessment, patients experience an increase in anxiety and depressive symptoms in the early postoperative period after laparoscopic CRC surgery. This finding is consistent with that of a previous study, which found that patients experienced an increase in depressive symptoms in the early postoperative period after CRC surgery[41,42]. To the best of our knowledge, this study is the first to explore the role of PCIA using dezocine in relieving depression symptoms after laparoscopic CRC surgery. We found that patients receiving dezocine PCIA had significantly lower depression scores than those of the control group at 2 days after surgery, indicating that dezocine has the potential to relieve postoperative depression symptoms. A recent study found that postoperative patient-controlled epidural analgesia using dezocine can decrease depression scores at 3 days after cesarean delivery and increase the patients’ serum serotonin concentration compared to controls without dezocine[14]. This study supports our finding that dezocine can decrease the depression scores in surgery patients, and the underlying mechanism may be its effect on the serotonin and norepinephrine reuptake. The interaction of dezocine with serotonin and norepinephrine transporters at their ligand-binding site and its concentration-dependent inhibitory effect on the serotonin and norepinephrine reuptake have been confirmed by several studies[16,43]; however, these studies did not provide direct clinical evidence.

Previous studies have demonstrated that deficiency of monoamine neurotransmitters, such as serotonin, noradrenaline, and dopamine, in the central and peripheral nervous system is a major cause of depression[20,44]. The changes in the serum levels of monoamine neurotransmitters and their metabolites can be used as important biomarkers for diagnosis of depression[17,18]. In the current study, we explored the possible changes in the serum serotonin and norepinephrine concentrations when dezocine was intravenously administered during PCIA. Interestingly, the results showed that both the serum serotonin and norepinephrine concentrations at 1 and 2 days after surgery were higher in the dezocine group than in the control group. Another recent study also found that plasma norepinephrine and serotonin concentrations at 1 day after laparoscopic cholecystectomy were higher in participants receiving intravenous dezocine before surgery than in controls[45]. This clinical evidence further supports the interaction of dezocine with serotonin and norepinephrine transporters. Based on our results and the available evidence, we speculated that postoperative dezocine use can relieve depression symptoms in patients undergoing CRC surgery and that this effect may be associated with its ability to elevate the serum levels of serotonin and norepinephrine.

Beyond its effect in improving the psychological state, we also found that patients in the dezocine group reported better night sleep quality at the day of surgery and 1 day after surgery. In particular, the rate difference for good night sleep at 1 day after surgery reached 35%, indicating that dezocine use during PCIA may have a profound effect in improving patients’ sleep quality. There are currently no available studies focusing on the role of dezocine in improving patients’ sleep quality, and the underlying mechanism remains unknown. There was one previous study[46,47] showing that selective serotonin reuptake inhibitors may induce sleep quality changes. Based on the current finding, we speculated that the effect of dezocine on the serotonin and norepinephrine reuptake may contribute to its role in sleep quality improvement. Nevertheless, the current finding may extend the clinical benefit of postoperative analgesia using dezocine for patients undergoing CRC surgery.

Despite the favorable effects of dezocine use on the postoperative psychological state and sleep quality during the first 2 days after surgery, the mean QoR-15 score in the current study at postoperative 7 days was higher in the dezocine than in the control group, but without a significant difference between the groups. This result could have potentially be caused by a type II error because of the relatively small sample size. Qor-15 is a comprehensive assessment scale for postoperative recovery, which depends on many factors, including age, surgical technique, postoperative complications, and surgical care. The average hospitalization time of the patients in our study reached more than 10 days, indicating that CRC surgery requires long-term recovery. Thus, although dezocine demonstrated favorable short-term (48-h) effects on the psychological state and sleep quality, these positive effects might not persist over time. However, the improved perioperative mental state and sleep quality are certainly associated with improved postoperative recovery[48]. Therefore, postoperative analgesia using dezocine might also be effective in other surgical populations. Future studies with a larger sample size are needed to verify this finding.

