Intra-articular injection of methylprednisolone for reducing pain in knee osteoarthritis: A systematic review and meta-analysis.

BACKGROUND: To evaluate the efficacy and safety of intra-articular methylprednisolone for reducing pain in patients with knee osteoarthritis.
METHODS: We conduct electronic searches of Medline (1966-2017.11), PubMed (1966-2017.11), Embase (1980-2017.11), ScienceDirect (1985-2017.11), and the Cochrane Library (1900-2017.11) for randomized clinical trials comparing the use of methylprednisolone to treat knee osteoarthritis. The primary outcomes are Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain scores and WOMAC function scores. Each outcome was combined and calculated using the statistical software STATA 12.0. Fixed/random effect model was adopted based on the heterogeneity tested by I statistic.
RESULTS: A total of 739 patients were analyzed across 4 randomized controlled trials (RCTs). The present meta-analysis revealed that there were significant differences between groups regarding the WOMAC pain scores at 4 weeks (WMD = -1.384, 95% CI: -1.975 to -0.793, P = .000), 12 weeks (WMD = -1.587, 95% CI: -2.489 to -0.685, P = .001), and 24 weeks (WMD = -1.563, 95% CI: -2.245 to -0.881, P = .000). Significant differences were identified in terms of physical function at 4 weeks (WMD = -7.925, 95% CI: -13.359 to -2.491, P = .004), 12 weeks (WMD = -7.314, 95% CI: -13.308 to -1.320, P = .117), and 24 weeks (WMD = -6.484, 95% CI: -11.256 to -1.711, P = .008).
CONCLUSION: Intra-articular methylprednisolone injection was associated with an improved pain relief and physical function in patients with knee osteoarthritis. Additionally, no severe adverse effects were observed. Due to the limited quality of the evidence currently available, higher quality RCTs were required.

Introduction

Osteoarthritis (OA) is common degenerative disease of knee joint especially occurs in elderly patients.[ It is one of the major causes of pain and deformity, resulting in additional medical expenses and poor quality of life.[ It is reported that approximately 6% adults whose age above 30 years occurs symptomatic OA.[ The number of patients with knee osteoarthritis has increased in tandem with population aging and it remains a huge healthcare challenge. However, knee OA is usually associated with moderate to severe pain which is recognized as important factors for functional recovery.[

Guideline on management knee OA has recommended that exercise therapy is benefit for improving functional outcomes and decreasing inflammatory reactions. Moreover, a combination of intra-articular injection of steroid drugs and non-pharmacologic treatment also contributes to pain relief.[ Heard et al[ reported that intra-articular administration of dexamethasone appeared to mitigate the inflammation response within the joint, which prevented subsequent joint damage. van et al[ performed a meta-analysis from randomized controlled trials (RCTs) and demonstrated that patients with severe knee pain could benefit from intra-articular steroid drugs injection. Methylprednisolone is a moderate efficacy corticosteroid medication which is used to decrease inflammation and suppress the immune system.[ The possible mechanism is to inhibit peripheral phospholipase, which decreases the pain-aggravating products from the cyclooxygenase and lipoxygenase pathways. Published articles have demonstrated that intraoperative use of methylprednisolone can be considered an effective, safe, and simple therapeutic means to reduce postoperative pain in orthopedic surgery.[

Recent studies have focused on the intra-articular injection of methylprednisolone for pain management and functional restoration for patients suffering from knee OA. However, the efficacy of methylprednisolone remains controversial due to the small published articles. Therefore, we performed a meta-analysis from RCTs to assess the efficacy and safety of intra-articular injection of methylprednisolone in patients with knee OA.

Methods

This article is reported according to the guideline of PRISMA statement. Ethical approval is not required because it is a meta-analysis of previously published articles.

Search strategy

We conduct electronic searches of Medline (1966-2017.11), PubMed (1966-2017.11), Embase (1980-2017.11), ScienceDirect (1985-2017.10) and the Cochrane Library (1966-2017.11). The following keywords are used on combination with Boolean operators AND or OR: “knee osteoarthritis OR arthritis OR arthrosis OR arthritic,” “methylprednisolone,” and “random.” References of the included articles are also scanned for potentially relevant studies. No language or date exclusions are applied. Two reviewers independently scan all titles and abstracts to remove duplicates and assess the relevance according to the inclusion and exclusion criteria. Subsequently, the full text of the potential articles is screened, and a final decision is made. Disagreement is resolved by consulting with a third investigator.

