Introduction

Biomedical Reports

2049-9434 2049-9442

D.A. Spandidos

BR-22-4-01935

10.3892/br.2025.1935

Articles

Efficacy and safety of loxoprofen sodium cataplasms in the treatment of osteoarthritis: A randomized, multicenter study

Lei

Yutian

1 * Liu

Zeyu

1 * Jin

Xin

2 Gao

Guicheng

3 Luo

Sen

1 Gao

4 Liu

Qirang

1 Yang

Pei

1 Tian

Run

1Department of Bone and Joint Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China 2Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China 3Department of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China 4Department of Orthopedics, Xi'an Honghui Hospital, Xi'an, Shaanxi 710054, P.R. China

Correspondence to: Professor Pei Yang or Professor Run Tian, Department of Bone and Joint Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West Fifth Road, Xincheng, Xi'an, Shaanxi 710004, P.R. China ortianrun@163.com yangpei@xjtu.edu.cn

^*Contributed equally

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; COX, cyclooxygenase; FPC, flurbiprofen cataplasm; LSC, loxoprofen sodium cataplasm; NSAIDs, non-steroidal anti-inflammatory drugs; OA, osteoarthritis; VAS, Visual Analog Scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index

04 2025

04 02 2025

22 4

13 09 2024 03 12 2024

2025

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

The present study aimed to compare the efficacy and safety of loxoprofen sodium cataplasm (LSC) with those of flurbiprofen cataplasm (FPC) in osteoarthritis (OA) treatment. In this multicenter, randomized controlled trial, subjects meeting the inclusion and exclusion criteria were randomly assigned to the two treatment groups. According to the manufacturer's instructions, the first group received LSC once daily, with the application of one patch per area for 2 weeks, whereas the second group received FPC twice daily, with the application of one patch per area for 2 weeks. The treatment response was evaluated based on the Visual Analog Scale (VAS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) global score, Lysholm score and adverse events for 296 patients enrolled across three subcenters, with 192 patients in the LSC group and 104 patients in the FPC group. The treatment effectiveness rates, based on the VAS, WOMAC global and Lysholm scores, were 74.46, 61.41 and 85.25%, respectively, for the LSC group and 43.14, 31.37 and 66.67%, respectively, for the FPC group. Regardless of the effectiveness criterion used, the LSC group exhibited a superior treatment effectiveness rate compared with the FPC group. After 2 weeks of treatment, OA symptoms improved in both groups, with the LSC group exhibiting lower VAS (P<0.05) and WOMAC global scores (comprising pain, stiffness and physical function scores) compared with the FPC group (P<0.05), while the Lysholm score was higher in the LSC group compared with the FPC group (P<0.05). The FPC group experienced more general adverse events (P>0.05) and dressing shedding (P<0.05) compared with the LSC group, whereas the LSC group had more specific adverse events (such as skin itching, fever and allergy) compared with the FPC group (P>0.05). The results suggested that compared with FPC, LSC exhibited higher short-term efficacy and a consistent safety profile. The present study was registered at Chinese Clinical Trial Register (chictr.org.cn; ChiCTR2300072504; date of registration, June 15, 2023).

loxoprofen sodium cataplasm flurbiprofen cataplasm osteoarthritis efficacy safety

Funding: The present study was supported by the Key Program of Shaanxi Province (grant no. 2023-YBSF-102).

Introduction

Osteoarthritis (OA), among the most common joint disorders, is characterized by articular cartilage damage and involves the entirety of joint tissues, leading to the eventual degeneration, fibrosis and fracture of the articular cartilage and damage to the complete joint surface (1-3). The clinical manifestations of OA primarily include pain, stiffness, hypertrophy and restricted movement, particularly in weight-bearing joints such as knees and hips (4-6). Thus, effective pain management is important throughout OA treatment, with the selection, administration mode and dosage of medications being critical (7-10).

Topical nonsteroidal anti-inflammatory drugs (NSAIDs) can inhibit prostaglandin synthesis in the body, thereby exerting anti-inflammatory and analgesic effects and treating OA mechanistically (11). Clinical research has demonstrated that NSAIDs have a superior therapeutic efficacy in knee OA (12-14). At present, various commonly used topical formulations are available. One such formulation called cataplasms are hydrophilic polymer materials that serve as matrices for transdermal drug delivery. They possess several advantages, such as high drug-loading capacity, moisture retention capability, breathability, and non-allergenic and non-irritating properties. Common topical NSAIDs in the cataplasm form include loxoprofen sodium and flurbiprofen (15). However, head-to-head clinical studies and comparative data regarding these two drugs are lacking. Thus, the present study aimed to systematically compare the clinical effectiveness and related indicators of loxoprofen sodium cataplasm (LSC) and flurbiprofen cataplasm (FPC) in OA treatment, and to evaluate the efficacy and safety of LSC in this context.

FPC is a topical NSAIDs that is commonly used for the treatment of OA. It works by inhibiting cyclooxygenase (COX) enzymes, thereby reducing the synthesis of prostaglandins, which are mediators of inflammation and pain (16). The justification for comparing FPC and LSC in the present study was based on the need for a direct evaluation of the efficacy and safety profiles of these two commonly used topical NSAIDs in the treatment of OA. While both medications are established treatments for OA, there has been a lack of head-to-head clinical studies that provide comparative data regarding their effectiveness and safety (17,18). FPC is widely recognized and used in clinical practice for OA management (19-21); by selecting it as the control, the present study aimed to provide meaningful insights into the relative benefits of LSC. This comparison is particularly relevant given the increasing prevalence of OA and the importance of optimizing treatment options to improve patient outcomes (22,23). Osteoarthritis is a debilitating, long-lasting condition affecting the structure and function of synovial joints, affecting >200 million people globally and having doubled in incidence over the past 50 years. The present study contributed valuable evidence to inform clinical decision-making regarding the use of topical NSAIDs in OA treatment.

The 2-week follow-up was chosen to focus on the short-term efficacy and safety outcomes, which are critical for assessing the initial response to treatment in patients with OA. This duration allowed for the evaluation of immediate pain relief and functional improvement, which are often the primary concerns for patients seeking treatment. Additionally, a shorter follow-up period is common in studies evaluating topical treatments, as it enables the observation of early adverse effects and therapeutic responses without the confounding influence of long-term treatment adherence or cumulative side effects (24,25).