Although the current study presented some interesting findings regarding postoperative analgesia using dezocine, several limitations should be considered when interpreting the results. First, dezocine was investigated as a combination analgesic, but its possible interaction with sufentanil is unclear. The effects of dezocine on postoperative depression or sleep quality when used alone remain unknown. Second, to exclude the potential interference from difference in the analgesic effect, an equivalent dose of the two analgesic strategies was selected. Thus, the possible bias induced by the different dose of sufentanil could not be avoided in the study. Third, because postoperative analgesia only lasted 2 days in this study, we performed psychological assessment shortly after surgery. Hence, it is unknown whether the mental improvement can last a longer time, and this needs further study. Fourth, one calculation error must be noted that the calculated sample size is estimated to be 20% of the missed follow-up patients, and the total sample size should be 125 but not 120, however no patient was missed during the study and through power calculation based on the primary outcomes (9.9±3.5 vs. 7.3±3.4, n = 60) the power reached 0.984. In addition, the sleep quality in this study was assessed only by patients’ subjective report. Future studies should apply an objective method, such as polysomnography, to further explore the effects of dezocine on sleep improvement.

Conclusions

In conclusion, PCIA using dezocine combined with sufentanil can significantly reduce postoperative depression symptoms and improve sleep quality in patients undergoing CRC surgery. Postoperative analgesia using dezocine as a combination analgesic might be an optional analgesic strategy and should be recommended for patients with cancer. Further study is needed to validate these findings in greater detail and determine the effect of dezocine on the postoperative recovery of other cancer surgery patients.

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3 Jan 2020

PONE-D-19-20751

Postoperative analgesia using Dezocine may alleviate depressive symptoms after colorectal cancer surgery: A randomized controlled double-blind trial

PLOS ONE

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4. In the Methods, we note that “Depression and anxiety questionnaires were applied to measure their preoperative depression and anxiety scores”. Could you please clarify what questionnaires were used? Were they the Beck Depression Inventory and Beck Anxiety Inventory?

5. Please add citations when discussing each of the questionnaires and surveys used in this work.

6. Thank you for stating the following in the Acknowledgments Section of your manuscript:

'Clinical Research Projects of Second Affiliated Hospital of Army Medical University (No.2015YLC09 and No. 2016YLC10). The sponsors had no role in the study design, survey process, data analysis, or manuscript preparation.'

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

"NO - The sponsors had no role in the study design, survey process, data analysis, or manuscript preparation.Include this sentence at the end of your statement: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

Please provide an amended Funding Statement that declares *all* the funding or sources of support received during this specific study (whether external or internal to your organization) as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now

Please state what role the funders took in the study.  If any authors received a salary from any of your funders, please state which authors and which funder. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

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Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: 1. in the methods section, as an exclusion criteria you have introduced "known psychiatric disease". In my opinion you might also add "history of administration of anti-psychotic drugs for any reason" as these classes of medications might be used for purposes other than psychiatric disease, for instance, neurologic disorders or pain syndromes.

2. Maintenance dose for Propofol has been presented as mg/kg/h. Please present it as mg/kg/min

3. You have used BIS to monitor the depth of anesthesia. You have used both Propofol and volatile agents for anesthesia maintenance. I suppose you might suggest balanced anesthesia as the reason but what is the rationale behind it while you could use solely TIVA?

Reviewer #2: The manuscript " Postoperative analgesia using Dezocine may alleviate depressive symptoms after colorectal cancer surgery: A randomized controlled double-blind trial " presents an interesting study on the availability of dezocine in alleviating depressive symptoms in patients undergoing colorectal cancer surgery. Some specific comments with line number where applicable based on the downloaded PDF:

L-133, Are you sure randomization number and group allocation information in envelopes were stored until the end of the study? If so, how can you made the randomized control?

L-153, When was the tracheal tube extubated? In the operating room or PACU? If patients had significant pain after extubation in PACU, how did your members do? Are there any other analgesic beside the PCIA at that time?

L-227, NRS was continuous assessed at multiple time points, comparison of the two group should completed by use of repeated ANOVA analysis. Besides, statistic data should analyzed by SPSS of new version.

There are a few spelling mistakes need careful checking.

Reviewer #3: The authors conducted a randomized controlled double-blind single center trial with a parallel group design to compare sufentanil (1.3μg/kg) with dezocine (1mg/kg) to sufentanil (2.3μg/kg) without dezocine in patients with colorectal cancer surgery with respect to Beck Depression Inventory at 2 days after surgery. They concluded, that for patients undergoing colorectal cancer surgery, intravenous analgesia using dezocine can relieve postoperative depression scores.

In general, the presentation appears to be sound scientific.

I start my revision with some general comments:

• The interpretation of the study is not clear to me. Both groups receive the same dose of anastaesia, one with a mix of sufentanil and dezocine, the other with the monosubstance of sufentanil alone. So one might argue, that the effect of sufentanil does not increase linear with dose, and thus it remains unclear, whether the comparators should be recommended.

• The authors are encouraged to include an individual patient data file which may be anonymized, but let the reviewer and the reader follow the arguments.

