Abstract
Background:
Osteoarthritis is a degenerative disease with a growing burden in South Korea. Corresponding drugs are commonly used for pain relief and joint function improvement. Specifically, symptomatic slow-acting drugs for osteoarthritis are frequently used, with diacerein being the most common symptomatic slow-acting drugs for osteoarthritis in South Korea. In this study, we evaluated the efficacy and safety of diacerein and celecoxib combination therapy in patients with osteoarthritis.
Methods:
A total of 71 subjects were randomly assigned to group 1 (diacerein and celecoxib), 2 (diacerein and placebo), or 3 (celecoxib and placebo). The primary outcome measure was the change in the visual analog scale (VAS) score 12 weeks after treatment.
Results:
The combination therapy group exhibited a significant decrease in the VAS score, alongside the other control monotherapy groups. Although there was no significant difference between the groups, the combination therapy group exhibited a greater decrease in the absolute value of the VAS score than the other groups. Four weeks after treatment, the combination therapy group showed significantly higher improvement in the stiffness and physical function categories of the Western Ontario and McMaster Universities Osteoarthritis Index than the other groups. Additionally, no serious adverse events occurred following combination therapy, with most adverse events being mild and resolving without specific treatment.
Conclusions:
Diacerein and celecoxib combination therapy is as safe and effective as corresponding monotherapies. A relatively early improvement in stiffness and physical function following treatment with this combination therapy indicates that physicians should consider this for the early-stage treatment of patients with symptomatic osteoarthritis.
Keywords: celecoxib, diacerein, knee osteoarthritis
1. Introduction
Osteoarthritis is a degenerative disease with increasing importance in South Korea owing to an aging society. The prevalence of symptomatic knee osteoarthritis is 19.2% in women, and the corresponding disease burden and societal impact of osteoarthritis is large.[1] Drugs are a commonly used treatment option for pain relief and joint function improvement in osteoarthritis. Symptomatic slow-acting drugs for osteoarthritis (SYSADOA), along with nonsteroidal anti-inflammatory drugs (NSAIDs), are frequently used in osteoarthritis treatment. In South Korea, over half of the patients with knee osteoarthritis are treated with a combination of more than 2 categories of drugs. The combination of NSAIDs and SYSADOAs, the second most common treatment strategy after NSAIDs alone (27.2%), is prescribed to 22.3% of patients with knee osteoarthritis in South Korea. According to this 2014 Korean Health Insurance Review and Assessment Service database, diacerein is the most used SYSADOA in South Korea.[2] Several studies on the comparative efficacy, safety, and effects of diacerein and celecoxib on osteoarthritis have been published; the corresponding results indicated that diacerein is an effective treatment for osteoarthritis.[3,4] Nonetheless, in clinics, NSAID and diacerein combination therapy is frequently prescribed despite there being few studies comparing the efficacy and safety of NSAID and diacerein combination therapy. Additionally, the studies that have been conducted failed to include a placebo.[5]
Therefore, this study was conducted to evaluate the efficacy and safety of diacerein and celecoxib combination therapy in patients with osteoarthritis via a randomized placebo-controlled trial.
2. Ethics approval
This prospective randomized placebo-controlled study was approved by the institutional review board of Seoul St. Mary’s Hospital, The Catholic University of Korea College of Medicine (IRB approval date 2017.12.21, 2017GR1772) and Korea University Guro Hospital (IRB approval date 2017.12.19, KC17MEDV0703). Informed consent was obtained from each participant in written document.
3. Materials and methods
Between January 2018 and December 2018, 87 patients aged > 50 years who had been diagnosed with primary knee osteoarthritis and assessed for knee pain with a visual analog scale (VAS) score > 40 mm were enrolled across multiple medical centers. The exclusion criteria were as follows: secondary knee osteoarthritis, inflammatory arthritis, including gout and rheumatoid arthritis, and any other conditions that could affect the results of this study.