The scientific demand for comparing LSC and FPC arises from the increasing prevalence of OA and the need for effective management strategies that minimize systemic side effects. The two medications are widely used in clinical practice (17,18), but there is a lack of direct comparative studies that assess their efficacy and safety in a controlled environment. By addressing this gap, the present study provided essential insights that can help clinicians make informed decisions regarding the choice of topical NSAIDs for OA treatment.

Materials and methods <sec> <title>Ethical approval

The present study was approved by the Ethics Committees of The Second Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, China [ethics approval no. Lun Shen (2023) no. 003 Xi'an, China] and The Second Affiliated Hospital of Nanchang University, Jiangxi Chian [ethics approval no Lun Shen (2022) no. 16; Nanchang, China] and Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China [ethics approval no. Lun Shen (2021) no. (0117)-01; Wuhan, China]. The participants provided their written informed consent to participate in the present study.

Subject enrollment. Inclusion and exclusion criteria

The inclusion criteria were as follows: i) Participants voluntarily consenting to participate in the study and providing written informed consent; ii) male and female participants aged between 20 and 85 years; iii) participants clinically diagnosed with OA; iv) participants with joint pain symptoms; and v) participants taking only study-specified/control medication.

The exclusion criteria were as follows: i) Patients with bleeding disorders; ii) patients with bronchial asthma; iii) patients with severe cardiac, hepatic and renal insufficiency, with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels exceeding twice the normal value, and serum creatinine levels exceeding the normal value. Normal values: <40 U/l for AST, <50 U/l for ALT, 35-80 µmol/l for serum creatinine; iv) pregnant and lactating women or women of childbearing age planning to conceive; v) patients with known hypersensitivity to NSAIDs; and vi) patients who participated in clinical studies of other drugs within the past month or had other concurrent diseases or complications that may affect the assessment of drug efficacy (skin breakage, infection at the site of drug application or skin rash).

Discontinuation and withdrawal criteria. The discontinuation and withdrawal criteria were as follows: i) Adverse events such as skin sensitization preventing the subject from continuing treatment; ii) unwillingness to continue treatment; iii) noncompliance with the study protocol; iv) use of prohibited drugs during the study; and v) pregnancy.

Between June 2023 and April 2024, 351 subjects from three hospitals were invited to participate. The three hospitals included The Second Affiliated Hospital of Xi'an Jiaotong University, the Second Affiliated Hospital of Nanchang University, and Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. Among the subjects, 34 were excluded due to not meeting the inclusion criteria and 21 declined to participate. Additionally, two subjects in the FPC group and eight in the LSC group were lost to follow-up (Fig. 1). The LSC group included 83 male and 104 female patients, with five individuals whose sex was not recorded, totaling 192 individuals, whereas the FPC group comprised 63 male and 41 female patients. The age of the 192 participants in the LSC group ranged between 24 and 84 years, with a mean age of 58.46 years; the age of 5 individuals was not included in the analysis. In addition, the age of the 104 individuals in the FPC group ranged between 35 and 84 years, with a mean age of 59.82 years.

Research methods

The two groups received topical analgesic drugs in addition to basic treatment for 2 weeks. The basic treatment provided to all participants included non-pharmacological interventions such as physical therapy and education on joint protection techniques. LSC (Hunan Jiudian Pharmaceutical Co., Ltd.; state drug license H20173272; specifications, 100 mg/patch) was administered to the LSC group and FPC (Beijing Tide Pharmaceutical Co., Ltd.; state drug license H20103549; specifications, 40 mg/patch) was administered to the FPC group. LSC was applied topically to the affected area once daily, with one patch applied per area for 2 weeks according to the manufacturer's instruction. FPC was applied twice daily, with one patch applied per area for 2 weeks, according to the manufacturer's instructions. The treatment duration was 2 weeks and follow-up visits were scheduled at the end of the second week after the initial treatment.

Assessment. Efficacy assessment

Treatment effectiveness at week 2 was the primary indicator, and this was assessed using three types of evaluation. The first evaluation type was based on the Visual Analog Scale (VAS) score as follows (26): 0, no pain; 1-3, mild pain; 4-6, moderate pain; 7-10, severe pain; and 10, most severe pain. The efficacy index was defined as follows: Cured, efficacy index ≥95%; apparent efficacy, efficacy index between ≥70 and <95%; effective, efficacy index between ≥30 and <70%; and ineffective, efficacy index <30%. The treatment effectiveness rate was calculated as (number of cured cases + number of apparent effective cases + number of effective cases)/total number of cases x100%.

The second evaluation type was based on Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (27-29). The criteria for cured, apparent efficacy and effective were the same as those for the first evaluation type. For patients with disease in both knees, the side of the patient with the more severe disease was evaluated and statistically analyzed. The treatment effectiveness rate was analyzed as (number of cured cases + number of apparent effective cases + number of effective cases)/total number of cases x100%.

The third evaluation type was based on the Lysholm score (30). The efficacy was defined as follows: Cured, pain and morning stiffness completely disappeared, and the Lysholm score improved by ≥30 points; improvement, improvement in pain, morning stiffness and other symptoms as well as in the Lysholm score by <30 points but ≥6 points; and ineffective, no improvement in pain, morning stiffness and other symptoms, with <6-point improvement in the Lysholm score. The treatment effectiveness rate was assessed as (number of cured cases + number of improvement cases)/total number of cases x100%.

Secondary efficacy indicators were changes in the VAS score, WOMAC global score (0-240), WOMAC knee pain score (0-50), WOMAC knee stiffness score (0-20), WOMAC knee physical function score (0-170) and Lysholm score (0-100) (28-30).

Safety assessment. The incidence of general adverse events, severe adverse events, special adverse events (including skin itching, skin fever and allergy) and dressing shedding was documented.

Statistical analysis

The study data were analyzed using SAS version 9.4 (SAS Institute). and descriptive statistics. Continuous variables are presented as the mean, standard deviation, median, 25th percentile, 75th percentile, minimum and maximum. Qualitative data are summarized as frequencies and percentages, with confidence intervals for overall percentages wherever applicable. Differences in treatment efficacy between the two groups were assessed using the χ² test, or using Fisher's exact test where appropriate. To compare categorical variables, the χ² test or Fisher's exact test were used as appropriate. However, for continuous variables such as data presented as the mean ± standard deviation and median, descriptive statistics were employed and appropriate parametric test including independent samples t-test and paired t-test was used. The 95% confidence interval for the difference in overall effective rates between the two groups was calculated using the Newcombe-Wilson method. P<0.05 was considered to indicate a statistically significant difference.