Inclusion criteria and study selection

Participants: Published articles enrolling adult human with knee osteoarthritis; Interventions: The intervention groups received intra-articular methylprednisolone injection for pain management; Comparisons: The control groups received placebo; Outcomes: The primary outcomes were Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain scores and WOMAC function scores at 4, 12, and 24 months follow-up. The secondary outcomes were drug-related adverse effects; Study design: RCTs with placebo report. The exclusion criteria are as follows: insufficient clinical outcome data and reviews, case reports, letters, or conference articles.

Data extraction

Data were extracted from the enrolled literatures by 2 reviewers independently. The following data were extracted: article titles, first author's names, publication year, samples size, population, age, gender, intervention procedures, duration of follow-up, and outcome measures. Corresponding authors were consulted to gain required information that was incomplete. The outcomes included: WOMAC pain scores and WOMAC function scores at 4, 12, and 24 months.

Quality assessment

Two investigators independently assessed quality of the included RCTs according to the Cochrane Handbook for Systematic Reviews of Interventions to determine the risk of bias. The following domains were assessed: adequate sequence generation, allocation of concealment, blinding, incomplete outcome data, free of selective reporting, and free of other bias. The risk of bias for each domain was graded as either low, high, or unclear. Disagreement was settled by consulting with a third investigator.

Evidence synthesis

The evidence grade for the main outcomes was assessed using the guidelines of the Recommendations Assessment, Development and Evaluation (GRADE) system including the following items: risk of bias, inconsistency, indirectness, imprecision, and publication bias. The recommendation level of evidence was divided into the following categories: high which means that further research is unlikely to change confidence in the effect estimate; moderate which means that further research is likely to significantly change confidence in the effect estimate but may change the estimate; low which means that further research is likely to significantly change confidence in the effect estimate and to change the estimate; and very low which means that any effect estimate is uncertain.

Data analysis

STATA 12.0 software (Stata Corp, College Station, TX) was used for data analyses. Statistical heterogeneity was tested depending on the value of P and I2 using the standard chi-square test. A fixed-effects model was adopted when no statistical evidence of heterogeneity was found (I2 < 50%, P > .05); Otherwise, a random-effect model was applied. Continuous outcomes (pain scores and functional outcomes) were expressed as the weighted mean differences (WMD) with a 95% confidence intervals (CIs). Dichotomous outcomes (adverse effects) were expressed as the risk difference (RD) with a 95% CI.

Results

Literature search

A total of 378 relevant studies were identified with the first search strategy. After reviewing the titles and abstracts of 87 records, 83 irrelevant articles were excluded. Finally, a total of 4 RCTs[ that published between 2014 and 2016 were included in the present meta-analysis. No additional studies were included after the reference review. The search process was proceed as presented in Table 1.

Table 1

Search results and the selection procedure.

Demographic characteristics

The characteristics of the included studies were reported in Table 2. Only patients with knee osteoarthritis were included in the present meta-analysis. These articles involved 378 participants in the methylprednisolone groups and 361 patients in the control groups. The individual sample sizes ranged from 100 to 425 and average age ranged from 61 to 66. The trials were performed in the Canada, Brazil, Denmark, and Spain. WOMAC pain scores and function scores were used for the evaluation of the clinical outcomes. The last follow-up duration ranged from 24 to 26 weeks.

Table 2

Trials characteristics.

Risk of bias

The Cochrane Handbook for Systematic Review of Interventions was used to assess risk of bias of the RCTs. All RCTs showed clear inclusion and exclusion criteria and reported their randomization methodology by using computer-generated randomization. Three of them demonstrated that allocation concealment was done by sealed, opaque, and consecutively numbered envelopes.[ All included articles reported blinding to the participants, care providers, and 3 of them attempted to blind the assessors.[ The methodological quality of the included studies was presented in Table 3. Judgments regarding each risk of bias item were presented as percentages across all the included studies in Table 4.

Table 3

Methodological quality of the randomized controlled trials.

Table 4

Risk of bias.

Evidence level

Main outcomes in this meta-analysis were evaluated using the Recommendations Assessment, Development and Evaluation (GRADE) system. The evidence quality for main outcomes were moderate (Table 5), which means that further research is likely to significantly change confidence in the effect estimate but may change the estimate.

Table 5

The GRADE evidence quality for main outcome.

Results of the meta-analysis

WOMAC pain scores at 4 weeks

At 4 weeks, 4 RCTs reported the WOMAC pain scores (5 items, score 0–20). The pooled results revealed that there was significant difference between groups with regard to the WOMAC pain scores (WMD = −1.384, 95% CI: −1.975 to −0.793, P = .000; Fig. 1). There was significant heterogeneity among the articles (χ2 = 4.59, df = 3, I2 = 68.9%, P = .022) and a random-effects model was adopted.