A total of 87 subjects were randomly assigned by independent statistician using SAS Proc Plan to 3 groups: group 1 (diacerein and celecoxib), group 2 (diacerein and placebo), and group 3 (celecoxib and placebo) (Fig. 1). The subjects’ demographic data, medical records, and laboratory test results were recorded during their first visit. Clinical scoring of the VAS, numeric rating scale, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Gastrointestinal Symptom Rating Scale was also conducted. Oral tablets (diacerein: 1 cap, 50 mg; celecoxib: 1 cap, 100 mg) and corresponding placebo tablets were administered twice a day for the 12-week treatment period. The subjects received 500 mg oral tablets of acetaminophen as a pain relief medication and were allowed to take a maximum of 3 g/d. During the study, 500 mg oral tablets of almagate were prescribed for dyspepsia relief, with a maximum of 6 g of almagate being permitted per day. The subjects were instructed to not take other medications for pain or dyspepsia during the study period. At the end of the 12-week treatment period, an additional 4-week follow-up period was conducted, after which the subjects’ clinical scores were recorded. The primary outcome measure of this study was the change in the VAS score 12 weeks after the start of this treatment (Fig. 2). Out of the 87 enrolled subjects, 70 completed the study, and 71 subjects were available as full analysis group.
Figure 1.
Study flow.
Figure 2.
Study schedule.
3.1. Statistical analysis
The results of the descriptive statistical analysis were presented as means, standard deviations (SD), and proportions. Data normality was confirmed using a Kolmogorov–Smirnov test. Comparisons among the 3 groups were performed using an ANOVA or Kruskal–Wallis test. If there was a significant difference between the groups, a paired t test or Wilcoxon signed-rank test was performed.
All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC). Statistical significance was defined as P < .05.
4. Results
The mean age of the subjects was 65.67 (SD: 7.76) years, and the mean body mass index = weight/height2 (kg/m2) was 25.58 (SD: 3.57) kg/m2. Overall, the demographic data showed no statistically significant differences between the groups (Table 1).
Table 1.
Demographic data of the patients in this study.
| Diacerein and celecoxib combination group (N = 29) | Diacerein group (N = 26) | Celecoxib group (N = 27) | Total (N = 82) | P value* | ||
|---|---|---|---|---|---|---|
| Age | Mean ± SD | 66.17 ± 7.82 | 64.92 ± 7.85 | 65.85 ± 7.85 | 65.67 ± 7.76 | .8315 |
| Sex | Male | 4 (13.79%) | 4 (15.38%) | 5 (18.52%) | 13 (15.85%) | .8868 |
| Female | 25 (86.21%) | 22 (84.62%) | 22 (81.48%) | 69 (84.15%) | ||
| Smoking status | Smoker | 0 (0.00%) | 0 (0.00%) | 1 (3.70%) | 1 (1.22%) | .2639 |
| Ex-smoker | 0 (0.00%) | 1 (3.85%) | 2 (7.41%) | 3 (3.66%) | ||
| Non-smoker | 29 (100.00%) | 25 (96.15%) | 24 (88.89%) | 78 (95.12%) | ||
| Alcohol consumption | Drinker | 6 (20.69%) | 4 (15.38%) | 2 (7.41%) | 12 (14.63%) | .0597 |
| Ex-drinker | 0 (0.00%) | 4 (15.38%) | 6 (22.22%) | 10 (12.20%) | ||
| Non-drinker | 23 (79.31%) | 18 (69.23%) | 19 (70.37%) | 60 (73.17%) | ||
| Height (cm) | Mean ± SD | 156.94 ± 7.13 | 156.23 ± 5.20 | 157.97 ± 6.57 | 157.06 ± 6.35 | .1196 |
| Weight (kg) | Mean ± SD | 64.96 ± 12.75 | 60.18 ± 8.82 | 64.37 ± 9.84 | 63.25 ± 10.76 | .1125 |
| BMI (m2/kg) | Mean ± SD | 26.31 ± 4.31 | 24.60 ± 2.75 | 25.75 ± 3.30 | 25.58 ± 3.57 | .2832 |
SD = standard deviation.
One-way ANOVA or Kruskal–Wallis test for continuous variables; chi-square test or Fisher’s exact test for categorical variables.
All 3 groups exhibited significant improvements in VAS scores after 12 weeks of treatment. However, the VAS scores after this 12-week treatment were not significantly different between groups (Table 2).
Table 2.
