Positive Preemptive Analgesia Effectiveness of Pregabalin Combined with Celecoxib in Total Knee Arthroplasty: A Prospective Controlled Randomized Study

Objective The purpose of the present study (a randomized clinical trial) was to evaluate the preemptive analgesic effects of pregabalin combined with celecoxib in total knee arthroplasty (TKA). Methods From January 2019 to June 2021, we enrolled 149 patients who underwent TKA and divided them into four groups: the placebo group (n = 36), celecoxib group (n = 38), pregabalin group (n = 38), and combination group (n = 37). Each group was given the corresponding preemptive analgesia regimen at 12 and 2 hours before surgery. The pain score at rest and upon movement, cumulative dosage of sufentanil, knee range of motion (ROM), high-sensitivityC-reactive protein (hs-CRP) level, and adverse effects were evaluated after TKA to compare the effects of the preemptive analgesia regimens among the four groups. Results The pain scores upon movement were significantly lower in the combination group than in the other three groups at 6, 12, 24, and 48 hours after surgery (P < 0.05). The cumulative dose of sufentanil within 48 hours after surgery was lowest in the combined group among the four groups (P < 0.05). Hs-CRP, ROM, and postoperative nausea and vomiting (PONV) were within 72 hours after surgery significantly improved in the combination group compared with those of the three other groups (P < 0.05). Conclusion The preemptive analgesia regimen of pregabalin combined with celecoxib had positive effects on improving acute pain and reducing the cumulative dose of opioids after TKA. This trial is registered with ChiCTR2100041595.


Introduction
Total knee arthroplasty (TKA), a surgical method for the treatment of terminal stage knee osteoarthritis, can efectively relieve pain and restore knee function. However, patients experience moderate to severe pain after TKA. Acute pain after TKA can have a negative efect on enhanced recovery after surgery among patients [1]. If acute postoperative pain is not well managed, it may seriously afect the patient's knee functional recovery, sleep, and cardiopulmonary function and prolong the hospital stay, and it may even develop into uncontrollable chronic pain, which can seriously afect the patient's quality of life [2].
Te mechanism of postoperative pain is complicated. In the past, it was believed that postoperative pain after TKA was mainly nociceptive pain caused by surgical trauma and tissue infammation [3]. However, recent studies have shown that tissue infammatory mediators can repeatedly stimulate pain sensory nerves, leading to a large sensitization of pain sensory nerves and resulting in neuropathic pain [4,5]. Terefore, postoperative pain after TKA is a mixed pain involving multiple mechanisms, and the analgesic efect of a single drug is often not sufcient. At present, multimodal analgesia is considered to be an efective treatment for postoperative analgesia after TKA [6]. It combines analgesic drugs of diferent mechanisms to exert a synergistic or additive efect on analgesia while reducing the single drug dose and adverse efects. Preemptive analgesia is an important part of multimodal analgesia, which means that various analgesic measures are adopted in advance to inhibit the sensitization of peripheral and central pain nerves. It can improve the pain threshold of patients and reduce the degree of pain experienced [7]. Many studies have demonstrated the positive efectiveness of preemptive analgesia in TKA [8][9][10].
Te use of oral analgesics in advance is a convenient and efective method for preemptive analgesia after TKA. Celecoxib or other cyclooxygenase-2 (COX-2) inhibitors selectively inhibit the activity of COX-2, reduce prostaglandin production and infammatory reactions, and achieve effective control of pain and anti-peripheral pain sensitization efects. In particular, it has a positive efect on reducing nociceptive pain mediated by infammatory mechanisms after TKA [11,12]. Many previous studies reported that celecoxib was efective in preemptive analgesia during TKA [13][14][15]. Pregabalin is a latest-generation analog of the inhibitory neurotransmitter c-aminobutyric acid (GABA). Diferent from the mechanism of traditional analgesics, it has obvious anti-central and peripheral pain sensitization efects through inhibiting the voltage-dependent calcium channels of the peripheral and central nervous systems [16]. Terefore, it can improve the pain threshold and be used to control neuropathic pain. Because of the stable pharmacokinetics of pregabalin and few adverse efects, it has attracted more attention as a new type of analgesic drug in TKA. Recent studies have reported preemptive analgesic efects of pregabalin in TKA [17,18]. Teoretically, the combination of two diferent analgesic mechanisms can improve the analgesic efect. However, whether the combination of celecoxib and pregabalin can further improve analgesia after TKA remains unknown. To our knowledge, there are currently few clinical studies combining these two drugs for the preemptive analgesia of TKA.
Te purpose of our study was to evaluate the efectiveness of pregabalin combined with celecoxib as TKA preemptive analgesia by compared the pain score, cumulative dosage of opioids, high-sensitivity C-reactive protein (hs-CRP) level, and adverse efects after TKA. We hypothesised that the efectiveness of pregabalin combined with celecoxib as TKA preemptive analgesia would lead to satisfactory clinical outcomes.