Results <sec> <title>Baseline data

Between June 2023 and April 2024, 351 subjects from three hospitals were invited to participate. Among them, 34 were excluded due to not meeting the inclusion criteria and 21 declined to participate. Additionally, 2 subjects in the FPC group and 8 in the LSC group were lost to follow-up (Fig. 1). The LSC group included 83 male and 104 female patients, with 5 individuals whose sex was not recorded, whereas the FPC group comprised 63 male and 41 female patients. A significant difference was detected between the groups in terms of sex distribution (P<0.05). The age of the 192 participants in the LSC group ranged between 24 and 84 years, with a mean age of 58.46 years; the age of 5 individuals was not included in the analysis. In addition, the age of the 104 individuals in the FPC group ranged between 35 and 84 years, with a mean age of 59.82 years. The difference in age was not significant (P>0.05; Table I; Fig. 2).

Clinical outcomes

After 2 weeks of treatment, the treatment effectiveness rate in the LSC group was 74.46% according to the VAS score, 61.41% according to the WOMAC global score and 85.25% according to the Lysholm score. By comparison, in the FPC group, the rates were 43.14, 31.37 and 66.67%, respectively (Table II, Table III and Table IV). Across the primary indicators, the LSC group achieved significantly higher effectiveness rates compared with the FPC group (P<0.05; Fig. 3). Newcombe-Wilson analysis confirmed this advantage, indicating that the lower limit of the 95% confidence interval exceeded zero for differences in treatment effectiveness between the LSC and FPC groups, indicating the superiority of LSC treatment (Table II, Table III and Table IV).

During the screening period, no significant differences were observed between the two groups in terms of the VAS score, WOMAC global score (encompassing pain, stiffness and physical function scores) and Lysholm score (P>0.05; Table VII). After 2 weeks of treatment, both the LSC and FPC groups showed reductions in the WOMAC global score (including scores for knee pain, stiffness and physical function) and VAS score compared with scores at the screening period, with their Lysholm score increasing (P<0.05; Tables V and VI; Fig. 4). Furthermore, after 2 weeks of treatment, the LSC group exhibited a lower WOMAC global score and VAS score and higher Lysholm score compared with the FPC group (P<0.05), indicating that the therapeutic effect of LSC was superior to that of FPC (Tables VII and VIII; Figs. 5 and 6).

Safety

The FPC group experienced a higher rate of adverse events (P>0.05) and dressing shedding (P<0.05) compared with the LSC group, while the LSC group had more specific adverse events than the FPC group, including skin itching, skin fever and allergy (P>0.05; Table IX; Fig. 7).

Discussion

OA is a degenerative joint disease that markedly impairs the quality of life of patients, and is primarily characterized by joint pain, pressure sensitivity, restricted movement and joint deformity, which together contribute to decreased bodily function and diminished quality of life (31,32). The prevalence of OA has been increasing with aging and obesity trends; from 1990-2019 >50% of individuals aged >65 years in China suffer from OA, a leading cause of pain and disability among the elderly (33-35). The American College of Rheumatology, Arthritis Foundation, Osteoarthritis Research Society International and European Society for Clinical Economics of Osteoporosis all recommend NSAIDs as a cornerstone of pharmacological treatment and pain management for OA (12,36-38). However, prolonged or frequent oral NSAIDs use can lead to tolerance and safety concerns, particularly in the elderly and those with comorbidities (39,40). Furthermore, NSAIDs overuse is associated with adverse gastrointestinal, cardiovascular, renal and hepatic events (41,42). Topical NSAIDs formulations, which minimize systemic exposure, are thus recommended for managing OA symptoms in middle-aged and elderly patients (40).

Loxoprofen sodium, a novel NSAIDs and propionic acid derivative, exerts its pharmacological effects by inhibiting COX enzymes, thereby blocking the conversion of arachidonic acid to prostaglandins. This inhibition leads to anti-inflammatory, analgesic and antipyretic effects (43). The control group in the present study was selected based on the common clinical practice of using FPC as a standard treatment for OA. Flurbiprofen is a well-established topical NSAID with documented efficacy and safety in managing OA symptoms (44). By comparing LSC against the established FPC treatment, the present study aimed to provide a meaningful evaluation of the efficacy and safety profile of LSC. The selection of FPC as a control enabled a direct comparison of treatment outcomes, thereby enhancing the clinical relevance of the findings.

After 2 weeks of treatment, the LSC group had treatment effectiveness rates of 74.46 (VAS score), 61.41 (WOMAC global score) and 85.25% (Lysholm score). In comparison, the FPC group achieved rates of 43.14, 31.37 and 66.67%, respectively. Across the primary indicators, the LSC group exhibited significantly higher effectiveness (P<0.05). Additionally, after two weeks of treatment, the LSC group had a lower WOMAC knee pain score and VAS score than the FPC group (P<0.05), indicating more effective pain management. The LSC group exhibited a lower WOMAC knee stiffness score and improved physiological function score in addition to a higher Lysholm score compared with the FPC group (P<0.05), suggesting superior knee function recovery. This enhanced performance may be attributed to the rapid absorption and distribution of loxoprofen sodium and its active metabolites, making it one of the fastest-acting NSAIDs available (45). Of note, the LSC group was administered a higher daily dose of loxoprofen sodium (100 mg) compared with that administered to the FPC group (flurbiprofen; 80 mg), LSC can more effectively alleviate knee joint pain in patients, which contributes to significant early symptomatic improvement in patients.

After 2 weeks of treatment, the FPC group exhibited a higher rate of dressing shedding compared with the LSC group (P<0.05), which may be attributed to FPC being applied twice as often as LSC. However, there was no significant difference between the LSC and FPC groups with respect to general adverse events, skin itching, skin fever or allergies (P>0.05). Despite the LSC group receiving a daily dose of 100 mg of loxoprofen sodium compared with the FPC group receiving 80 mg daily dose of flurbiprofen, the incidence of adverse events did not differ markedly, indicating comparable safety profiles for the two treatment options.