Differences in VAS scores before and after 12-wk treatment.
| Diacerein and celecoxib combination group (N = 25) | Diacerein group (N = 24) | Celecoxib group (N = 22) | P value* | P value‡ | P value§ | ||
|---|---|---|---|---|---|---|---|
| Baseline (visit 2) | Mean ± SD | 62.24 ± 15.51 | 60.50 ± 15.81 | 64.09 ± 13.92 | .5544 | .7639 | .5432 |
| Visit 5 (12 wk) | Mean ± SD | 31.32 ± 24.19 | 36.08 ± 16.54 | 42.41 ± 25.40 | .2124 | .2039 | .1120 |
| Difference between baseline and visit 5 | Mean ± SD | −30.92 ± 23.26 | −24.42 ± 22.62 | −21.68 ± 24.70 | .3835 | .2223 | .2720 |
| P value† | <.0001 | <.0001 | .0005 | ||||
SD = standard deviation, VAS = visual analog scale.
One-way ANOVA or Kruskal–Wallis test for continuous variables between groups.
Paired t test or Wilcoxon signed rank test for intragroup comparison.
Independent t test or Wilcoxon rank sum test for comparison between combination group and diacerein group.
Independent t test or Wilcoxon rank sum test for comparison between combination group and celecoxib group.
All 3 groups exhibited significant improvements in WOMAC pain scores after 4, 8, and 12 weeks of treatment compared with their corresponding baseline WOMAC scores. Nonetheless, at each visit, the WOMAC pain scores were not significantly different between the groups (Table 3).
Table 3.
WOMAC pain scores throughout the treatment period.
| Diacerein and celecoxib combination group (N = 25) | Diacerein group (N = 24) | Celecoxib group (N = 22) | P value* | P value‡ | P value§ | ||
|---|---|---|---|---|---|---|---|
| Baseline (visit 2) | Mean ± SD | 9.20 ± 4.54 | 8.71 ± 3.79 | 9.09 ± 4.16 | .9120 | .9281 | .9488 |
| Visit 3 (4 wk) | Mean ± SD | 6.12 ± 4.09 | 6.75 ± 3.49 | 7.27 ± 3.99 | .4147 | .2598 | .2837 |
| Difference between baseline and visit 3 | Mean ± SD | −3.08 ± 3.60 | −1.96 ± 4.06 | −1.82 ± 3.61 | .4469 | .3499 | .2507 |
| P value† | .0003 | .0269 | .0278 | ||||
| Visit 4 (8 wk) | Mean ± SD | 6.56 ± 4.08 | 5.75 ± 3.19 | 6.05 ± 3.61 | .7353 | .5871 | .7071 |
| Difference between baseline and visit 4 | Mean ± SD | −2.64 ± 3.46 | −2.96 ± 2.05 | −3.05 ± 2.82 | .8742 | .5935 | .6141 |
| P value† | .0008 | <.0001 | .0001 | ||||
| Visit 5 (12 wk) | Mean ± SD | 5.88 ± 4.00 | 4.50 ± 2.04 | 5.91 ± 4.26 | .6052 | .2592 | .8640 |
| Difference between baseline and visit 5 | Mean ± SD | −3.32 ± 3.41 | −4.21 ± 3.23 | −3.18 ± 4.23 | .5756 | .2357 | .8809 |
| P value† | .0001 | <.0001 | .0020 | ||||
| Visit 6 (16 wk) | Mean ± SD | 7.04 ± 4.98 | 5.75 ± 3.40 | 5.41 ± 3.76 | .5619 | .5975 | .2842 |
| Difference between baseline and visit 6 | Mean ± SD | −2.21 ± 4.62 | −2.96 ± 3.69 | −3.68 ± 4.18 | .4930 | .6047 | .2745 |
| P value† | .0281 | .0007 | .0005 | ||||
SD = standard deviation, WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.
One-way ANOVA or Kruskal–Wallis test for continuous variables between groups.
Paired t test or Wilcoxon signed rank test for intragroup comparison.
Independent t test or Wilcoxon rank sum test for comparison between combination group and diacerein group.
Independent t test or Wilcoxon rank sum test for comparison between combination group and celecoxib group.
All 3 groups exhibited significant improvements in their corresponding WOMAC stiffness scores after this 12-week treatment period. At visit 3 (4 weeks after treatment), the combination therapy group showed significant improvement in WOMAC stiffness score compared to the baseline WOMAC stiffness score. Additionally, the combination group also exhibited a significant difference compared to the monotherapy groups. However, at each subsequent visit, the WOMAC stiffness scores were not significantly different between the groups (Table 4).
Table 4.