Ethical Approval.
Te present study was a double-blind randomized clinical trial and was conducted in the afliated hospital of our university. Te study was approved by the ethics committee of the afliated hospital of our university and conducted in accordance with the Declaration of Helsinki. In addition, the study was retrospectively registered at http://www.chictr.org.cn (ChiCTR2100041595, January 1, 2021). All patients signed written informed consent forms.

Inclusion and Exclusion
Criteria. From January 2019 to June 2021, 201 patients who underwent TKA were subjected to a strict eligibility review. Te inclusion criteria were as follows: patients who received elective, initial, and single TKA. Te exclusion criteria were as follows: (1) patients with an American Society of Anesthesiologists (ASA) classifcation of grade 4 or higher, (2) patients with a history of liver and kidney insufciency, severe cardiopulmonary disease, severe digestive tract disease, and mental illness, (3) patients with an allergy to celecoxib or pregabalin or to anesthetic drugs, (4) patients who had taken celecoxib or pregabalin within 2 weeks before surgery, and (5) patients with cognitive impairment. A total of 160 patients were fnally included in the study.

Design and Conduct of the Study.
Pregabalin and celecoxib are produced by Pfzer in the United States under the trade names Lyrica and Celebrex, respectively. Pregabalin, celecoxib, and the placebo were packaged in the same opaque packaging by the University Hospital Health Research Center pharmacy. Te placebo capsule contained a mixture of 50% cellulose and 50% starch. An assistant from the Clinical Research Center used a random number table to divide the patients into four groups: the control group, celecoxib group, pregabalin group, and combination group. Te patient group assignments were sealed in envelopes. Anesthesiologists who did not participate in the study opened the envelope 12 hours before the surgery, distributed drugs according to the patient group assignment, and distributed the same drugs again 2 hours before the surgery. Te researchers involved did not know the patient group assignment during the surgery or data analysis. Te medication program was as follows: placebo group: 200 mg + 150 mg placebo; pregabalin group: 150 mg pregabalin + 200 mg placebo; celecoxib group: 200 mg celecoxib + 150 mg placebo; and pregabalin combined with celecoxib group: 150 mg pregabalin + 200 mg celecoxib. Each group was given the same medication program again 2 hours before surgery. Te patients were closely monitored for adverse efects after each administration of the medicine. All patients were given general anesthesia by senior anesthesiologists in our hospital. All operations were performed by two senior doctors with more than ten years of experience in TKA. Periarticular infltration of the cocktail ingredient (0.5% ropivacaine + 10 mg/ml triamcinolone acetonide acetate + 0.1% epinephrine hydrochloride) was performed before closed the incision. Afterwards, the four groups of patients received patientcontrolled intravenous analgesia (PCIA) immediately after the laryngeal mask was removed. Te analgesic formula was sufentanil 2 μg/kg + ondansetron 0.3 mg/mL + 0.9% sodium chloride injection, which were diluted to 100 mL. Te frst loading dose was 3 mL; there was no background dose. Te additional dose of self-controlled analgesia was 1 mL each time, the lock-in time was 15 min, and the use of PCIA lasted for 48 hours. After the surgery, if the patients had a visual analog scale (VAS) score >4, 10 mg morphine was given as remedial analgesia, and none of the patients underwent a nerve block. All patients were managed with a standardized TKA accelerated rehabilitation program, and immediately after the operation, they were instructed to perform lower limb quadriceps muscle contraction exercises, lower limb ankle pump exercises, and active and passive knee fexion activities.
Te main observation indicators included the following: (1) VAS pain score at rest and upon movement at 6, 12, 24, and 48 hours after the surgery (from 0: no pain to 10: worst possible pain; pain upon movement was pain upon maximum fexion of the knee); (2) cumulative dose of opioids within 48 hours (including total sufentanil and morphine remedial analgesic dosages, all converted to sufentanil equivalent); (3) the hs-CRP level before and after the surgery; (4) time of frst successful straight leg elevation: the standard is that the patient can maintain a fexed ankle joint and straight leg raise at least 40 cm above the bed for more than 4 s; (5) maximum knee fexion range of motion (ROM) at 24, 48, and 72 hours after surgery; (6) time to frst remedial analgesia after surgery; and (7) complications including postoperative nausea and vomiting (PONV), dizziness, gastrointestinal hemorrhage, urinary retention, deep vein thrombosis (DVT), and severity of sedation.