The baseline data indicated a disparity in terms of sex between the LSC and FPC groups, probably attributable to the small sample size. In a randomized controlled trial, comparability between the two groups is essential and inherent to the study design. The LSC group contained a higher proportion of women, who, according to a previous study, may experience heightened pain sensitivity in arthritic conditions (46). Nevertheless, the LSC group exhibited superior outcomes after 2 weeks of treatment, suggesting that LSC exhibited more effective short-term results than FPC. LSC and FPC both belong to the class of NSAIDs and exert their analgesic and anti-inflammatory effects primarily through the inhibition of COX enzymes (40,44). LSC selectively inhibits COX-1 and COX-2, leading to a reduction in the synthesis of prostaglandins, which are mediators of pain and inflammation (43). By contrast, FPC also inhibits both COX-1 and COX-2 but may have a slightly different affinity for these enzymes, which can influence its overall efficacy and side effect profile (44). The differences in the mechanism of action may contribute to variations in the onset and duration of analgesic effects between the two drugs (47). The pharmacokinetic profiles of LSC and FPC differ in several aspects. LSC is known for its rapid absorption and distribution, which allows for a quicker onset of analgesic effects. It is primarily metabolized in the liver and its metabolites have a longer half-life, providing sustained therapeutic action. By contrast, FPC has a slower absorption rate and may take a longer time to reach the peak plasma concentration. Additionally, the pharmacokinetics of FPC can be influenced by factors such as formulation and skin permeability, which may affect its overall efficacy in topical applications (45). These pharmacokinetic differences may serve a role in the observed variations in treatment effectiveness and safety profiles between LSC and FPC in the management of OA.

A previous study obtained results that the analgesic effect of FPC in the treatment of OA is superior to that of LSC, which contradicts the findings of the present study (47), which may be attributed to the current study assessing short-term efficacy (2 weeks), while the aforementioned study evaluated long-term efficacy (4 weeks). Thus, although LSC was associated with improved initial results, FPC showed greater effectiveness with longer use. The current study emphasized early pain relief and functional recovery, whereas the other study focused on sustained pain relief and long-term safety. Therefore, the opposing conclusions may have resulted from the different time points of efficacy evaluation.

The present study has several limitations. First, the sample size was small, limiting the ability to draw more broadly applicable conclusions from the results. Second, the brief observation period was insufficient to evaluate long-term efficacy and potential gastrointestinal and cardiovascular adverse events. Third, other biomarkers that could also be relevant for assessing safety in both animal and human use were not analyzed. These include liver function tests (such as ALT and AST levels), renal function tests (such as serum creatinine level) and gastrointestinal biomarkers (such as fecal occult blood). Additionally, inflammatory markers (such as C-reactive protein) and pain biomarkers (such as substance P level) may provide additional insights into the safety profile of the treatments. Future studies should consider incorporating these additional biomarkers to enhance the comprehensiveness of safety assessments. Finally, the absence of blinding may have introduced bias. In the future, a larger sample size will be employed to ensure the accuracy of the study, the follow-up period will be extended to clarify the long-term efficacy and side effects of the drug, and blinding shall be performed to reduce bias.

In conclusion, OA could be effectively treated with both LSC and FPC. However, LSC had a higher short-term efficacy, lower dressing removal rate and improved effect on the knee joints of patients with OA compared with FPC. Thus, LSC is a safe and effective treatment for OA.

Acknowledgements

Not applicable.

Availability of data and materials

The data generated in the present study may be requested from the corresponding author.

Authors' contributions

All the authors contributed substantially to the conception and design of the study. YL and ZL conceived and designed the work, collected original data, wrote and edited the manuscript and confirmed the authenticity of the raw data. GG, SL, XG and QL collected original data. XJ, PY and RT directed the conception and design of the work. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

The present study was approved by the Ethics Committees of The Second Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, China [ethics approval nos. Lun Shen (2023) no. 003 and Lun Shen (2022) no. 16; Xi'an, China] and Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China [ethics approval no. Lun Shen (2021) no. (0117)-01; Wuhan, China]. The patients/participants provided their written informed consent to participate in the present study. The present study was registered at Chinese Clinical Trial Register (chictr.org.cn; ChiCTR2300072504). Date of registration: June 15, 2023.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References 1

Bennell

Paterson

Metcalf

Duong

Eyles

Kasza

Wang

Cicuttini

Buchbinder

Forbes

Effect of intra-articular platelet-rich plasma vs placebo injection on pain and medial tibial cartilage volume in patients with knee osteoarthritis: The RESTORE Randomized Clinical Trial

JAMA326202120302021

34812863

10.1001/jama.2021.19415

Katz

Arant

Loeser

Diagnosis and treatment of hip and knee osteoarthritis. A review

JAMA3255685782021

33560326

10.1001/jama.2020.22171

Duong

Ding

Culvenor

Hunter

Evaluation and treatment of knee pain: A review

JAMA33015682023

37874571

10.1001/jama.2023.19675

Neogi

Colloca

Placebo effects in osteoarthritis: Implications for treatment and drug development

Nat Rev Rheumatol196136262023

37697077

10.1038/s41584-023-01021-4

Duan

Zhao

Zhang

Kong

Cao

Guan

Wang

Yang

Tian

Prediction of early functional outcomes in patients after robotic-assisted total knee arthroplasty: A nomogram prediction model

Int J Surg109310731162023

37352526

10.1097/JS9.0000000000000563

Tian

Duan

Kong

Wang

Tian

Shi

Yan

Lyu

Wang

Yang

Robotic-assisted total knee arthroplasty is more advantageous for knees with severe deformity: A randomized controlled trial study design

Int J Surg1092872962023

36927832

10.1097/JS9.0000000000000002

Geenen

Overman

Christensen

åsenlöf

Capela

Huisinga

Husebø

MEP

Köke

AJA

Paskins

Pitsillidou

Eular recommendations for the health professional's approach to pain management in inflammatory arthritis and osteoarthritis

Ann Rheum Dis777978072018

29724726

10.1136/annrheumdis-2017-212662

Bichsel

Liechti

Schlapbach

Wertli

Cross-sectional analysis of recommendations for the treatment of hip and knee osteoarthritis in clinical guidelines

Arch Phys Med Rehabil103559569.e52022

34411512

10.1016/j.apmr.2021.07.801

Geraghty

Obeidat

Ishihara

Wood

Lopes

EBP

Scanzello

Griffin

Malfait

Miller

Age-associated changes in knee osteoarthritis,pain-related behaviors, and dorsal root ganglia immunophenotyping of male and female mice