WOMAC stiffness scores throughout the treatment period.
| Diacerein and celecoxib combination group (N = 25) | Diacerein group (N = 24) | Celecoxib group (N = 22) | P value* | ||
|---|---|---|---|---|---|
| Baseline (visit 2) | Mean ± SD | 3.92 ± 1.87 | 3.71 ± 1.90 | 3.55 ± 2.15 | .9050 |
| Visit 3 (4 wk) | Mean ± SD | 2.52 ± 1.94 | 3.04 ± 1.81 | 3.36 ± 2.15 | .3042 |
| Difference between baseline and visit 3 | Mean ± SD | −1.40 ± 1.53 | −0.67 ± 1.93 | −0.18 ± 1.82 | .0311 |
| P value† | .0001 | .0734 | .6435 | ||
| Visit 4 (8 wk) | Mean ± SD | 3.28 ± 1.97 | 2.63 ± 1.64 | 3.18 ± 2.11 | .5796 |
| Difference between baseline and visit 4 | Mean ± SD | −0.64 ± 1.50 | −1.08 ± 1.38 | −0.36 ± 2.17 | .2643 |
| P value† | .0429 | .0020 | .4411 | ||
| Visit 5 (12 wk) | Mean ± SD | 2.56 ± 2.00 | 2.71 ± 1.33 | 2.59 ± 1.89 | .6893 |
| Difference between baseline and visit 5 | Mean ± SD | −1.36 ± 1.38 | −1.00 ± 1.44 | −0.95 ± 1.99 | .6438 |
| P value† | .0001 | .0032 | .0351 | ||
| Visit 6 (16 wk) | Mean ± SD | 3.00 ± 2.32 | 2.42 ± 1.74 | 2.50 ± 1.74 | .8304 |
| Difference between baseline and visit 6 | Mean ± SD | −0.92 ± 2.10 | −1.29 ± 1.33 | −1.05 ± 2.08 | .7801 |
| P value† | .0437 | .0001 | .0283 | ||
SD = standard deviation, WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.
One-way ANOVA or Kruskal–Wallis test for continuous variables between groups.
Paired t test or Wilcoxon signed rank test for intragroup comparison.
All 3 treatment groups exhibited significant improvements in WOMAC physical function scores at the end of the 12-week treatment period. At visit 3 (4 weeks after treatment), the combination therapy group showed a significant improvement in WOMAC physical function score compared with the monotherapy group. Nonetheless, at each subsequent visit, the WOMAC stiffness scores were not significantly different between the groups (Table 5).
Table 5.
WOMAC physical function scores throughout the treatment period.
| Diacerein and celecoxib combination group (N = 25) | Diacerein group (N = 24) | Celecoxib group (N = 22) | P value* | ||
|---|---|---|---|---|---|
| Baseline (visit 2) | Mean ± SD | 34.04 ± 16.64 | 29.17 ± 12.39 | 27.27 ± 15.52 | .2794 |
| Visit 3 (4 wk) | Mean ± SD | 21.96 ± 15.30 | 24.29 ± 12.70 | 24.95 ± 13.34 | .4735 |
| Difference between baseline and visit 3 | Mean ± SD | −12.08 ± 13.48 | −4.88 ± 10.40 | −2.32 ± 8.57 | .0101 |
| P value† | .0002 | .0041 | .2185 | ||
| Visit 4 (8 wk) | Mean ± SD | 24.40 ± 14.75 | 20.79 ± 11.81 | 21.00 ± 11.89 | .5537 |
| Difference between baseline and visit 4 | Mean ± SD | −9.64 ± 12.28 | −8.38 ± 10.57 | −6.27 ± 12.01 | .6118 |
| P value† | .0006 | .0008 | .0232 | ||
| Visit 5 (12 wk) | Mean ± SD | 22.04 ± 15.68 | 18.42 ± 8.62 | 19.14 ± 13.59 | .7599 |
| Difference between baseline and visit 5 | Mean ± SD | −12.00 ± 14.11 | −10.75 ± 11.28 | −8.14 ± 15.20 | .6170 |
| P value† | .0003 | .0001 | .0203 | ||
| Visit 6 (16 wk) | Mean ± SD | 23.63 ± 17.44 | 18.50 ± 11.63 | 19.45 ± 14.40 | .7297 |
| Difference between baseline and visit 6 | Mean ± SD | −9.96 ± 16.90 | −10.67 ± 9.45 | −7.82 ± 14.59 | .7753 |
| P value† | .0083 | .0000 | .0202 | ||
SD = standard deviation, WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.