Statistical Analysis.
Power analysis was performed based on the data from a previous study [18] to calculate the sample size (PASS software, version 16.0; USA). To show a 30% reduction in sufentanil consumption, with a power of 80% and an alpha of 5%, each group requires 25 patients, and the 4 groups require 100 patients. Considering a 20% loss to follow-up rate, we recruited 160 patients, and 149 were included in the fnal data analysis. Te data were analyzed using SPSS 26.0 statistical software (version 26.0; IBM, USA). Te normality assessment of continuous numerical variables was analyzed with the Kolmogorov-Smirnov test. Continuous measurement data with normal distributions are represented by the mean-± standard deviation; otherwise, the median plus the interquartile range is used. Categorical variables are represented by the quantity and percentage. Repeated measures ANOVA was used for the repeated measures indicators (opioid cumulative dosages, postoperative pain scores, hs-CRP level, and ROM), and a simple efects model was used to explore the interaction between time and group. Te Bonferroni method was used to adjust the test level. Linear regression was used to explore the relationship between postoperative pain scores and the cumulative dosage of sufentanil. Chi-square, one-way ANOVA, Kruskal-Wallis, and Fisher exact probability tests were used as appropriate. P < 0.05 indicated that the diference was statistically signifcant.

Results
A total of 160 patients were enrolled in the study, 7 patients discontinued PCIA because of severe vomiting reaction to sufentanil. 2 patients asked to withdraw from the study and 2 patients were suspended surgery. Consequently, 149 patients were included in the fnal data analysis. Te CONSORT study participant fow diagram is shown in Figure 1.

Patient and Surgical Characteristics.
Tere were no signifcant diferences in the patient and surgical characteristics among the four groups (P > 0.05) ( Table 1).

VAS Pain Scores and the Cumulative Dose of Sufentanil.
As shown in Table 2 and Figure 2, the pain scores at rest in the combination group were signifcantly lower than those in the pregabalin group and the placebo group at 6, 12, and 24 hours after surgery (P < 0.05). Te pain scores at rest in the combination group were signifcantly lower than those in the celecoxib group at 6 hours after surgery (P � 0.018 < 0.05) (Figure 2(a)). Te pain scores upon movement in the combination group were signifcantly lower than those of the other three groups at 6, 12, 24, and 48 hours after surgery (P < 0.05) (Figure 2(b)). Tere was an interaction between time and group in the combined group (F (3,145) � 37.88, P < 0.001). Ten, a simple efects model was used for further analysis. In terms of a time efect, we observed that the pain score on movement in the combined group showed a signifcantly continuous downward trend over time within 48 hours after surgery (P < 0.05) (Figure 2(c)). Te cumulative dose of sufentanil in the combination group (49.30 ± 10.91 µg) was signifcantly lower than those of the other three groups within 48 hours after surgery (P < 0.05) (Figure 2(d)). Te frst rescue analgesic time of the combined group (203.89 ± 10.87 min) was signifcantly longer than those of the other three groups (P < 0.05). Table 3 and Figure 2, there was no signifcant diference in hs-CRP levels among the four groups before surgery (P � 0.386). Te hs-CRP level was signifcantly lower in the combination group than in the other three groups at 24, 48, and 72 hours after surgery (P < 0.05). Te hs-CRP level was signifcantly lower in the celecoxib group than that in the pregabalin and placebo groups at 24, 48, and 72 hours after surgery (P < 0.05) (Figure 2(e)). ROM increased signifcantly in the combination group compared with the three other groups at 24, 48, and 72 hours after surgery (P < 0.05) (Figure 2(f )). Te time of the frst straight leg elevation test was signifcantly shorter in the combined group (17.98 ± 2.09 h) than in the other three groups (P < 0.05). As shown in Table 4, the incidence of postoperative nausea and vomiting (PONV) was signifcantly lower in the combination group than in the other three groups (P < 0.05).