Arthritis Rheumatol75177017802023

37096632

10.1002/art.42530

Hunter

Mclachlan

Carroll

Wakefield

TAN

Stosic

Health literacy and appropriateness of self-care and pain management in osteoarthritis: An understanding of the patient's perspective

Arthritis Care Res (Hoboken)758488592023

34941010

10.1002/acr.24851

Greig

Garnock-Jones

Loxoprofen: A review in pain and inflammation

Clin Drug Investig367717812016

27444038

10.1007/s40261-016-0440-9

Bannuru

Osani

Vaysbrot

Arden

Bennell

Bierma-Zeinstra

SMA

Kraus

Lohmander

Abbott

Bhandari

OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis

Osteoarthritis Cartilage27157815892019

31278997

10.1016/j.joca.2019.06.011

Arden

Perry

Bannuru

Bruyère

Cooper

Haugen

Hochberg

McAlindon

Mobasheri

Reginster

Non-surgical management of knee osteoarthritis: Comparison of ESCEO and OARSI 2019 guidelines

Nat Rev Rheumatol1759662019

Weng

Goh

Persson

MSM

Wei

Sarmanova

Hall

Doherty

Jiang

Comparative efficacy of exercise therapy and oral non-steroidal anti-inflammatory drugs and paracetamol for knee or hip osteoarthritis: A network meta-analysis of randomised controlled trials

Br J Sports Med579909962023

Chen

Zhou

Mao

Efficacy and safety of topical nsaids combined with physiotherapy for frozen shoulder: A randomized controlled trial

Eur Rev Med Pharmacol Sci28376137702024

38884511

10.26355/eurrev_202406_36381

Voilley

Acid-sensing ion channels (ASICs): New targets for the analgesic effects of non-steroid anti-inflammatory drugs (NSAIDs)

Curr Drug Targets Inflamm Allergy371792004

15032643

10.2174/1568010043483980

Shu

Liu

Hao

Cui

Zheng

Intra-articular delivery of flurbiprofen sustained release thermogel: Improved therapeutic outcome of collagenase II-induced rat knee osteoarthritis

Drug Deliv27103410432020

32627602

10.1080/10717544.2020.1787555

Bao

Chen

Zheng

Wang

Zhao

Shao

Zhang

Efficacy and safety of loxoprofen hydrogel patch versus loxoprofen tablet in patients with knee osteoarthritis: A randomized controlled non-inferiority trial

Clin Rheumatol351651732016

24924603

10.1007/s10067-014-2701-4

Iguchi

Takahashi

Takeshita

Effectiveness and adherence rate of s-flurbiprofen plaster for the pain management of patients with moderate and end-stage knee osteoarthritis

Cureus15e445562023

37662513

10.7759/cureus.44556

Lin

Liu

Zhang

Effects of knee debridement with flurbiprofen on knee function, inflammatory levels, and bone metabolism activity in patients with knee osteoarthritis

Comput Math Methods Med202280313602022

35813424

10.1155/2022/8031360

Tomatsu

Yasuda

Fuady

Matsumoto

Sumariyono

Efficacy and safety of s-flurbiprofen plaster in knee osteoarthritis patients: A 2-week randomized controlled phase III clinical trial compared to diclofenac gel

Int J Rheum Dis255635702022

35199483

10.1111/1756-185X.14307

Pereira

Ramos

Branco

Osteoarthritis

Acta Med Port28991062015

25817486

10.20344/amp.5477

Wathier

Lakin

Cooper

Bansal

Bendele

Entezari

Suzuki

Snyder

Grinstaff

A synthetic polymeric biolubricant imparts chondroprotection in a rat meniscal tear model

Biomaterials18213202018

30099277

10.1016/j.biomaterials.2018.08.009

Lin

Poh

Panitch

Controlled release of anti-inflammatory peptides from reducible thermosensitive nanoparticles suppresses cartilage inflammation

Nanomedicine12209521002016

27241526

10.1016/j.nano.2016.05.010

Garriga

Sánchez-Santos

Judge

Hart

Spector

Cooper

Arden

Predicting incident radiographic knee osteoarthritis in middle-aged women within four years: The importance of knee-level prognostic factors

Arthritis Care Res (Hoboken)7288972020

31127870

10.1002/acr.23932

Jones

Togashi

Wilson

Heckmann

Vangsness

CT Jr

Intra-articular treatment options for knee osteoarthritis

Nat Rev Rheumatol1577902019

30498258

10.1038/s41584-018-0123-4

Boer

Radjabzadeh

Medina-Gomez

Garmaeva

Schiphof

Arp

Koet

Kurilshikov

Ikram

Intestinal microbiome composition and its relation to joint pain and inflammation

Nat Commun1048812019

31653850

10.1038/s41467-019-12873-4

Belk

Lim

Keeter

Mcculloch

Houck

Mccarty

Frank

Kraeutler

Patients with knee osteoarthritis who receive platelet-rich plasma or bone marrow aspirate concentrate injections have better outcomes than patients who receive hyaluronic acid: Systematic review and meta-analysis

Arthroscopy39171417342023

36913992

10.1016/j.arthro.2023.03.001

Stonehouse

Benassi-Evans

Bednarz

Vincent

Hall

Hill

Krill oil improved osteoarthritic knee pain in adults with mild to moderate knee osteoarthritis: A 6-month multicenter, randomized, double-blind, placebo-controlled trial

Am J Clin Nutr1166726852022

35880828

10.1093/ajcn/nqac125

Migliorini

Schäfer

Bell

Weber

Vecchio

Maffulli

Meniscectomy is associated with a higher rate of osteoarthritis compared to meniscal repair following acute tears: A meta-analysis

Knee Surg Sports Traumatol Arthrosc31548554952023

37812251

10.1007/s00167-023-07600-y

O'Neill

Felson

Mechanisms of osteoarthritis (OA) pain

Curr Osteoporos Rep166116162018

30155845

10.1007/s11914-018-0477-1

Perrot

Trouvin

Bouhassira

Three dimensions of pain in osteoarthritis: Development and validation of the osteoarthritis symptom inventory scale

Pain164156615772023

36602324

10.1097/j.pain.0000000000002856

Allen

Thoma

Golightly

Epidemiology of osteoarthritis

Osteoarthritis Cartilage301841952022

34534661

10.1016/j.joca.2021.04.020

Cui

Wang

Zhong

Chen

Global, regional prevalence, incidence and risk factors of knee osteoarthritis in population-based studies