• The trial registration does not met the international standard according to ICMJE and PLoSOne

• The sample size calculation is incorrect. Taking the assumptions the study appears to be underpowered. Taking the two tailed significance level 5%, 90% power, effect size 0.5 using a homoscedastic variance t-test it results 87/group.

• Give details of measurement of the primary endpoint, to make clear, whether detection bias can be excluded.

• Please give details of additional analgesia within groups, to make clear, whether performance bias can be excluded.

Line 52: Give the complete trial design specification, see above. Missing information e.g. no. of centers, interim analysis etc.

Line 58-60: Remove to Method section.

Line 60: Add setting of the study to Method section.

L107: write: “randomized, double-blind, single center trial with a parallel group design in a second …”

L130: Give the name of the randomization procedure, applied.

L134: The blinding remains unclear. Describe whether study drugs could be distinguished or not.

L 206: See comments about the sample size calculation above. Give the name of the statistical test used for sample size calculation.

L215: Specify, how intention to treat was implemented.

L220: t-test using homogeneous variances

L224: abnormal is not clear. Further U-Test does not overcome non-normal distribution, so the argument is weak.

As several test procedures are used, give the name of the test, where it is used with the value of the test statistic in the result section.

L240: Test for baseline characteristics are not meaningful in randomized trials. So skip the information as well as the last column in table 1.

L274/6/9: avoid “p>0.05”, give exact p-values.

L293: Avoid * notation, give exact p-values.

**********

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Reviewer #1: Yes: Samad EJ Golzari

Reviewer #2: No

Reviewer #3: No

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8 Feb 2020

February 8, 2020

Iratxe Puebla

Senior Managing Editor

PLOS ONE

Dear Editor:

We wish to re-submit the manuscript titled “Postoperative analgesia using dezocine alleviates depressive symptoms after colorectal cancer surgery: A randomized, controlled, double-blind trial.” The manuscript ID is PONE-D-19-20751.

We thank you and the reviewers for your thoughtful suggestions and insights. The manuscript has benefited from these insightful suggestions. I look forward to working with you and the reviewers to move this manuscript closer to publication in PLOS ONE.

The manuscript has been rechecked and the necessary changes have been made in accordance with the reviewers’ suggestions. All changes in the revised document are marked in red font. The responses to all comments have been prepared and are given below. In addition, we used a professional language editing service to improve the English language throughout the manuscript.

In line with the journal’s requirements and your recommendations please find below the revised acknowledgements and funding statements:

Acknowledgements: We would like to thank Editage (www.editage.cn) for English language editing.

.

Amended Funding Statement: The study was supported by Clinical Research Projects of the Second Affiliated Hospital of Army Medical University, PLA (No. 2015YLC09 to HL and No. 2016YLC10 to GD) in design of the study andcollection, analysis, and interpretation of data.

Regarding data availability, there are no ethical or legal restrictions. The minimal anonymized data of the current study were uploaded as a Supporting Information file (S1Data).

Thank you for your consideration. I look forward to hearing from you.

Sincerely,

Hong Li

****************************************************

Editor:

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Response: We thank the editor for the thoughtful comments and suggestions. We have made the necessary changes to ensure the manuscript meets the style requirements of PLOS ONE, including those for file naming.

2. We suggest you thoroughly copyedit your manuscript for language usage, spelling, and grammar. If you do not know anyone who can help you do this, you may wish to consider employing a professional scientific editing service.

The name of the colleague or the details of the professional service that edited your manuscript.

A copy of your manuscript showing your changes by either highlighting them or using track changes (uploaded as a *supporting information* file)

A clean copy of the edited manuscript (uploaded as the new *manuscript* file)

Response: Thank you for your suggestion. We had the manuscript edited and formatted by Editage, a professional science editing service. We believe that it now meets the requirements of PLOS ONE. All relevant data and files were uploaded.

3. Please note that according to our submission guidelines (http://journals.plos.org/plosone/s/submission-guidelines), outmoded terms and potentially stigmatizing labels should be changed to more current, acceptable terminology.

Response: We have sought a professional language editing service to ensure acceptable terminology throughout the manuscript.

4. In the Methods, we note that “Depression and anxiety questionnaires were applied to measure their preoperative depression and anxiety scores”. Could you please clarify what questionnaires were used? Were they the Beck Depression Inventory and Beck Anxiety Inventory?

