Impact of Perioperative Use of Parecoxib on Chronic Postsurgical Pain in Elderly Patients Undergoing Hepatectomy: A Prospective Randomized Controlled Study

Background Chronic postsurgical pain (CPSP) in elderly patients negatively impacts recovery, quality of life, and physical functioning. This study aimed to test parecoxib's superiority versus placebo in combination with epidural anesthesia in preventing chronic post-hepatectomy pain in elderly patients. Methods One hundred and ve elderly patients undergoing hepatectomy were randomized to the parecoxib group or placebo group combined with epidural anesthesia. The primary outcome was the proportion of patients with CPSP at postoperative three months. The secondary outcomes included the Short-Form McGill Pain Questionnaire score in CPSP-positive responders, acute pain intensity, postoperative analgesic demand, inammatory markers change, and postoperative complications within 28 days. Results in verbal analog lower Signicantly and vs.


Background
In China, liver cancer is one of the most commonly diagnosed malignant tumors, mainly treated by surgical procedures. Though liver cancer incidence and mortality trend was decreasing signi cantly in recent years [1], China accounts for about half of the world's new cases each year [2]. Chronic postsurgical pain (CPSP), as a common long-existing postoperative complication, has been studied extensively in various surgeries [3] but rarely in open hepatectomy. However, the incidence of CPSP in living liver donors was reported as 31% at six months and 27% at one year postoperatively [4]. For patients undergoing liver transplantation, it was up to 70.5% at three months [5]. Approximately half of the elderly patients undergoing open hepatectomy complain of chronic pain during postoperative follow-up in our surgical center. For elderly patients, CPSP has no bene cial biologic signi cance and is believed to negatively impacts recovery, quality of life, and physical functioning [6]. Currently, preventing transformation from acute pain into chronic pain is becoming an essential part of Enhanced Recovery After Surgery (ERAS) [7,8].
The right subcostal incision is the most applicable method to open hepatectomy. With abdominal muscles and nerves transected, this incision brings many in ammatory mediators released and massive cellular reactions to severe tissue injury at surgical sites [9]. Persistent in ammatory changes enhance peripheral nociceptor sensitivity and further act on the central nervous system, which leads to peripheral sensitization and central sensitization. It is central sensitization that is thought to be the underlying mechanism for postoperative pain chroni cation. Nonsteroidal anti-in ammatory drugs (NSAIDs) are essential in perioperative multimodal analgesia strategy [8]. They have an inhibitory effect on cyclooxygenases, which play an anti-in ammatory role both in the spinal and peripheral nerve system [10]. As a representative, parecoxib acts selectively on cyclooxygenase-2 (COX-2), and it has been reported to be bene cial for acute postsurgical pain management [11]. Nevertheless, there is no substantial evidence to prove its function on CPSP. Therefore, we hypothesized that parecoxib could prevent CPSP by inhibiting the perioperative in ammatory reaction that facilitated central sensitization in elderly patients.
To test the hypothesis, we designed and conducted this prospective randomized controlled study enrolling elder patients undergoing hepatectomy in Zhongshan Hospital a liated to Fudan University.
Our institution has developed a routine practice of combined general-epidural anesthesia followed by patient-controlled epidural analgesia (PCEA) in liver surgery. We established a multimodal analgesia system by adding perioperative parecoxib to the routine practice. We set relatively strict criteria for entry and enrolled patients carefully to avoid possible adverse reactions due to parecoxib. Simultaneously, we evaluated other potential risk factors for CPSP after hepatectomy in our cohort.

Study Design
This study was a prospective, double-blind, random, placebo-controlled single-centered trial of perioperative analgesia to prevent CPSP in elderly patients undergoing hepatectomy. The trial's objective was to test the superiority of parecoxib's perioperative use compared to placebo in combination with epidural anesthesia in preventing CPSP at three months after surgery in the previously mentioned cohort.

