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. Meanwhile, with a similar incision to hepatectomy, open cholecystectomy has reported an incidence of CPSP varying from 3–50% . The difference in CPSP incidence originated from differences in study design or selected study populations. Generally, CPSP is a substantial issue with clinical significance after open liver resection in elderly patients, though pain intensity is mild.
According to our results, parecoxib could not significantly 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 . In contrast, Ling et al. 's study showed that parecoxib restrains chronic pain development significantly . 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 significantly reduce the prevalence of chronic post-hepatectomy pain in elderly patients at three months but has a potential benefit 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 confirmed by many studies, uncontrolled acute postoperative pain is a strong predictor of CPSP, possibly by provoking central sensitization. In our study, the intensity of acute postoperative pain in two groups varied following similar trends: the pain intensity was trivial during the first 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 sufficient epidural anesthesia. However, since the first day after surgery, the effects of epidural analgesia began to seem insufficient. Then the parecoxib’s effect stood out: pain intensity tended to be significantly lower in the parecoxib group than in the placebo group. Meanwhile, a higher percentage of patients in the placebo group developed moderate-to-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 inflammatory 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 inflammatory 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. Bjurstrom et al. reported that proinflammatory mediators in cerebrospinal fluid are associated with persistent postsurgical pain. In clinical trials, due to technical limitations, real-time monitoring of central neuroinflammation is challenging to achieve. Though peripheral inflammatory markers are insensitive to reflect the real picture of neuroinflammation, our results suggest that1) level of systemic inflammation may indicate the intensity of acute pain;2) postoperative inflammatory and anti-inflammatory reactions are conducted simultaneously;3) the anti-inflammatory effect provided by parecoxib is insufficient to fight with the enormous postoperative inflammatory response that promotes central sensitization. Coincidentally, Turan et al. reported that even with glucocorticoids, the most potent anti-inflammatory drug, CPSP could not be prevented effectively. Therefore, there may exist other mechanisms that dominate the development of central sensitization besides inflammation.
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. 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. Other studies have reported that psychologic factors, history of pre-existing 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 significant 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 first 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 verification.
Our study has several limitations. It is a single-center RCT based on small sample size. The lack of statistical significance 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 but similar to Anwar's. However, few patients were lost to follow-up after receiving the assigned intervention, and sensitivity analysis showed that the final 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.