Linear Regression Analysis.
In the linear regression analysis, the mean pain score upon movement within 48 hours after surgery (4.78 ± 1.02) was the independent variable (X), and the cumulative dose of sufentanil within 48 hours was the dependent variable (Y). Te regression equation (Y � 14.743X − 7.353, R 2 � 0.884, F � 51.661, P < 0.001) (Figure 3) suggested that for every 1-point decrease in the mean pain score upon movement within 48 hours after surgery, the cumulative dose of sufentanil will decrease by 14.743 ug.

Discussion
Perioperative pain management is key to the smooth implementation of enhanced recovery after surgery (ERAS), which has rapidly become a popular concept in the feld of orthopedics. Although the combined application of various postoperative analgesia methods can improve the postoperative acute pain of TKA patients, many still sufer from moderate or even severe pain [19,20].
Preemptive analgesia is an important part of multimodal analgesia, and its value is increasingly recognized by clinicians and researchers. Some studies have found that preemptive analgesia can further improve postoperative pain in TKA patients [8][9][10]. However, the optimal preemptive analgesia regimen for TKA is controversial.
In the present study, we observed that the combination group had better improvement in pain scores at rest and upon movement than the other three groups. Te pain scores at rest in the combined group were always low level within 48 hours, and unlike the placebo group, there were no large fuctuations in pain scores, which indicated that the analgesic efect of the combination regimen was stable and relatively durable. However, the pain upon movement was more signifcant than that at rest because all of the patients need to exercise as soon as possible after TKA to enhance recovery. In the study of Lee et al. [21], patients used 150 mg pregabalin and 200 mg celecoxib 2 hours before TKA, and the pain scores upon movement at 6, 12, 24, and 48 hours after the surgery were signifcantly lower than those of the control group. Kien et al. [22] used 150 mg pregabalin and 200 mg celecoxib preoperatively for lumbar spine surgery patients and observed that the pain score upon movement was signifcantly lower than that of the control group within 48 hours after surgery; this result is consistent with our study. Te pain scores upon movement at 6, 12, 24, and 48 hours after surgery were signifcantly lower in the combination group than in the other three groups. Furthermore, we demonstrated that the pain score upon movement decreased continuously over the frst 48 hours in the combination group, while such a trend was not observed in the other groups. Tis positive trend may have a positive impact on early functional exercise in patients after TKA. Postoperative functional exercise involves greater pain sensitization compared with rest, and a large number of infammatory mediators are released during functional exercise. Te combined application of celecoxib and pregabalin had positive efects on the control of peripheral hyperalgesia and central hyperalgesia and cascading efects on infammatory mediator release. Terefore, we believe that the analgesic regimen of pregabalin combined with celecoxib    VAS, visual analog scale (0: no pain to 10: worst possible pain); pain upon movement: pain upon maximum fexion; diference was signifcant at the P < 0.05 level. a means there was a signifcant diference compared with the placebo group (P < 0.05). b means there was a signifcant diference compared with the celecoxib group (P < 0.05). c means there was a signifcant diference compared with the pregabalin group (P < 0.05). ▲ means there was a signifcant diference compared with a previous time point in the combination group, suggesting that the pain scores upon movement in the combined group decreased continuously over time. may have more practical application value in TKA preemptive analgesia than a single drug. Currently, analgesia after TKA mainly involves a variety of opioids, such as sufentanil, tramadol, and morphine. Opioids mainly act on opioid receptors in the pain center of the brain to inhibit the generation and amplifcation of pain signals. However, opioids have signifcant side efects, such as nausea and vomiting, drug dependence, urinary retention, excessive sedation, and respiratory depression. Te majority of TKA patients are elderly patients, and the incidence of opioid side efects is signifcantly higher in elderly patients than in young and middle-aged patients [23]. One of the goals of multimodal analgesia is to reduce the amount of opioids to improve postoperative complications and drug addiction [24]. Te cumulative dose of sufentanil and the incidence of PONV within 48 hours after surgery were signifcantly lower in the combination group than in the other three groups. Tis may suggest that the opioid-sparing efects of the preemptive analgesic regimen of pregabalin combined with celecoxib can reduce the incidence of postoperative complications. Furthermore, the linear regression analysis results showed that for every 1-point decrease in the mean pain score upon movement within 48 hours after surgery, the cumulative dose of sufentanil will decrease by 14.743 ug. Tis result suggests that if an efective preemptive analgesia regimen is used before TKA, the pain scores upon movement will be controlled at a low level, which would reduce the cumulative dose of opioids after TKA and consequently opioid side efects.