EClinicalMedicine29-301005872020

34505846

10.1016/j.eclinm.2020.100587

Long

Liu

Yin

Wang

Diao

Zhang

Lin

Guo

Prevalence trends of site-specific osteoarthritis from 1990 to 2019: Findings from the global burden of disease study 2019

Arthritis Rheumatol74117211832022

35233975

10.1002/art.42089

Kolasinski

Neogi

Hochberg

Oatis

Guyatt

Block

Callahan

Copenhaver

Dodge

Felson

2019 American college of rheumatology/arthritis foundation guideline for the management of osteoarthritis of the hand, hip, and knee

Arthritis Care Res (Hoboken)721491622020

31908149

10.1002/acr.24131

Bruyère

Honvo

Veronese

Arden

Branco

Curtis

Al-Daghri

Herrero-Beaumont

Martel-Pelletier

Pelletier

An updated algorithm recommendation for the management of knee osteoarthritis from the european society for clinical and economic aspects of osteoporosis, osteoarthritis and musculoskeletal diseases (ESCEO)

Semin Arthritis Rheum493373502019

31126594

10.1016/j.semarthrit.2019.04.008

Mezey

Máté

Paulik

Factors influencing pain management of patients with osteoarthritis: A cross-sectional study

J Clin Med1113522022

35268444

10.3390/jcm11051352

Schjerning

Mcgettigan

Gislason

Cardiovascular effects and safety of (non-aspirin) NSAIDs

Nat Rev Cardiol175745842020

32322101

10.1038/s41569-020-0366-z

Zeng

Wei

Persson

MSM

Sarmanova

Doherty

Xie

Wang

Long

Relative efficacy and safety of topical non-steroidal anti-inflammatory drugs for osteoarthritis: A systematic review and network meta-analysis of randomised controlled trials and observational studies

Br J Sports Med526426502018

29436380

10.1136/bjsports-2017-098043

Da Costa

Pereira

Saadat

Rudnicki

Iskander

Bodmer

Bobos

Gao

Kiyomoto

Montezuma

Effectiveness and safety of non-steroidal anti-inflammatory drugs and opioid treatment for knee and hip osteoarthritis: Network meta-analysis

BMJ375n23212021

34642179

10.1136/bmj.n2321

Ozen

Pedro

Michaud

Major adverse cardiovascular events and mortality with opioids versus NSAIDs initiation in patients with rheumatoid arthritis

Ann Rheum Dis82148714942023

37460169

10.1136/ard-2023-224339

Zhang

Dong

Loxoprofen sodium alleviates oxidative stress and apoptosis induced by angiotensin II in human umbilical vein endothelial cells (HUVECs)

Drug Des Devel Ther14508750962020

33239867

10.2147/DDDT.S266175

Nelson

Osteoarthritis year in review 2017: Clinical

Osteoarthritis Cartilage263193252018

29229563

10.1016/j.joca.2017.11.014

Kien

Geiger

Van Chuong

Cuong

Van Dinh

Pho

Anh

Giang

Preemptive analgesia after lumbar spine surgery by pregabalin and celecoxib: A prospective study

Drug Des Devel Ther13214521522019

31308627

10.2147/DDDT.S202410

Walker Taylor

Campbell

Thorpe

RJ Jr

Whitfield

Nkimbeng

Szanton

Pain, racial discrimination, and depressive symptoms among African American women

Pain Manag Nurs1979872018

29422125

10.1016/j.pmn.2017.11.008

Cheng

Yuan

Liu

Kan

Zhang

Wang

Zhang

Efficacy and safety of flurbiprofen cataplasms versus loxoprofen sodium cataplasms in knee osteoarthritis: A randomized controlled trial

Chin Med J (Engl)136218721942023

37545031

10.1097/CM9.0000000000002797

Figure 1

Consolidated Standards of Reporting Trails flow diagram of patients enrolled in the study. LSC, loxoprofen sodium cataplasm; FPC, flurbiprofen cataplasm.

Figure 2

Comparison of sex and age distribution of patients. (A) Sex distribution and (B) age distribution. LSC, loxoprofen sodium cataplasm; FPC, flurbiprofen cataplasm.

Figure 3

Comparison of treatment effectiveness rate between the LSC and FPC groups after 2 weeks of treatment. (A) Visual Analog Scale score, (B) Western Ontario and McMaster Universities Osteoarthritis Index global score, and (C) Lysholm score. LSC, loxoprofen sodium cataplasm; FPC, flurbiprofen cataplasm.

Figure 4

Comparison of secondary indicators in the FPC and LSC groups. (A) LSC and (B) FPC groups. LSC, loxoprofen sodium cataplasm; FPC, flurbiprofen cataplasm; VAS, Visual Analog Scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

Figure 5

Comparison of secondary indicators between the LSC and FPC groups. LSC, loxoprofen sodium cataplasm; FPC, flurbiprofen cataplasm; VAS, Visual Analog Scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

Figure 6

Comparison of changes in secondary indicators relative to baseline between the LSC and FPC groups. LSC, loxoprofen sodium cataplasm; FPC, flurbiprofen cataplasm; VAS, Visual Analog Scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

Figure 7

Comparison of the incidence of adverse events between the LSC and FPC groups. LSC, loxoprofen sodium cataplasm; FPC, flurbiprofen cataplasm.

Table I

Baseline data.

Variable	LSC group	FPC group	P-value
No. (missing values)	192(5)	104 (0)
Sex			0.012
Male (%)	83 (44.39)	63 (60.58)
Female (%)	104 (55.61)	41 (39.42)
Age, years			0.251
Mean (SD)	58.46 (10.12)	59.82 (8.77)
Median (Q1, Q3)	58.00 (52.00, 66.00)	60.50 (54.00, 65.00)
Min, max	24.00, 84.00	35.00, 84.00

P-value for sex calculated using χ² test. P-value for age calculated using the two independent samples t-test. LSC, loxoprofen sodium cataplasm; FPC, flurbiprofen cataplasm.

Table II

Treatment effectiveness rate (based on the Visual Analog Scale score) after 2 weeks of treatment.