One-way ANOVA or Kruskal–Wallis test for continuous variables between groups.
Paired t test or Wilcoxon signed rank test for intragroup comparison.
The percentage of subjects who experienced adverse events was not significantly different among the 3 groups (P = .2957). Further, no serious adverse effects were observed. Among the adverse events that did occur, the most common were gastrointestinal disorders (9.76%). Nonetheless, only 1 patient did not complete the entire course of treatment due to dyspepsia (diacerein monotherapy group). Overall, there was no significant difference between the adverse effects observed within the groups (P = .3361).
5. Discussion
The study’s findings indicated that diacerein and celecoxib combination therapy was effective, as all the 3 groups showed significant improvements in the VAS scores after 12 weeks of treatment and the VAS scores were not significantly different between groups (Table 2). WOMAC scores in total 3 categories improved significantly in all groups after treatment. Compared with monotherapy groups, the diacerein and celecoxib combination therapy group showed significant improvement in WOMAC stiffness scores and physical function scores specifically at visit 3 (4 weeks after treatment). For subsequent visits, that is, after visit 3, there was no significant difference between the groups.
Diacerein is a non-steroidal anti-inflammatory drug that has anti-catabolic and pro-anabolic properties on the cartilage; these mechanisms include anti-inflammatory activity, in which diacerein interferes with the pro-inflammatory cytokine interleukin-1. Although diacerein is most commonly used in combination with celecoxib, there is currently no consensus on the optimal treatment strategy for the improvement of osteoarthritis symptoms.[6] There have been a few prior reports comparing the effects of diacerein to NSAIDs; nonetheless, the current study utilized placebos to maximize and control bias. In addition, this study attempted to record clinical scores at every patient visit and analyzed data in subgroups in a more comprehensive manner.
The WOMAC score is widely used to evaluate hip and knee osteoarthritis. This questionnaire consists of 24 items that assess 3 subscales: pain, stiffness, and function. The results of this study indicated no significant difference in the WOMAC scores between the groups at the endpoint of this study. However, following the comprehensive evaluation of this data, the diacerein and celecoxib combination treatment was revealed to significantly improve the corresponding WOMAC score subscale for stiffness and function compared to the other monotherapy groups 3 weeks after the start of the therapeutic period.
Overall, these results support the understanding of the corresponding mechanism of diacerein, with pro-anabolic effects on the cartilage and synovial membrane, responsible for improving stiffness and function.[7] However, the primary outcome results of this study showed no significant difference in the VAS scores between the combination and monotherapy groups. Nonetheless, the absolute value of the VAS score improvement was higher in the combination therapy group than in the other groups.
In this study, no serious adverse events were found, the frequency of adverse events was low, and no significant differences were observed between the groups. Therefore, diacerein and celecoxib combination therapy is a safe and effective therapeutic strategy for the improvement of osteoarthritis symptoms and may possess an advantage in early symptom improvement.
Nonetheless, this study has some limitations. First, because the design of this study was to evaluate the efficacy and safety of diacerein and celecoxib combination therapy, the number of cases was relatively small; nonetheless, this was still sufficient to evaluate statistical differences. The primary outcome of the VAS score after 12 weeks of treatment was not significantly different between the groups; however, the combination therapy group exhibited a greater decrease in the absolute value of the VAS score than the other groups. Therefore, further studies with larger sample sizes are warranted. A further limitation that must be considered is that acetaminophen was administered as a pain relief medicine. Therefore, to determine the possibility of bias conferred by pain relief medicines, the use of acetaminophen was recorded. Nonetheless, there was no significant difference between the groups in terms of the average number of days of use or the number of doses per day. The number of patients who used pain relief medication differed significantly between groups. However, the combination group exhibited a significantly lower frequency of pain relief medication use than the other groups, with a low possibility of bias conferred by acetaminophen (Table 6). Further, the use of acetaminophen as a pain relief medicine was necessary in this study due to ethical issues.
Table 6.