Study Participants
All patients scheduling to undergo elective open hepatectomy for hepatocellular carcinoma, aged 65 to 80, with American Society of Anesthesiologists (ASA) physical status classi cation of I or II at Zhongshan Hospital, Fudan University, were considered eligible for this study. We excluded patients who underwent the previous hepatectomy, who gave a history of chronic pain, who were treated with radiation or chemotherapy, who were not suitable for epidural anesthesia, especially with coagulopathy, who had a history of psychology or mental illness. Given the potential adverse reactions of COX-2 inhibitors, patients were excluded if they met one of the following conditions: 1. allergy to parecoxib; 2. active gastrointestinal bleeding or ulceration; 3. history of congestive heart failure or ischemic cardiac diseases; 4. Child-Pugh scores 6 points or resection of more than three hepatic segments; 5. disease of peripheral arteries or cerebral vessels; 6. estimated glomerular ltration rate of less than 60 ml/min. All participating patients gave written informed consent for this clinical trial, approved by the Ethics Committee of Zhongshan Hospital, Fudan University. A trial registration number (ChiCTR2000035198) was obtained from the Chinese Clinical Trial Registry.

Randomization and Blinding
By using a computer-generated randomization sequence, patients were recruited and allocated 1:1 to one of the following two treatment groups: 2.3.1. Parecoxib group: Parecoxib sodium of 40 mg diluted with normal saline to 4 ml was administrated intravenously immediately before initiating the surgical procedure and every 12 hours for three days.
2.3.2. Placebo group: Placebo was given on the same protocol with parecoxib sodium replaced by normal saline of 4 ml.
In this study, the patients, anesthesiologists, postoperative follow-up group, and data-processors were all blinded from the patients' grouping until all data were collected. Based on randomization, the pharmacist prepared the parecoxib sodium and placebo with identical appearance.

Baseline psychological distress
All patients completed a questionnaire of the Hospital Anxiety and Depression Scale (HADS) the night before surgery.

Anesthesia implement
After the patient entered the operating room, we followed a standardized protocol to achieve general anesthesia combined with epidural block: 1) A central venous catheter was placed through the internal jugular vein to guide intraoperative uid therapy. 2) An epidural catheter was properly placed at the T8-T9 interval, and the anesthesia plane was tested by 2% lidocaine of 3 ml. 3) General anesthesia was induced with fentanyl 3ug/kg, propofol plasma TCI, and rocuronium 0.6 mg/kg. 4) Intraoperative monitoring includes an electrocardiogram (lead II and lead V5), oxygen saturation, arterial blood pressure, central venous pressure, and end-tidal CO 2 partial pressure. 5) Anesthesia was maintained by 0.7MAC sevo urane and continuous epidural anesthesia. Intraoperative fentanyl and muscle relaxants were administered on demand.

Multimodal analgesia
Patient-controlled epidural analgesia (PCEA) pump was applied to each patient after emergence from anesthesia, with the formulation of 0.12% ropivacaine and 2 ug/mL fentanyl. The infusion rate was 2 mL/h, bolus volume was 4 mL, and lock time was 10 min. Patients received parecoxib sodium or placebo intravenously immediately before the incision and once every 12 h till the 3rd day after surgery. Besides, non-NSAIDS rescue analgesia was available according to the surgeon's preference for postoperative breakthrough pain.

Postoperative pain assessment and follow-up
Pain intensity was evaluated using a verbal analog scale (VAS) from 0 cm as no pain to 10 cm as the worst pain imaginable. Patients were assessed for pain intensity separately at rest and with coughing at 2, 4, 8, 24, 48, and 72 h post-surgery. The consuming volume and press times of the PCEA pump, the suspicious analgesic-associated adverse reactions, and any postoperative complications within 28 days were recorded.
Patients participating in the clinical trials were requested to complete a questionnaire via telephone three months after the surgery. They were questioned whether there was CPSP. If the answer was positive, states of CPSP was assessed using the Short-form McGill Pain Questionnaire (SF-MPQ).