Group	Cured, n (%)	Apparent efficacy, n (%)	Effective, n (%)	Ineffective, n (%)	Treatment effectiveness rate, n (%)	P-value	95% confidence interval for the difference in efficacy rates between LSC and FPC after 2 weeks of treatment (%)
LSC (n=184)	2 (1.09)	39 (21.20)	96 (52.17)	47 (25.54)	137 (74.46)	<0.001	31.32 (19.51-42.16)
FPC (n=102)	0 (0.00)	5 (4.90)	39 (38.24)	58 (56.86)	44 (43.14)

P-value calculated using χ² test. LSC, loxoprofen sodium cataplasm; FPC, flurbiprofen cataplasm.

Table III

Treatment effectiveness rate (based on Western Ontario and McMaster Universities Osteoarthritis Index global score) after 2 weeks of treatment.

Group	Cured, n (%)	Apparent efficacy, n (%)	Effective, n (%)	Ineffective, n (%)	Treatment effectiveness rate, n (%)	P-value	95% confidence interval for the difference in efficacy rates between LSC and FPC after 2 weeks of treatment. (%)
LSC (n=184)	1 (0.54)	20 (10.87)	92 (50.00)	71 (38.59)	113 (61.41)	<0.001	30.04 (18.09-40.64)
FPC (n=102)	0 (0.00)	2 (1.96)	30 (29.41)	70 (68.63)	32 (31.37)

P-value calculated using χ² test. LSC, loxoprofen sodium cataplasm; FPC, flurbiprofen cataplasm.

Table IV

Treatment effectiveness rate (based on the Lysholm score) after 2 weeks of treatment.

Group	Cured, n (%)	Improvement, n (%)	Ineffective, n (%)	Treatment effectiveness rate, n (%)	P-value	95% confidence interval for the difference in efficacy rates between LSC and FPC after 2 weeks of treatment. (%)
LSC (n=184)	29 (15.85)	127 (69.40)	27 (14.75)	156 (85.25)	<0.001	18.58 (8.34-29.15)
FPC (n=102)	3 (2.94)	65 (63.73)	34 (33.33)	68 (66.67)

P-value calculated using χ² test. LSC, loxoprofen sodium cataplasm; FPC, flurbiprofen cataplasm.

Table V

Comparison of secondary indicators in the loxoprofen sodium cataplasm group.

Scores	Screening period (n=192)	Second week (n=184)	P-value
VAS score			<0.001
Mean (SD)	5.78 (1.77)	3.14 (1.87)
Median (Q1, Q3)	6.00 (4.00, 7.00)	3.00 (2.00, 4.00)
Min, max	2.00, 10.00	0.00, 8.00
WOMAC global scores			<0.001
Mean (SD)	33.21 (17.60)	20.47 (14.49)
Median (Q1, Q3)	28.5 (20.00, 44.50)	15.5 (10.00, 28.50)
Min, max	2.00, 75.00	2.00, 73.00
WOMAC knee pain score (missing values)	192 (0)	184(8)	<0.001
Mean (SD)	8.46 (4.26)	4.77 (3.65)
Median (Q1, Q3)	8.00 (5.00, 11.00)	4.00 (2.00, 6.50)
Min, max	2.00, 19.00	0.00, 18.00
WOMAC knee stiffness score			<0.001
Mean (SD)	3.43 (1.84)	1.84 (1.76)
Median (Q1, Q3)	3.00 (2.00, 5.00)	1.00 (0.00, 3.00)
Min, max	0.00, 8.00	0.00, 7.00
WOMAC knee physical function score			<0.001
Mean (SD)	21.32 (12.27)	13.86 (9.72)
Median (Q1, Q3)	18.0 (12.00, 28.50)	10.00 (7.00, 19.00)
Min, max	0.00, 50.00	1.00, 48.00
Lysholm score			<0.001
Mean (SD)	53.60 (17.98)	72.27 (17.48)
Median (Q1, Q3)	58.0 (42.00, 67.00)	76.0 (61.00, 86.00)
Min, max	7.00, 90.00	19.00, 99.00

P-value calculated using paired t-test. VAS, Visual Analog Scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

Table VI

Comparison of secondary indicators in the flurbiprofen cataplasm group.

Scores	Screening period (n=104)	Second week (n=102)	P-value
VAS score			<0.001
Mean (SD)	5.79 (1.77)	4.26 (2.12)
Median (Q1, Q3)	6.00 (4.00, 7.00)	4.00 (2.00, 6.00)
Min, max	2.00, 9.00	1.00, 8.00
WOMAC global scores			<0.001
Mean (SD)	33.51 (21.76)	28.00 (21.27)
Median (Q1, Q3)	23.0 (17.50, 51.00)	18.0 (12.00, 50.00)
Min, max	10.00, 75.00	4.00, 69.00
WOMAC knee pain score			<0.001
Mean (SD)	8.66 (4.85)	6.80 (5.18)
Median (Q1, Q3)	7.00 (5.00, 13.00)	5.00 (3.00, 11.00)
Min, max	3.00, 18.00	1.00, 18.00
WOMAC knee stiffness score			<0.001
Mean (SD)	3.58 (2.36)	2.55 (2.25)
Median (Q1, Q3)	3.00 (2.00, 6.00)	2.00 (1.00, 5.00)
Min, max	0.00, 8.00	0.00, 7.00
WOMAC knee physical function score			<0.001
Mean (SD)	21.27 (14.97)	18.65 (14.16)
Median (Q1, Q3)	14.00 (11.00, 33.50)	12.50 (8.00, 31.00)
Min, max	3.00, 50.00	2.00, 45.00
Lysholm score			<0.001
Mean (SD)	51.66 (22.32)	62.86 (22.97)
Median (Q1, Q3)	56.00 (41.50, 67.00)	70.00 (50.00, 81.00)
Min, max	7.00, 88.00	15.00, 91.00

P-value calculated using paired t-test. VAS, Visual Analog Scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

Table VII

Secondary indicators in the LSC and FPC groups.