Response: The depression and anxiety questionnaires refer to the Beck’s Depression Inventory (BDI) and Beck’s Anxiety Inventory (BAI). The manuscript has been revised accordingly (Page 6, lines 110-111)

5. Please add citations when discussing each of the questionnaires and surveys used in this work.

Response: We have included relevant citations in the revised manuscript.

Beck’s Depression Inventory (BDI) (Page 6, line 112; Page 9, line 173)

Beck AT, Beamesderfer A. Assessment of depression: the depression inventory. Mod Probl Pharmacopsychiatry. 1974;7(0):151–169.

Beck’s Anxiety Inventory (BAI) (Page 6, line 112; Page 9, line 178)

Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol. 1988;56:893–897.

Chinese Version of Beck’s Depression Inventory (Page 9, line 179)

Sun XY, Li YX, Yu CQ, Li LM. [Reliability and validity of depression scales of Chinese version: a systematic review]. Zhonghua Liu Xing Bing Xue Za Zhi. 2017;38:110-6.

Chinese Version of Beck’s Anxiety Inventory (Page 9, line 179)

Liang Y, Wang L, Zhu J. Factor structure and psychometric properties of Chinese version of Beck Anxiety Inventory in Chinese doctors. J Health Psychol. 2018;23:657-66.

Quality of recovery-15 items (Qor-15) ( Page 9, line 185)

Bu XS, Zhang J, Zuo YX. Validation of the Chinese Version of the Quality of Recovery-15 Score and Its Comparison with the Post-Operative Quality Recovery Scale. Patient. 2016;9:251-9.

6. Thank you for stating the following in the Acknowledgments Section of your manuscript:

'Clinical Research Projects of Second Affiliated Hospital of Army Medical University (No.2015YLC09 and No. 2016YLC10). The sponsors had no role in the study design, survey process, data analysis, or manuscript preparation.'

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

"NO - The sponsors had no role in the study design, survey process, data analysis, or manuscript preparation .Include this sentence at the end of your statement: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

Please provide an amended Funding Statement that declares *all* the funding or sources of support received during this specific study (whether external or internal to your organization) as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now

Please state what role the funders took in the study. If any authors received a salary from any of your funders, please state which authors and which funder. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

c. Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

Response: We have included the revised statements in the cover letter.

7. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

Response: Thank you for your advice. There are no ethical or legal restrictions. The minimal anonymized data of the current study was uploaded as a Supporting Information file (S1 Data).

8. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information

Response: Thank you for your advice. We have revised accordingly.

Reviewer #1:

1. in the methods section, as an exclusion criteria you have introduced "known psychiatric disease". In my opinion you might also add "history of administration of anti-psychotic drugs for any reason" as these classes of medications might be used for purposes other than psychiatric disease, for instance, neurologic disorders or pain syndromes.

Response: We thank the reviewer for the thoughtful comments and suggestions. Patients with a history of administration of antipsychotic drugs would not be included in the current study. Based on your suggestion, we have added "history of administration of antipsychotic drugs for any reason" in the exclusion criteria (Page5, line 105-106).

2. Maintenance dose for Propofol has been presented as mg/kg/h. Please present it as mg/kg/min

Response: Thank you for your suggestion. We have revised accordingly (Page 7, line 141-142).

3. You have used BIS to monitor the depth of anesthesia. You have used both Propofol and volatile agents for anesthesia maintenance. I suppose you might suggest balanced anesthesia as the reason but what is the rationale behind it while you could use solely TIVA?

Response: In China, combined intravenous and inhalation anesthesia is a common anesthesia method, which is considered to have the advantages of enhancing the anesthetic effect and reducing the dosage of anesthetics. Furthermore, combined intravenous and inhalation anesthesia have been used in many previous studies (e.g. Lan Yuan , Wei Tang , Guo-qiangFu, et al. Combining interscalene brachial plexus block with intravenous-inhalation combined anesthesia for upper extremity fractures surgery: a randomized controlled trialInt J Surg. 2014;12:1484-1488 and World Neurosurg. 2018;111:e267-e276).

Reviewer #2:

The manuscript " Postoperative analgesia using Dezocine may alleviate depressive symptoms after colorectal cancer surgery: A randomized controlled double-blind trial " presents an interesting study on the availability of dezocine in alleviating depressive symptoms in patients undergoing colorectal cancer surgery. Some specific comments with line number where applicable based on the downloaded PDF:

L-133, Are you sure randomization number and group allocation information in envelopes were stored until the end of the study? If so, how can you made the randomized control?