Outcomes
The primary outcome was the proportion of patients with CPSP at three months after hepatectomy. Diagnostic criteria of CPSP were referring to the International Association For The Study Of Pain (IASP) de nition [3]: 1) pain that develops or increases in intensity after surgical procedure and persists at least three months after surgery. 2) localized to the surgical eld or projected to the innervation territory of a nerve situated around the surgical area. 3) a pain score on the VAS of greater than 1 cm. 4) pain due to pre-existing pain conditions or infections, malignancy was excluded. Secondary outcomes included the SF-MPQ score in CPSP-positive responders,acute pain intensity within 72 h after surgery, PCEA consumption, postoperative nausea and vomiting score at 24 h (0 = none, 10 = unbearable), perioperative change of hematology indexes and postoperative complications within 28 days.

Statistical Analysis
An observational data unpublished from patients undergoing liver surgery in our center revealed a CPSP prevalence of 48.6%. Based on an α of 5% and a power of 80%, a sample size of 44 patients per group was su cient to detect a difference between the parecoxib group and the placebo group, given the occurrence rate of 20% and 50%, respectively. To allow for 10% early withdrawals and loss to follow-up, 49 patients per group were enough. We nally included 105 patients in total. Based on a two-sided Fisher's Exact, the power for the primary outcome proportion of patients with CPSP was calculated as over 85%.
Database establishment and two-pass veri cation were performed using EpiData (version3.1, EpiData Association, Denmark), and data analysis was conducted with IBM SPSS Statistics (version 22, IBM Corporation, USA). Data were reported as mean ± SD, median (interquartile range), or number (percentage) of patients.
Data were compared using the Pearson chi-square test, t-test, or nonparametric test as appropriate. For repeated measurement, ANOVA was employed. Analysis of primary outcome was based on an intentionto-treat basis according to the previous randomization categories. To analyze the sensitivity of the results, the worst-case scenario and per-protocol analysis were both operated. The proportions of patients developing CPSP were compared using the Pearson chi-square test. No imputation was performed for missing data for the secondary outcomes.
To investigate other potential risk factors for CPSP after hepatectomy, logistic regression was performed by involving gender, ASA status, coexisting hypertension, the neutron-lymphocyte ratio (NLR) at baseline, and intervention. A type 1 error of 0.05 was used for all analyses.

Results
A total of 525 patients were screened, and 105 patients were recruited and assigned to receive intervention from November 2018 to July 2020 ( Fig. 1). Ninety-ve patients completed the follow-up at three months. Three patients lost to follow up due to death within three months. Seven patients withdrew from the study before the last assessment: one due to anaphylaxis, two due to failure epidural puncture, one due to recurrence, and three chose to stop. Data of all the ten patients above were included in the nal analysis. Baseline patient characteristics were similar between the two groups (Table 1). Though patients in the parecoxib group have signi cantly different depression scores from those in the placebo group (P = 0.03), the clinical signi cance was inapparent. Because the cut-off of depression score in Hospital Anxiety and Depression Scale was 8 points, the depression status between-group was similar. a Though patients in parecoxib group have signi cantly different depression scores from those in placebo group(P = 0.03), the clinical signi cance was inapparent. Because the cut-off of depression score in HADS was 8 points, the depression status between-group was similar.