Pain Research and Management
Te key core of preemptive analgesia is to reduce the degree of peripheral and central pain sensitization and to improve the pain threshold of patients in advance [25]. Lower levels of infammatory factors are strongly correlated with reduced peripheral and central pain sensitization [26]. hs-CRP levels at 24, 48, and 72 hours after surgery were  Pain score upon movement 0 50 100 150 Figure 3: Linear regression analysis. Te mean pain score upon movement within 48 hours after surgery was the independent variable (X). Te cumulative dose of sufentanil within 48 hours after surgery was the dependent variable (Y). Te diference was signifcant at the P < 0.05 level. 8 Pain Research and Management signifcantly lower in the combination group than in the other three groups. An animal experiment performed by Bannister et al. [26] demonstrated that pregabalin reduces central pain sensitization by reducing the release of spinal pain neurotransmitters and inhibiting the excitability of the pain nerve center. On the other hand, several studies have reported that celecoxib improves the levels of hs-CRP by inhibiting infammatory reactions [11,13,27]. In a clinical study by Jianda et al. [28], 400 mg celecoxib was given 2 hours before surgery to patients undergoing TKA. Tey found that the hs-CRP level in the preemptive analgesia group was signifcantly lower than that in the control group within one week after surgery. Terefore, we suggest that celecoxib and pregabalin may have a synergistic efect on the control of body infammation levels. However, because infammatory and pain sensitization mechanisms involve multiple links and multiple factors, further research is needed.
Our study has some limitations. First, our research was limited to within 72 hours after surgery, so we cannot be sure whether control of acute postoperative pain can promote long-term knee function recovery and reduce the possibility of long-term chronic pain. Second, we did not accurately estimate sample size, which may afect the efcacy of the present study. Tird, according to the relevant study [29], the minimal clinically important diferences (MCIDs) of pain was defned as 1.3 score at rest and 1.5 score during motion on a 0-10 VAS score. Terefore, only the pain upon movement at 12 hours of combination group reached the MCIDs compared the other three groups.
Last, in terms of postoperative complications, our sample size was too small to comprehensively and objectively evaluate the safety of analgesia programs.

Conclusion
Te preemptive analgesia regimen of pregabalin combined with celecoxib had positive efects on improving acute pain and reducing the cumulative dose of opioids after TKA.

Data Availability
Te data used to support the fndings of this study are available from the corresponding author upon request.

Ethical Approval
Tis study was approved by the institutional review board and retrospectively registered at http://www.chictr.org.cn (ChiCTR2100041595, January 1, 2021).

Conflicts of Interest
Te authors declare that there are no conficts of interest.