Response: We agree with the reviewer that the descriptions regarding the randomization were unclear. We have revised the text to ensure clarity, as follows: “A biostatistician, who was not included in data management and statistical analysis, generated random numbers (in a 1:1 ratio) using the SPSS 22.0 software (SPSS Inc., Chicago, IL). An independent assistant who was not involved in the study or data analysis prepared the allocation sequence and hid the random numbers in opaque, numbered, and sealed envelopes. During the study period, patients were recruited consecutively and were randomly assigned to receive either sufentanil with dezocine (dezocine group) or sufentanil without dezocine (control group) in the operating room according to the random number in the envelopes. A study nurse, who was independent from data collection and analysis, prepared the drugs according to the randomization sequence. After the intervention was performed according to the randomization number, the envelopes were sealed again and stored until the end of the study. The study investigators, healthcare team members, and patients were blinded to the treatment group allocation throughout the study period. Perioperative data collection and postoperative follow-up interviews during the hospitalization period were performed by study investigators. (Pages 6-7, lines 115-131)

L-153, When was the tracheal tube extubated? In the operating room or PACU? If patients had significant pain after extubation in PACU, how did your members do? Are there any other analgesic beside the PCIA at that time?

Response: We thank the reviewer for the comments regarding postoperative analgesia, which should be described in the manuscript. We have revised accordingly, as follows: “At the time of skin closure, all patients were given sufentanil 0.1 μg/kg. After sobering in the post-anesthesia care unit, patients were extubated and transferred to the surgery ward. If patients reported pain ≥ 4 on the numerical rating scale (NRS), 5-ug boluses of sufentanil were given (Page 7, lines 143-146)

L-227, NRS was continuous assessed at multiple time points, comparison of the two group should completed by use of repeated ANOVA analysis. Besides, statistic data should analyzed by SPSS of new version.

Response: Thank you for comment. In this study, the pain NRS scores were abnormally distributed data; thus, repeated ANOVA was not applicable. In addition, comparing the pain NRS scores at different time points is acceptable, as seen in many previous studies (e.g.: Reynolds JW, et al. Analgesic Benefit of Pectoral Nerve Block II Blockade for Open Subpectoral Biceps Tenodesis: A Randomized, Prospective, Double-Blinded, Controlled Trial. Anesth. Analg. 2019 08;129(2)), as these comparisons could reflect the potential difference in the analgesic effect between different interventions. We have reanalyzed the data using a newer version of SPSS software (SPSS 22.0) and the results were consistent with the previous (Page 12, line 229)

There are a few spelling mistakes need careful checking.

Response: We have sought a professional language editing service to improve the English language usage throughout the manuscript.

Reviewer #3:

The authors conducted a randomized controlled double-blind single center trial with a parallel group design to compare sufentanil (1.3μg/kg) with dezocine (1mg/kg) to sufentanil (2.3μg/kg) without dezocine in patients with colorectal cancer surgery with respect to Beck Depression Inventory at 2 days after surgery. They concluded, that for patients undergoing colorectal cancer surgery, intravenous analgesia using dezocine can relieve postoperative depression scores.

In general, the presentation appears to be sound scientific.

I start my revision with some general comments:

• The interpretation of the study is not clear to me. Both groups receive the same dose of anastaesia, one with a mix of sufentanil and dezocine, the other with the monosubstance of sufentanil alone. So one might argue, that the effect of sufentanil does not increase linear with dose, and thus it remains unclear, whether the comparators should be recommended.

Response: We thank the reviewer for the thoughtful comments and suggestions. We agree with the reviewer’s opinion that the effect of sufentanil may not increase linearly with the dose. However, at present, this is unknown and needs to be compared through further research. In addition, the use of combinations (i.e. two analgesic combinations) has been compared with single drugs in many studies (Wu L, et al. Low Concentration of Dezocine in Combination With Morphine Enhance the Postoperative Analgesia for Thoracotomy.J Cardiothorac Vasc Anesth. 2015 Aug;29(4):950-4.; Guangming Yan, et al. A prospective randomized trial of intravenous ketorolac vs. acetaminophen administered with opioid patient-controlled analgesia in gynecologic surgery. BMC Anesthesiol 2018 12 19;18(1); Wang C, Li L, Shen B, et al. A multicenter randomized double-blind prospective study of the postoperative patient controlled intravenous analgesia effects of dezocine in elderly patients[J]. Int J Clin Exp Med,2014,7(3):530-539.; Shangkun Li, et al. Application of Patient-Controlled Intravenous Analgesia of Dezocine Combined With Sufentanil in Burn Patients After Surgery. Zhonghua Shao Shang Za Zhi 31 (1), 48-51. Feb 2015. PMID 25876640.; and Lu Jing, et al. Analgesic effect of morphine combined sufentanil PCIA in patients undergoing cardiac valve surgery[J]. Journal of Clinical Anesthesiology 2014-4.