Primary Outcome
The overall incidence of CPSP at three months was 40.0% (42 of 105) in the studied cohort. As stated in
As represented in Table 3, postoperative pain intensity within 72 h in the parecoxib group was signi cantly higher than that in the placebo group, especially at 24, 48, and 72 h both at rest and with coughing. Meanwhile, patients in placebo group consumed more PCEA volume(219.2 ± 42.4 mL vs.197.4 ± 43.6 mL, P = 0.01)and needed more rescue analgesia(median(IQR) 1(1, 6)vs.0(0, 0), P 0.001; Table 3).There were no differences between the two groups in postoperative analgesiaassociated adverse reactions, length of stay in hospital after surgery, and postoperative complications within 28 days (Table 3.).  Asterisks for signi cance values.
Perioperative changes in in ammatory indexes were illustrated in Fig. 2.We could not nd a signi cant in uence of parecoxib than placebo on peripheral in ammatory parameters, including leukocyte count, NLR, hs-CRP, TNF-α, IL-1β, IL-6, IL-8, and IL-10. Between-group differences of prothrombin time(P = 0.262) and activated partial thrombin time(P = 0.250) were not signi cant as well.
Post hoc analysis using logistic regression for gender, ASA status, coexisting hypertension, the NLR at baseline, and group intervention was set out in Table 4. In this model, ASA status and coexisting hypertension did not signi cantly affect the occurrence of CPSP at three months. However, the male and higher NLR at baseline were signi cantly related to developing CPSP in elderly patients undergoing primary hepatectomy.

