This prospective, double-blind, random, placebo-controlled, single-centered trial of perioperative analgesia to prevent CPSP in elderly patients after hepatectomy. The objective of the study was to test the superiority of parecoxib vs. placebo in preventing chronic post-hepatectomy pain in elderly patients over 65 under combined general-epidural anesthesia.
All patients, aged 65–80-years-old, with American Society of Anesthesiologists (ASA) physical status classification of I or II, scheduled to undergo elective open hepatectomy for hepatocellular carcinoma at the Zhongshan Hospital, Fudan University, were considered eligible for this study. We excluded patients who underwent hepatectomy previously, had a history of chronic pain, were treated with radiation or chemotherapy, were not suitable for epidural anesthesia (especially with coagulopathy), and had a history of psychology or mental illness. Given the potential adverse reactions of COX-2 inhibitors, patients were excluded if they fulfilled 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 score > 6 points or resection of more than three hepatic segments; 5. disease of peripheral arteries or cerebral vessels; 6. estimated glomerular filtration rate of < 60 mL/min.
All participating patients provided 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
A computer-generated randomization sequence was used to recruit and enroll patients consecutively. Only the statistician and the pharmacists were aware of the concealed allocation schedule. The participants were randomly assigned to one of the following treatment groups in a 1:1 ratio.
Parecoxib sodium of 40 mg diluted with normal saline to 4 mL was administered intravenously, starting from 10 min before incision and once every 12 h until the sixth dose.
A volume of 4 mL normal saline was administered intravenously, starting from 10 min before incision and once every 12 h until the sixth dose.
Based on the allocation schedule, the unblinded pharmacist prepared the parecoxib sodium or placebo with an identical appearance in the same type of syringe. The nurse (blinded to allocation) followed the study protocol and administered the medication according to the sequence. To reduce the bias, the patients, anesthesiologists, surgeons, nursing staff, postoperative follow-up group, and data processors were blinded to patient grouping until all the data were collected.
Baseline psychological distress
All patients completed a questionnaire of the Hospital Anxiety and Depression Scale (HADS)  on the night before surgery.
Surgery and anesthesia implementation
All surgical operations were performed through a right subcostal incision by senior physicians with surgical experience of > 5 years. Our institute developed a routine practice of combined general-epidural anesthesia, followed by patient-controlled epidural analgesia (PCEA) in liver surgery. After the patient entered the operating room, a standardized protocol was followed to achieve general anesthesia combined with an epidural block: 1) A central venous catheter was placed through the internal jugular vein to guide intraoperative fluid therapy. 2) An epidural catheter was placed properly at the T8-T9 interval, and the anesthesia plane was tested by 2% lidocaine in a volume of 3 mL. 3) General anesthesia was induced with fentanyl 3 μg/kg, propofol plasma target controlled infusion, and rocuronium 0.6 mg/kg. 4) Intraoperative monitoring was carried out via an electrocardiogram (lead II and lead V5); also, oxygen saturation, arterial blood pressure, central venous pressure, and end-tidal CO2 partial pressure were recorded. 5) Anesthesia was maintained by 0.7 minimum alveolar concentration sevoflurane and continuous epidural anesthesia. Intraoperative fentanyl and muscle relaxants were administered on demand.
PCEA pump was applied to each patient after emergence from anesthesia, with the formulation of 0.12% ropivacaine and 2 μg/mL fentanyl. The infusion rate was 2 mL/h, bolus volume was 4 mL, and lock time was 10 min. The patients received parecoxib sodium or placebo intravenously, starting from 10 min before the incision and once every 12 h till the sixth dose. In addition, non-NSAIDs rescue analgesia, according to the surgeon’s preference for postoperative breakthrough pain.
Index of hematology
Venous blood was collected separately for each patient before surgery (D0) and on the day1 (D1) and day 3 (D3) after surgery to measure levels of the following items: leukocyte count (WBC), neutrophil count (N), lymphocyte count (L), prothrombin time (PT), activated partial thrombin time (APTT), highly sensitive C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8, and IL-10.
Postoperative pain assessment and follow-up
Pain intensity was evaluated using a visual 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 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.
The patients participating in the clinical trials were requested to complete a questionnaire via telephone 3 months after the surgery. They were questioned about CPSP, and if the answer was positive, the state of CPSP was assessed using the Short-form McGill Pain Questionnaire (SF-MPQ).
The primary outcome was the proportion of patients with CPSP at 3 months after hepatectomy. The diagnostic criteria of CPSP were referred to the International Association for The Study of Pain (IASP) definition : 1) Pain that develops or increases in intensity after surgical procedure and persists for at least 3 months after surgery. 2) Localized to the surgical field or projected to the innervation territory of a nerve situated around the surgical area. 3) A pain score on the VAS > 1 cm. 4) Pain due to pre-existing pain conditions or infections and 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 in hematological indexes, and postoperative complications within 28 days.
The observational data unpublished from patients after liver surgery revealed a CPSP prevalence of 48.6%. Previous studies [16, 17] were used to determine the sample size. Based on an α of 5% and a power of 80%, a sample size of 44 patients per group was sufficient to detect a difference between the parecoxib and placebo groups, given the occurrence rate of 20 and 50%, respectively. In order to allow for 10% early withdrawals and loss to follow-up, 49 patients were sufficient in each group. Finally, we included 105 patients in this study. In addition the two-sided Fisher’s exact test, the power for the primary outcome proportion of patients with CPSP was calculated as > 85%.
The database was established, a two-pass verification was performed using EpiData (version3.1, EpiData Association, Denmark), and data were analyzed using IBM SPSS Statistics (version 22, IBM Corporation, USA). Continuous variables were reported as mean ± standard deviation (SD), and categorical variables were reported as the number (percentage) of patients. The primary outcomes were analyzed based on an intention-to-treat basis according to the previous randomization categories. The proportion of patients developing CPSP between groups was compared using Pearson’s chi-square test. The relative risk (RR) value and its 95% confidence interval (CI) of CPSP were calculated for the parecoxib group. To analyze the sensitivity of the results, the worst-case scenario and per-protocol analysis were operated. For the baseline characteristics and secondary outcomes, normally distributed continuous data were compared using t-test. Non-normally distributed continuous data were compared using the Mann–Whitney U test. The categorical variables were compared using Pearson’s chi-square test or Fisher’s exact test. For repeated measurement, such as inflammation index and VAS within 72 h, an analysis of variance (ANOVA) was employed to assess the between-group difference. To compare the difference in SF-MPQ score between the two groups, we used Mann–Whitney U 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 with respect to gender, ASA status, coexisting hypertension, the neutron-lymphocyte ratio (NLR) at baseline, and intervention. The multivariate logistic regression model was constructed after the removal of collinear variables. A type 1 error of 0.05 was used for all analyses.