In the present study, because PCIA with sufentanil has been widely used for postoperative analgesia in China and considering that using dezocine alone might not be effective for pain control in patients undergoing CRC surgery, we used sufentanil combined with dezocine for the experimental intervention, which is a commonly used combination in clinical practice and in many previous studies. Based on this comparison, this study aimed to explore whether dezocine use during postoperative PCIA may relieve postoperative depression symptoms in patients undergoing CRC surgery.

• The authors are encouraged to include an individual patient data file which may be anonymized, but let the reviewer and the reader follow the arguments.

Response: Thank you for your advice. The minimal anonymized data of the current study were uploaded as a Supporting Information file (S 1 Data).

• The trial registration does not met the international standard according to ICMJE and PLoS One

Response: The study protocol was approved by the Institutional Ethics Committee of the Second Affiliated Hospital of the Army Medical University (2018-029). The trial was registered prior to patient enrollment at the Chinese Clinical Trial Registry (www.chictr.org.cn; ChiCTR1800016246). The registration procedures of the Chinese Clinical Trial Registry are in full compliance with the requirements of the WHO International Clinical Trial Registration Platform (WHO ICTRP) and International Committee Medical Journal Editors (ICMJE).

• The sample size calculation is incorrect. Taking the assumptions the study appears to be underpowered. Taking the two tailed significance level 5%, 90% power, effect size 0.5 using a homoscedastic variance t-test it results 87/group.

Response: We apologize for the clerical error; we have revised the text. The power should be 80%. The sample size was calculated by a statistician from the Department of medical statistics in the hospital. Based on our pilot investigation (n=10), the mean BDI score 2 days after CRC surgery was 10.2 (standard deviation [SD], 4.2). Comparison of the two means of parallel variables was performed as in the main analysis. According to the set minimum of 0.5 SD for clinically important differences between the experimental and control groups [35], we assumed that dezocine could reduce the mean BDI scores of the experimental group by 2.1 points relative to those of the control group in this study. With significance set at 0.05 and power set at 80%, the sample size required to detect the assumed differences was 50 patients, calculated using the PASS 11.0 software (NCSS, LLC. Kaysville, Utah, USA). Taking into account a lost-to-follow-up rate of about 20%, we aimed to include a total of 120 patients.

• Give details of measurement of the primary endpoint, to make clear, whether detection bias can be excluded.

Response: According to the standardized process, the BDI and BAI tests were administered to patients by a study investigator at the general surgery ward. In order to minimize detection bias, the tests were administered by the same investigator who had been trained by psychology experts (Page 9, lines 168-171).

• Please give details of additional analgesia within groups, to make clear, whether performance bias can be excluded.

Response: If patients reported pain ≥ 4 on the NRS, clinicians provided additional intravenous injection of 50 mg flurbiprofen axetil. To minimize performance bias, additional analgesia within groups was administered by clinicians who were blinded to the group allocation (Page 8, lines 162-165).

Line 52: Give the complete trial design specification, see above. Missing information e.g. no. of centers, interim analysis etc.

Response: This was a randomized, parallel-controlled, double-blind, single-center trial performed in the Second Affiliated Hospital of the Army Medical University, Chongqing, China. All patients were first screened in the general surgery ward and were recruited according to the inclusion and exclusion criteria 1 day before the surgery (Page 5, lines 98-101). In the current study, no interim analysis was performed. (Page 11, lines 214-215).

Line 58-60: Remove to Method section.

Response: We have revised accordingly.

Line 60: Add setting of the study to Method section.

Response: We have revised accordingly (Page 2, lines 34-36).

L107: write: “randomized, double-blind, single center trial with a parallel group design in a second …”

Response: We have revised accordingly (Page 5, lines 98).

L130: Give the name of the randomization procedure, applied.

Response: We have revised accordingly: “Randomization was performed using the sealed envelope method. A biostatistician, who was not included in data management and statistical analysis, generated random numbers (in a 1:1 ratio) using the SPSS 22.0 software (SPSS Inc., Chicago, IL). An independent assistant who was not involved in the study or data analysis prepared the allocation sequence and hid the random numbers in opaque, numbered, and sealed envelopes. During the study period, patients were recruited consecutively and were randomly assigned to receive either sufentanil with dezocine (dezocine group) or sufentanil without dezocine (control group) in the operating room according to the random number in the envelopes. A study nurse, who was independent from data collection and analysis, prepared the drugs according to the randomization sequence. After the intervention was performed according to the randomization number, the envelopes were sealed again and stored until the end of the study (Pages 6-7, lines 115-131).