Discussion
In our study, the overall prevalence of CPSP at three months after hepatectomy was 40%(42 of 105), and moderate-to-severe pain accounts for 3.8% 4 of 105 . The result is consistent with a single-center observational study reporting a CPSP prevalence at three months of 50% in patients undergoing liver transplantation [5]. Meanwhile, with a similar incision to hepatectomy, open cholecystectomy has reported an incidence of CPSP varying from 3-50% [12]. The difference in CPSP incidence originated from differences in study design or selected study populations. Generally, CPSP is a substantial issue with clinical signi cance after open liver resection in elderly patients, though pain intensity is mild.
According to our results, parecoxib could not signi cantly reduce the prevalence of CPSP, despite an absolute decrease of 9.1%. This difference is far less than the 30% difference anticipated when estimating sample size. Results remained consistent in both the worst-case scenario and per-protocol analysis. Helmond et al. reached a similar conclusion in the patients after breast cancer surgery [13]. In contrast, Ling et al. 's study showed that parecoxib restrains chronic pain development signi cantly [14].
However, when interviewing those experiencing chronic pain by SF-MPQ, we observed a milder pain intensity in the parecoxib group. Moreover, all four cases with moderate-to-severe average pain, ranging from 4 cm to 7 cm in VAS, occurred in the placebo group. Therefore, the study suggested that parecoxib does not signi cantly reduce the prevalence of chronic post-hepatectomy pain in elderly patients at three months but has a potential bene t of reducing chronic pain intensity. Perioperative use of parecoxib may be thereby helping to improve the quality of life in elderly patients with CPSP.
To understand how perioperative parecoxib took effect, we recorded a series of changes during the medication period. As con rmed by many studies [15], uncontrolled acute postoperative pain is a strong predictor of CPSP, possibly by provoking central sensitization [9]. In our study, the intensity of acute postoperative pain in two groups varied following similar trends: the pain intensity was trivial during the rst eight postoperative hours, which gradually increased and reached the peak on the 3rd postoperative day. Some previous studies described consistent trajectories [16,17]. We agree with the explanation that the excellent analgesia on the day of surgery is mainly due to su cient epidural anesthesia. However, since the rst day after surgery, the effects of epidural analgesia began to seem insu cient. Then the parecoxib's effect stood out: pain intensity tended to be signi cantly lower in the parecoxib group than in the placebo group. Meanwhile, a higher percentage of patients in the placebo group developed moderateto-severe pain and needed more PCEA and rescue analgesia. Thus, the multimodal analgesia with parecoxib was proven to perform superior acute pain management in our study.
With analysis on a series of peripheral in ammatory indexes, we caught sight of the following facts:1) concentrations of hs-CRP and IL-6 increase gradually over time, the trend coincided with the postoperative pain intensity;2)peripheral leukocyte count, NLR, and IL-10 increase and reach the peak on the 1st postoperative day, then decrease on the 3rd day;3)there seems no connection between parecoxib and in ammatory changes in peripheral blood. Peng et al. found in aged rats that parecoxib inhibits hepatectomy-induced IL-1β and TNF-αexpression in the hippocampus through downregulation of the COX-2/PGE2 pathway [10]. Bjurstrom et al. reported that proin ammatory mediators in cerebrospinal uid are associated with persistent postsurgical pain [18]. In clinical trials, due to technical limitations, real-time monitoring of central neuroin ammation is challenging to achieve. Though peripheral in ammatory markers are insensitive to re ect the real picture of neuroin ammation, our results suggest that1) level of systemic in ammation may indicate the intensity of acute pain;2) postoperative in ammatory and antiin ammatory reactions are conducted simultaneously;3) the anti-in ammatory effect provided by parecoxib is insu cient to ght with the enormous postoperative in ammatory response that promotes central sensitization. Coincidentally, Turan et al. reported that even with glucocorticoids, the most potent anti-in ammatory drug, CPSP could not be prevented effectively [19]. Therefore, there may exist other mechanisms that dominate the development of central sensitization besides in ammation.
Surprisingly, we found that females had a reduced risk of developing CPSP in elder patients undergoing hepatectomy. The association between sex and pain has been widely studied. Sorge et al. revealed remarkably different pathways in male and female mice that determine pain hypersensitivity [20]. Hormone levels may play a role. We also found that a higher preoperative NLR was associated with the development of CPSP. Bugada et al. reported that NLR > 4 is correlated with persistent postsurgical pain after inguinal hernia repair [21]. Other studies [22] have reported that psychologic factors, history of preexisting chronic pain, and preoperative chemotherapy are also predictors. Therefore, CPSP may have been predetermined before surgery.
The application of NSAIDs in elderly patients has been controversial for the concerns of severe adverse reactions. NSAIDs-related adverse reactions include myocardial infarction, acute kidney failure, severe gastrointestinal ulceration, anaphylaxis, and coagulopathy. There was no signi cant difference between the two groups in postoperative complications and coagulation change in our study. Moreover, none of the above side effects were reported. One patient in parecoxib withdrew from the trial because of severe anaphylaxis on the rst day after surgery. But parecoxib turned out to be innocent. However, given our small sample size, the power to evaluate those side effects is limited. Thus, the safety of parecoxib use in elderly patients remains further veri cation.
Our study has several limitations. It is a single-center RCT based on small sample size. The lack of statistical signi cance might result from low statistical power due to the small sample size. In consideration of potential adverse reactions associated with COX-2 inhibitors, we used stringent inclusion criteria. It inevitably reduced the sample size and affected the generalisability of our results. Our study's sample size was smaller than that in Kehlet's study [19] but similar to Anwar's [23]. However, few patients were lost to follow-up after receiving the assigned intervention, and sensitivity analysis showed that the nal results were not affected by the lost cases. Similarly, we evaluated CPSP with SF-MPQ instead of using an objective clinical diagnosis. Investigation on the nature of chronic pain might be limited. In the future, multi-centered RCT for objective assessment with larger sample sizes should be conducted to seek better perioperative analgesia strategy for preventing chronic postsurgical pain in elderly patients.

Conclusions
In conclusion, parecoxib reduced the prevalence of CPSP in elderly patients undergoing hepatectomy under epidural analgesia from 44.4% to 35.3% with no statistical signi cance. Besides, parecoxib has a potential effect on reducing the CPSP intensity and optimizing postoperative acute pain management.
Prudent but individualized use of parecoxib in those relatively healthy elder patients undergoing liver resection is recommended.  a Though patients in parecoxib group have signi cantly different depression scores from those in placebo group(P=0.03), the clinical signi cance was inapparent. Because the cut-off of depression score in HADS was 8 points, the depression status between-group was similar.