Use of pain relief medicine by the participants in this study.
| Diacerein and celecoxib combination group (N = 25) | Diacerein group (N = 24) | Celecoxib group (N = 22) | Total (N = 71) | P value* | ||
|---|---|---|---|---|---|---|
| Use of pain relief medicine | YES | 10 (40.00%) | 19 (79.17%) | 15 (68.18%) | 44 (61.97%) | .0143 |
| NO | 15 (60.00%) | 5 (20.83%) | 7 (31.82%) | 27 (38.03%) | ||
| Average days of use | Mean ± SD | 36.10 ± 28.34 | 26.47 ± 28.06 | 29.00 ± 24.10 | 29.52 ± 26.48 | .6142 |
| Dose per day | Mean ± SD | 0.97 ± 0.65 | 0.99 ± 0.85 | 1.25 ± 0.71 | 1.08 ± 0.75 | .4060 |
Dose per day = total use/total days of use.
SD = standard deviation.
One-way ANOVA or Kruskal–Wallis test for continuous variables; chi-square test or Fisher’s exact test for categorical variables.
6. Conclusion
This clinical trial shows that diacerein and celecoxib combination therapy has advantage over single therapy as early treatment for symptomatic osteoarthritis. Early improvement in stiffness and physical function was confirmed in diacerein and celecoxib combination therapy. In addition, diacerein and celecoxib combination therapy is as safe and effective as corresponding monotherapies in reducing the pain caused by osteoarthritis.
Author contributions
Conceptualization: Chulmin Kim, Seon-Mee Kim, Whan Seok Choi.
Data curation: Chulmin Kim, Seon-Mee Kim, Whan Seok Choi.
Validation: Chulmin Kim, Seon-Mee Kim, Ji Hye Choi, Whan Seok Choi.
Visualization: Whan Seok Choi.
Writing – original draft: Sangah Youn, Ji Hye Choi.
Writing – review & editing: Ji Choi, Whan Seok Choi.
Abbreviations:
- NSAIDs
- nonsteroidal anti-inflammatory drugs
- SD
- standard deviations
- SYSADOA
- symptomatic slow-acting drugs for osteoarthritis
- VAS
- visual analog scale
- WOMAC
- Western Ontario and McMaster Universities Osteoarthritis Index
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
How to cite this article: Youn S, Choi JH, Kim C, Kim S-M, Choi WS. Efficacy and safety of diacerein and celecoxib combination therapy for knee osteoarthritis: A double-blind, randomized, placebo-controlled prospective study. Medicine 2023;102:39(e35317).
Contributor Information
Sangah Youn, Email: drsayoung@gmail.com.
Ji Hye Choi, Email: fmchs@catholic.ac.kr.
Chulmin Kim, Email: ksmpdh@korea.ac.kr.
Seon-Mee Kim, Email: ksmpdh@korea.ac.kr.
References
- [1].Lee S, Kim SJ. Prevalence of knee osteoarthritis, risk factors, and quality of life: the Fifth Korean National Health And Nutrition Examination Survey. Int J Rheum Dis. 2017;20:809–17. [DOI] [PubMed] [Google Scholar]
- [2].Park HR, Cho SK, Im SG, et al. Treatment patterns of knee osteoarthritis patients in Korea. Korean J Intern Med. 2019;34:1145–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [3].Zeng F, Wang K, Duan H, et al. Diacerein versus non-steroidal anti-inflammatory drugs in the treatment of knee osteoarthritis: a meta-analysis. J Orthop Surg Res. 2023;18:308. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [4].Pelletier JP, Raynauld JP, Dorais M, et al.; DISSCO Trial Investigator Group. An international, multicentre, double-blind, randomized study (DISSCO): effect of diacerein vs celecoxib on symptoms in knee osteoarthritis. Rheumatology. 2020;59:3858–68. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [5].Wang G-D, Yang L-Y, He B, et al. Effectiveness and safety of celecoxib combined with diacerein in the treatment of senile degenerative knee osteoarthritis: study protocol and preliminary results of a randomized controlled trial. Clin Trials Degenerative Dis. 2017;2:90. [Google Scholar]
- [6].Fidelix TS, Macedo CR, Maxwell LJ, et al. Diacerein for osteoarthritis. Cochrane Database Syst Rev. 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [7].Almezgagi M, Zhang Y, Hezam K, et al. Diacerein: recent insight into pharmacological activities and molecular pathways. Biomed Pharmacother. 2020;131:110594. [DOI] [PubMed] [Google Scholar]