L134: The blinding remains unclear. Describe whether study drugs could be distinguished or not.

Response: Since both analgesic drugs are colorless and transparent, they cannot be distinguished based on their appearance from the PCIA mechanical pump box (Pages 6, lines 124-126).

L 206: See comments about the sample size calculation above. Give the name of the statistical test used for sample size calculation.

Response: We have added the related description in the revision manuscript. Comparison of the two means of parallel variables was performed as the main analysis. (Page 10, lines 202-203)

L215: Specify, how intention to treat was implemented.

Response: The intention-to-treat principle implies that all patients who are randomized in a clinical trial should be analyzed according to their original allocation. According to original allocation, all patients who are randomized in this study for the validity of the statistical calculations (Page 11, lines 213-214). In fact, in this study, all data assessments were completed during the patient's hospital stay. There were no patients crossing over to another treatment group or patients lost to follow-up.

L220: t-test using homogeneous variances

Response: We have revised accordingly (Page 11, lines 218-219)

L224: abnormal is not clear. Further U-Test does not overcome non-normal distribution, so the argument is weak.

As several test procedures are used, give the name of the test, where it is used with the value of the test statistic in the result section.

Response: We have described the principle of analysis in the manuscript. In fact, the pain NRS scores were abnormally distributed data after normal test. Hence, the pain scores were compared between the groups using a two independent samples nonparametric test (the Mann-Whitney U test) (Page 11, line223- 225).

L240: Test for baseline characteristics are not meaningful in randomized trials. So skip the information as well as the last column in table 1.

Response: Thank you for your comment. We have revised accordingly.

L274/6/9: avoid “p>0.05”, give exact p-values.

Response: Thank you for your comment. We have added exact P-values in the manuscript.

L293: Avoid * notation, give exact p-values.

Response: We have added exact P-values in the manuscript.

Submitted filename: Response to Reviewers.doc

Click here for additional data file.

19 Mar 2020

PONE-D-19-20751R1

Postoperative analgesia using dezocine alleviates depressive symptoms after colorectal cancer surgery: A randomized, controlled, double-blind trial

PLOS ONE

Dear Dr. Li,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

**********

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The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #3: (No Response)

**********

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Reviewer #2: Yes

Reviewer #3: (No Response)

**********

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Reviewer #2: Yes

Reviewer #3: (No Response)

**********

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Reviewer #2: Yes

Reviewer #3: (No Response)

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Thank you for resubmitting the manuscript to PLOS ONE. I think you have read the reviewer's comments carefully and made modifications. As a whole, the manuscript is well-modified. However, there are two small flaws that may need attention.First, L156-146, If patients reported pain ≥ 4 on the numerical rating 146 scale (NRS), 5-ug boluses of sufentanil were given. As sufentanil were given, how much time is needed for patient observation?Or, how do you ensure that the extra sufentanil does not affect the dosage of the PCIA? Second,though there was no significant difference with respect to the incidence of nausea and vomiting, but no antemetic were used in PCIA in both the two groups. Is this inappropriate for the patient recovery?

Reviewer #3: The sample size calculation can still not be followed. There are two reasons: a) the statement “According to the set minimum of 0.5 SD” is not clear, in particular without giving the SD. Further the test statistic used as basis for the calculation is not given.

And additionally the total sample size of 120 does not account for a 20% dropout, when 100 patients are intended. This last statement should be given as a calculation error in the limitation section.

Second the name of the randomization procedure used is still not given.

**********

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Reviewer #2: No

Reviewer #3: No

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27 Mar 2020

Dear Editor:

We wish to re-submit the manuscript titled “Postoperative analgesia using dezocine alleviates depressive symptoms after colorectal cancer surgery: A randomized, controlled, double-blind trial.” The manuscript ID is PONE-D-19-20751.

We thank you and the reviewers for your thoughtful suggestions and insights. The manuscript has benefited from these insightful suggestions. I look forward to working with you and the reviewers to move this manuscript closer to publication in PLOS ONE.

The manuscript has been rechecked and the necessary changes have been made in accordance with the reviewers’ suggestions. All changes in the revised document are marked in red font. The responses to all comments have been prepared and are given below.

