Patients with end-stage knee diseases are always eager to receive a clinical treatment for the severe pain. In these cases, arthroscopic knee surgery (AKS) is generally accepted as an efficient and long-lasting therapy.[1,2] To acquire a satisfactory postoperative physical function, and also a high quality of life, early rehabilitation protocol as soon as possible after surgery is necessary.[3,4] However, the overwhelming fear of severe pain from surgery would make patients, especially those sensitive to or less able to tolerate pain, reluctant to initiate early rehabilitative exercise postoperatively, resulting in a delayed recovery or an inferior knee function.[5,6]
Celecoxib, a novel selective cyclooxygenase (COX)-2 inhibitor, has inhibitory effects on prostaglandins synthesis, both in the spinal cord and peripheral nervous system, and reduces hyperalgesia status after surgical traumas. It is illuminated that compared with conventional nonsteroidal anti-inflammatory drugs, celecoxib has less gastrointestinal (GI) side effects and less influence on antiplatelet function with long-term use.[8–11]
The benefits of pain relief by celecoxib for preoperative analgesia have been observed in patients with hip arthroscopy.[6,12,13] To date, a few studies also illustrate that preoperative administration of celecoxib in AKS decreases patients’ pain score and lowers adverse effects.[7,14] However, few studies about the most appropriate time of celecoxib initiation before surgery have been explored in patients with AKS. Therefore, the purpose of this study was to compare the efficacy and safety of celecoxib 24 hours preoperative, 1 hour preoperative, and 4 hours postoperative administration in patients with AKS.
In all, 206 patients about to undergo arthroscopic knee surgery at Department of Orthopedics in Dongyang People's Hospital, Wenzhou Medical University, from Junuary 2014 to February 2017, were consecutively recruited in this randomized, controlled study. The inclusion criteria were: age above 18 and below 65 years; meniscal disease about to receive meniscectomy and partial meniscectomy by arthroscopy; and American Society of Anesthesiology physical status as I or II. The exclusion criteria were: about to receive repair of the meniscus, reconstructive procedures for concomitant knee injuries, or internal fixation of osteochondrosis dissecans; analgesic use within 1 week before the enrollment; intra-articular hyaluronic acid injections within 9 months or corticosteroid within 3 months before the enrollment; history of knee surgery; history of coagulopathy or thromboembolic disease; history of chronic pain and/or consumption of daily analgesics; history with GI disease, perforation, ulceration, obstruction, or bleeding; history with severe renal or hepatic disease; history with malignance tumor; known to be allergic to COX-2 selective inhibitors or pethidine; and women with lactating or pregnancy. This study was approved by Ethics Committee of Dongyang People's Hospital, Wenzhou Medical University. All the patients provided written informed consents. Moreover, this study was carried out in accordance with Helsinki statement.
This was a randomized, controlled study. After the eligibility, all the patients were randomized into 3 groups: (1) early preoperative analgesia group (EPEA group); (2) preoperative analgesia group (PEA group); (3) postoperative analgesia group (POA group). In EPEA group, patients were assigned to receive celecoxib 400 mg at 24 hours before the operation, and then 200 mg every 12 hours (12 hours preoperation, 1 and 13 hours postoperation). In PEA group, patients were required to receive celecoxib 400 mg at 1 hour before the operation, and then 200 mg every 12 hours (10 and 22 hours postoperation). In the POA group, patients received celecoxib 400 mg at 4 hours after the operation, and then 200 mg every 12 hours (16 hours postoperation). The treatment duration was until 24 hours postoperation, whereas the observation duration was until 36 hours postoperation. Pethidine injection (5 mg/kg) was given if required during the entire observation duration.
The randomization was conducted by a medical and statistic service company (Shanghai Qeejen, China) as follows: the randomization code was generated by a statistician using blocked randomization method (block length: 6) due to the need of allocation balance among 3 groups. The randomization documents were subsequently sent to the Department of Orthopedics in Dongyang People's Hospital kept by a doctor separately and a copy was kept in Shanghai Qeejen for backup. When a patient was eligible for the study, an unique subject identification number was provided from the randomized module and the patient was assigned to the identified group.
2.4 Data collection
Patient characteristics were recorded before the operation including age, sex, and body mass index (BMI). Operative time was collected during the surgery. Pain visual analog scale (VAS) score at rest, pain VAS score at flexion to 90°, patient global assessment (PGA) score were evaluated preoperation, at 4, 8, 12, 24, and 36 hours postoperation. Pethidine consumption during 36 hours was collected. Pain VAS score was graded as: 0, no pain; 1 to 3, light pain; 4 to 6, moderate pain; 7 to 10, severe pain.