Score	Period	LSC group	FPC group	P-value
VAS score	Beginning of screening period			0.954
	n	192	104
	Mean (SD)	5.78 (1.77)	5.79 (1.77)
	Median (Q1, Q3)	6.00 (4.00, 7.00)	6.00 (4.00, 7.00)
	Min, max	2.00, 10.00	2.00, 9.00
	Second week			<0.001
	n	184	102
	Mean (SD)	3.14 (1.87)	4.26 (2.12)
	Median (Q1, Q3)	3.00 (2.00, 4.00)	4.00 (2.00, 6.00)
	Min, max	0.00, 8.00	1.00, 8.00
WOMAC global scores	Beginning of screening period			0.897
	n	192	104
	Mean (SD)	33.21 (17.60)	33.51 (21.76)
	Median (Q1, Q3)	28.50 (20.00, 44.50)	23.00 (17.50, 51.00)
	Min, max	2.00, 75.00	10.00, 75.00
	Second week			<0.001
	n	184	102
	Mean (SD)	20.47 (14.49)	28.00 (21.27)
	Median (Q1, Q3)	15.50 (10.00, 28.50)	18.00 (12.00, 50.00)
	Min, max	2.00, 73.00	4.00, 69.00
WOMAC knee pain score	Beginning of screening period			0.707
	n	192	104
	Mean (SD)	8.46 (4.26)	8.66 (4.85)
	Median (Q1, Q3)	8.00 (5.00, 11.00)	7.00 (5.00, 13.00)
	Min, max	2.00, 19.00	3.00, 18.00
	Second week			<0.001
	n	184	102
	Mean (SD)	4.77 (3.65)	6.80 (5.18)
	Median (Q1, Q3)	4.00 (2.00, 6.50)	5.00 (3.00, 11.00)
	Min, max	0.00, 18.00	1.00, 18.00
WOMAC knee stiffness score	Beginning of screening period			0.547
	n	192	104
	Mean (SD)	3.43 (1.84)	3.58 (2.36)
	Median (Q1, Q3)	3.00 (2.00, 5.00)	3.00 (2.00, 6.00)
	Min, max	0.00, 8.00	0.00, 8.00
	Second week			0.003
	n	184	102
	Mean (SD)	1.84 (1.76)	2.55 (2.25)
	Median (Q1, Q3)	1.00 (0.00, 3.00)	2.00 (1.00, 5.00)
	Min, max	0.00, 7.00	0.00, 7.00
WOMAC knee physical function score	Beginning of screening period			0.974
	n	192	104
	Mean (SD)	21.32 (12.27)	21.27 (14.97)
	Median (Q1, Q3)	18.0 (12.00, 28.50)	14.0 (11.00, 33.50)
	Min, max	0.00, 50.00	3.00, 50.00
	Second week			<0.001
	n	184	102
	Mean (SD)	13.86 (9.72)	18.65 (14.16)
	Median (Q1, Q3)	10.00 (7.00, 19.00)	12.50 (8.00, 31.00)
	Min, max	1.00, 48.00	2.00, 45.00
Lysholm score	Beginning of screening period			0.418
	n	192	104
	Mean (SD)	53.60 (17.98)	51.66 (22.32)
	Median (Q1, Q3)	58.0 (42.00, 67.00)	56.0 (41.50, 67.00)
	Min, max	7.00, 90.00	7.00, 88.00
	Second week			<0.001
	n	184	102
	Mean (SD)	72.27 (17.48)	62.86 (22.97)
	Median (Q1, Q3)	76.0 (61.00, 86.00)	70.0 (50.00, 81.00)
	Min, max	19.00, 99.00	15.00, 91.00

P-value calculated using two independent samples t-test. VAS, Visual Analog Scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index; LSC, loxoprofen sodium cataplasm; FPC, flurbiprofen cataplasm.

Table VIII

Changes in secondary indicators relative to baseline in the LSC and FPC groups.

Variable	LSC group	FPC group	P-value
No. (missing values)	192(8)	104(2)
Change of VAS score
Mean (SD)	-2.66 (1.53)	-1.56 (1.01)	<0.001
Median (Q1, Q3)	-3.00 (-3.00, -2.00)	-1.00 (-2.00, -1.00)
Min, max	-7.00, 2.00	-6.00, 0.00
Change of WOMAC global scores
Mean (SD)	-13.29 (10.60)	-5.78 (3.93)	<0.001
Median (Q1, Q3)	-12.00 (-18.00, -6.00)	-6.00 (-8.00, -3.00)
Min, max	-53.00, 12.00	-20.00, 7.00
Change of WOMAC knee pain score
Mean (SD)	-3.80 (2.75)	-1.94 (1.39)	<0.001
Median (Q1, Q3)	-3.00 (-5.00, -2.00)	-2.00 (-3.00, -1.00)
Min, max	-12.00, 3.00	-8.00, 1.00
Change of WOMAC knee stiffness score
Mean (SD)	-1.64 (1.39)	-1.04 (0.89)	<0.001
Median (Q1, Q3)	-2.00 (-2.00, -1.00)	-1.00 (-2.00, 0.00)
Min, max	-7.00, 3.00	-3.00, 1.00
Change of WOMAC knee physical function score
Mean (SD)	-7.85 (7.59)	-2.80 (2.93)	<0.001
Median (Q1, Q3)	-7.00 (-12.00, -2.00)	-3.00 (-5.00, -1.00)
Min, max	-36.00, 11.00	-12.00, 6.00
Change of Lysholm score
Mean (SD)	18.76 (12.21)	11.28 (8.79)	<0.001
Median (Q1, Q3)	20.00 (11.00, 27.00)	10.00 (5.00, 16.00)
Min, max	-41.00, 57.00	-6.00, 39.00

Table IX

Incidence of adverse events in the LSC and FPC groups.

	LSC group		FPC group
Adverse events	Times	Number of individuals (%)	Times	Number of individuals (%)	P-value
General adverse events	10	7 (3.65)	20	7 (6.73)	0.258
Severe adverse events	0	0 (0.00)	0	0 (0.00)	-
Adverse events leading to discontinuation	0	0 (0.00)	0	0 (0.00)	-
Specific adverse events
Skin itching	5	5 (2.60)	0	0 (0.00)	0.166
Skin fever	3	3 (1.56)	0	0 (0.00)	0.554
Allergy	2	2 (1.04)	0	0 (0.00)	0.543
Dressing shedding	0	0 (0.00)	20	7 (6.73)	<0.001

P-value calculated using he Fisher's exact test. General adverse events refers to any unintended and unfavorable signs, symptoms or diseases temporally associated with the use of a medical treatment or procedure that do not necessarily have a causal relationship with the intervention. Severe adverse events are more critical events that have a marked effect on the health or well-being of a patient. LSC, loxoprofen sodium cataplasm; FPC, flurbiprofen cataplasm.