In line with the journal’s requirements and your recommendations, we deposit our laboratory protocols in protocols.io where a protocol can be assigned its own identifier (DOI). DOI link: http://dx.doi.org/10.17504/protocols.io.bdysi7we .

Thank you for your consideration. I look forward to hearing from you.

Sincerely,

Hong Li

Reviewer #2:

1. Thank you for resubmitting the manuscript to PLOS ONE. I think you have read the reviewer's comments carefully and made modifications. As a whole, the manuscript is well-modified. However, there are two small flaws that may need attention. First, L156-146, If patients reported pain ≥ 4 on the numerical rating scale (NRS), 5-ug boluses of sufentanil were given. As sufentanil were given, how much time is needed for patient observation? Or, how do you ensure that the extra sufentanil does not affect the dosage of the PCIA?

Response:

We thank the reviewer for the comments regarding postoperative analgesia, which should be described in the manuscript. If patients reported pain ≥ 4 on the numerical rating scale (NRS), 5-ug boluses of sufentanil were given in PACU. After 15 min, patients’ pain intensity would be assessed again. When Intensity of pain by NRS was less than 4 points and the vital signs was stable, the patient would be transferred to the surgical ward. In fact, because of intraoperative opioid use, it is rare to present pain NRS ≥4 in the PACU, and in this study there was no colorectal cancer (CRC) patient who reported pain ≥4 in PACU. Therefore, in this study PCIA dosage would not be affected by such analgesia protocol. We have revised the related descriptions in the revision manuscript accordingly. (Page7, line147-150; Page12, line245-247)

2. Second, though there was no significant difference with respect to the incidence of nausea and vomiting, but no antemetic were used in PCIA in both the two groups. Is this inappropriate for the patient recovery?

Response: We thank the reviewer for the comments regarding postoperative analgesia, which should be described in the manuscript. Actually, in our hospital all patients would be routinely injected intravenously metoclopramide 10 mg and dexamethasone 5 mg before anesthesia induction, in order to prevent intraoperative stress response and postoperative nausea. We have added this related descriptions in the revised manuscript. (Page7, line136-138)

Reviewer #3:

1.The sample size calculation can still not be followed. There are two reasons: a) the statement “According to the set minimum of 0.5 SD” is not clear, in particular without giving the SD. Further the test statistic used as basis for the calculation is not given.

And additionally the total sample size of 120 does not account for a 20% dropout, when 100 patients are intended. This last statement should be given as a calculation error in the limitation section.

Response: Thanks for the reviewer for the thoughtful comments and suggestions. We are sorry for the unclear descriptions regarding the sample size calculation. Based on the pilot investigation (n=10), the mean BDI scores at 2 days after CRC surgery was 10.2 (standard deviation [SD] 4.2). The minimum clinically important difference between the experimental and control groups was set as 0.5SD, e.g., 2.1. And the test statistic was based on two sample T-Test (difference). Here because the SD in experimental group is unknown, we assumed it as 3.0. Thus the sample size was calculated based on 10.2±4.2 in control group and assumed 8.1±3.0 in experimental group. With significance set at 0.05 and power set at 80%, the sample size required to detect the assumed differences was about 50 patients, calculated by using PASS 11.0 software (NCSS, LLC. Kaysville, Utah, USA). (Page6, line206-213)

Regarding the sample size calculation, we are sorry for the error, and we have added it in the limitation section. The calculated sample size is estimated to be 20% of the missed follow-up patients, and the total sample size should be 125 but not 120, however no patient was missed in the study and through power calculation based on the primary outcomes (9.9±3.5 vs. 7.3±3.4, n=60) the power reached 0.984. (Page22, line392-396)

2. Second the name of the randomization procedure used is still not given.

Response: We take the form of simple randomization procedure. (Page6, line115-116)

Submitted filename: Response to Reviewers.doc

Click here for additional data file.

6 May 2020

Postoperative analgesia using dezocine alleviates depressive symptoms after colorectal cancer surgery: A randomized, controlled, double-blind trial

PONE-D-19-20751R2

Dear Dr. Li,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Patrice Forget

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #3: I am fine with the changes, the authors made. Thus the paper is acceptable for publication from my side.

**********

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Reviewer #3: No

13 May 2020

PONE-D-19-20751R2

Postoperative analgesia using dezocine alleviates depressive symptoms after colorectal cancer surgery: A randomized, controlled, double-blind trial

Dear Dr. Li:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE.

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on behalf of

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PLOS ONE