2.5 Primary endpoints
The primary endpoints were the differences of pain VAS score at rest and pain VAS score at flexion to 90° among 3 groups after 12 and 24 hours postoperation.
2.6 Secondary endpoints
The secondary endpoints were: the difference of PGA score among 3 groups after 12 and 24 hours postoperation; the difference of pethidine consumption among 3 groups after 24 hours postoperation; the difference of common adverse events (AEs) among 3 groups within 36 hours observational period.
Statistical analysis was performed using SAS 9.4 software and GraphPad Prism 6 software. Data were mainly presented as mean value and standard deviation (SD), count, and percentage. Comparison between 2 groups was determined by t test and chi-square test. P < 0.05 was considered significant.
3.1 Study flow
In all, 292 patients were screened, among which 86 patients were excluded (31 patients exclusions and 55 patients disagreed to participate). Also, the remaining 206 patients were randomly assigned to EPEA group, PEA group, and POA group at the ratio of 1:1:1. In the POA group, there were 9 withdrawn patients (5 protocol violations, 3 insufficient efficacy, and 1 patient decision), and the remaining 60 (87%) patients completed the study. In the PEA group, there were 7 withdrawn patients, in which 4 were protocol violations, 2 insufficient efficacy, and 1 patient decision, and the remaining 62 (90%) patients fulfilled the study. As to EPEA group, 8 patients withdrawed (6 protocol violations, 2 insufficnent efficancy), and the remaining 60 patients (88%) finishd the study (Fig. 1).
3.2 Baseline characteristic
Sixty-eight patients aged 34.69 ± 7.05 years, with 44 males and 24 females, were included in EPEA group; and 69 patients aged 36.04 ± 6.06 years, with 34 males and 35 females, were included in PEA group; as to POA group, 69 patients aged 35.86 ± 6.64 years, with 41 males and 28 females, were included. There was no difference in age, sex, BMI, and operative time between each 2 groups (EPEA group vs PEA group; EPEA group vs POA group; PEA group vs POA group; all P > .05), neither did pain at rest, pain at flexion of 90°, and PGA score at baseline (all P > .05). The detailed information is present in Table 1.
3.3 The VAS scores of pain-rest in EPEA group, PEA group, and POA group
The pain-rest VAS scores increased after the operation in all 3 groups and then back to the level of preoperation gradually. At 8 and 12 hours postoperation, the pain-rest VAS score of EPEA group (both P < .05) and PEA group (both P < .05) were lowered than that of POA group, and no difference between EPEA and PEA group was found (P > .05) (Fig. 2A). As shown in Fig. 2B, the percentage of patients with moderate-severe pain at rest and at 8 and 12 hours postoperation in EPEA (both P < .05) and PEA groups (both P < .05) were also decreased compared with POA group, whereas no difference was found between the EPEA and PEA groups (P > .05). No difference of pain-rest VAS score nor pain severity between each 2 groups at other observational time was discovered.
3.4 The VAS scores of pain-flexion to 90o in EPEA group, PEA group, and POA group
As to pain-flexion to 90o VAS score, it ascended postsurgery in all 3 groups and descended to preoperative level gradually as well. Pain VAS score at flexion to 90° was found to be decreased in EPEA group (P < .05) and PEA group (P < .05) compared with POA group at 8 hours postoperation (Fig. 3A). Interestingly, at 4 hours postsurgery, percentage of patients with moderate-severe pain-flexion at 90o in EPEA group was lower than that in PEA (P < .05) and POA groups (P < .05). Besides, percentage of patients with moderate-severe pain-flexion at 90o in PEA group (P < .05) was lower than that of POA group at 8 hours postoperation (Fig. 3B). No difference of pain-flexion to 90° VAS score nor pain severity between each 2 groups at other observational time was observed.
3.5 The PGA score in EPEA group, PEA group, and POA group
As presented in Fig. 4, at 8 and 12 hours after surgery, the PGA score in EPEA group (both P < .05) and PEA group (both P < .05) was decreased compared with that in POA group, but no difference between EPEA group and PEA group (both P > .05) was found. No difference of PGA score between each 2 groups at other observational time was found.
3.6 The consumption of pethidine
Pethidine (5 mg/kg) was injected during the study if required. The consumption of pethidine in EPEA group (P = .060) and PEA group (P = .091) was numerically decreased compared with POA group (Fig. 5), but there was no statistical significance. However, there was no difference of pethidine usage between EPEA group and PEA group (P = .809).
Nausea, vomiting, constipation, drowsiness, and dizziness were the most frequent AEs in all groups. No difference existed between each 2 groups in AEs as showed in Fig. 6 (all P > .05).
In the present study, we found: the pain-rest and pain-flexion to 90o in EPEA group and PEA group seem to be decreased compared with those in POA group, which was validated by differences in pain VAS score among 3 groups at 8 and 12 hours; the PGA score in the EPEA group and PEA group was likely be reduced compared with that in POA group, which was validated by difference in PGA score among 3 groups at 8 and 12 hours; the consumptions of pethidine in EPEA group and PEA group were numerically decreased compared with POA group, whereas no difference between each 2 groups was found in AEs. These indicate preoperative analgesia with celecoxib is more effective compared with postoperative use of celecoxib, whereas early preoperative treatment (24 hours before operation) presents with the same outcomes with preoperative treatment (1 hour before operation).
Pain after AKS, 1 of the major causes of patient dissatisfaction, delays the recovery and increases the hospitalization cost. Achieving effective pain control after AKS continues to be a clinically important issue in facilitating the rehabilitation process and enhancing patient satisfaction. Although opioids are an important components of postoperative pain management, they are associated with side-effects, and so, the pre-emptive analgesic approach with the use of celecoxib, which has less adverse effects, has been recommended for relieving postoperative pain.[17,18]
Generally, the use of celecoxib for elders does not need to adjust the dose, but for elders with weight no more than 50 kg, it is better to have minimum recommended dose when starting treatment. Moreover, celecoxib should not be used in patients with glomerular filtration rate no more than 60 mL/min and patients with risk factors for stroke and myocardial infarction.
A randomized, double-blind, prospective clinical trial reveals that oral celecoxib 200 mg 2 hours before the operation is better than placebo for controlling of postoperative pain in patients who underwent lower-extremity orthopedic surgery under general anesthesia. Another triple-blinded, randomized, placebo-controlled clinical trial suggested that celecoxib as a pre-emptive analgesic agent is efficient in decreasing acute postoperative pain and 24 hours opioid consumption in patients who underwent AKS. Besides, a cohort study illuminates that pre-emptive analgesia by 3-day administration of celecoxib is an efficient and safe therapy regarding patients with total knee arthroplasty in alleviating postoperative pain. These studies prove that celecoxib as medicine of pre-emptive analgesia is effective and safe, which is consistent with our results that pain VAS score and the PGA score postoperative in EPEA and PEA groups were lower than those of POA group. The reason might be that: celecoxib could inhibit the synthesis of prostaglandins, which played a prominent role in inflammation and pain after AKS, both in the spinal cord and peripheral nervous system[20,21]; celecoxib is a concentration-dependent analgesic drug, the area under the plasma concentration-time curve in EPEA group and PEA group was larger than POA group at 8 and 12 hours, which makes the analgesia effect of EPEA and PEA groups superior to POA group.
As to pethidine consumption, we found it declined in EPEA group and PEA group compared with POA group, which may result from the less need of salvage pethidine treatment due to decreaded pain score in EPEA and PEA groups than POA group. Besides, no difference was found among 3 groups in AEs, which was in accordance with the study performed by Mardani-KiviM that AEs are not significantly different between celecoxib pre-emptive treatment group and placebo group such as nausea and vomiting. Similarly, a randomized controlled trial illuminates that incidence of AEs also presented with no difference among 1 hour preoperative etoricoxib, celecoxib and placebo groups for acute postoperative pain in patients with arthroscopic anterior cruciate ligament reconstruction.
Interestingly, no remarkable difference was found between EPEA and PEA groups in terms of pain VAS score and the PGA score postoperative, neither did pethidine consumption and AEs. But for the consideration of cost-saving and toxicity of medicine itself, we thought pre-emptive analgesia in PEA group (1 hour before operation) is the optimal choice for AKS.[12,19,23]
This was the first study comparing the efficacy and safety of celecoxib 24 hours preoperative, 1 hour preoperative, and 4 hours postoperative administration in patients with AKS. However, there were some limitations which existed in this study. Firstly, this was an open-labeled randomized controlled study, thus the influence of bias of doctors’ assessments and patients’ self-reported evaluations exist. Secondly, we evaluated efficacy of pre-emptive use of routine dose of celecoxib (200 mg, initial dose doubling), but this dose was based on the recommended dosage of the drug description which might not be the most suitable dose for pre-emptive analgesia for AKS operation. Thirdly, functional score was not assessed, resulting in the absence of direct evidence in favor of pre-emptive analgesia, improving the postoperative functional recovery. Fourthly, patients who are allergic to sulfonamide did not included in the exclusion criteria, even though no patient was allergic to sulfonamide. Thus, a further blinded randomized controlled trial study with multiple assessment of pain, function, satisfaction, and quality of life is needed in the future.
In conclusion, this study observed that celecoxib was effective and safe as pre-emptive analgesia in AKS, and 1 hour administration before operation might be an optimal choice.
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