Figure 1

Forest plot diagram showing WOMAC pain scores at 4 weeks. WOMAC = Western Ontario and McMaster Universities Arthritis Index.

WOMAC pain scores at 12 weeks

Four RCTs reported the WOMAC pain scores at 12 weeks. There was significant heterogeneity (χ2 = 16.26, df = 3, I2 = 81.6%, P = .001) and a random-effects model was adopted. The present meta-analysis indicated that there was significant difference in terms of the WOMAC pain scores at 12 weeks (WMD = −1.587, 95% CI: −2.489 to −0.685, P = .001; Fig. 2).

Figure 2

Forest plot diagram showing WOMAC pain scores at 12 weeks. WOMAC = Western Ontario and McMaster Universities Arthritis Index.

WOMAC pain scores at 24 weeks

Four RCTs showed the WOMAC pain scores at 24 weeks. A random-effects model was applied due to the significant heterogeneity among the articles (χ2 = 12.85, df = 3, I2 = 76.7%, P = .005). Meta-analysis showed that there was significant difference in the WOMAC pain scores at 24 weeks between groups (WMD = −1.563, 95% CI: −2.245 to −0.881, P = .000; Fig. 3).

Figure 3

Forest plot diagram showing WOMAC pain scores at 24 weeks. WOMAC = Western Ontario and McMaster Universities Arthritis Index.

Physical function at 4 weeks

At 4 weeks, 4 RCTs provided the physical function (17 items, score 0–68). Significant heterogeneity was found among the studies (χ2 = 34.45, df = 3, I2 = 91.3%, P = .000) and a random-effects model was used. The present meta-analysis demonstrated that there was significant difference between groups regarding to the physical function at 4 weeks (WMD = −7.925, 95% CI: −13.359 to −2.491, P = .004; Fig. 4).

Figure 4

Forest plot diagram showing physical function scores at 4 weeks.

Physical function at 12 weeks

Four studies provided the comparisons of physical function at 12 weeks between treatment groups. A random-effects model was used (χ2 = 33.93, df = 3, I2 = 91.2%, P = .000). The pooled results revealed that there was significant difference in terms of physical function at 12 weeks (WMD = −7.314, 95% CI: −13.308 to −1.320, P = .117; Fig. 5).

Figure 5

Forest plot diagram showing physical function scores at 12 weeks.

Physical function at 24 weeks

All RCTs reported the physical function at 24 weeks. There was significant heterogeneity, (χ2 = 20.97, df = 3, I2 = 0%, P = .000) and a random-effects model was used. The present meta-analysis revealed that there was significant difference regarding the physical function at 24 weeks between groups (WMD = −6.484, 95% CI: −11.256 to −1.711, P = .008; Fig. 6).

Figure 6

Forest plot diagram showing physical function scores at 24 weeks.

Adverse effects

All studies showed the adverse effects after intra-articular methylprednisolone. A fixed-effects model was used (χ2 = 1.31, df = 3, I2 = 0%, P = .726). No significant difference regarding to the adverse effects was identified (RD = 0.011, 95% CI: −0.005 to 0.026, P = .180; Fig. 7). All adverse effects were nonspecific and the symptoms included nausea, vomiting, sweating, and headache. No severe adverse effects were detected and all the events were self-resolved within a few days.

Figure 7

Forest plot diagram showing the adverse effects.

Discussion

To the best of our knowledge, this is the first meta-analysis from RCTs to evaluate the efficacy and safety of intra-articular methylprednisolone injection for pain control in patients with knee osteoarthritis. The most interesting finding of the present meta-analysis is that intra-articular methylprednisolone is associated with a reduced pain and improved physical function. In addition, no increased risk of adverse effects is observed in methylprednisolone groups. The evidence quality for each main outcome is moderate, which means that further research is likely to significantly change confidence in the effect estimate but may change the estimate.

Osteoarthritis is the most prevalent form of arthritis worldwide affecting nearly 52.5 million people or 22.7% of the population in the United States.[ With the aging population, the incidence of knee osteoarthritis is increasing and it becomes a serious social problem. The pathological process includes inflammation and structural changes of knee joints.[ Thus, it may result in pain and deformity. Conservative treatment, including physical therapy, intra-articular injections and oral medications, is the first choice for the treatment of knee osteoarthritis with mild to moderate. The therapeutic goal is to reduce pain, improve patient's satisfaction, quality of life and slow the progression of the disease. Multiple drugs, such as nonsteroidal anti-inflammatory drugs, glucocorticoids, glucosamine, hyaluronic acid, and corticosteroid have been implemented as nonsurgical therapy for pain management for patients with knee OA.[ The clinical outcomes for improving in physical function disability are with varying success rates.

Recently, the American Academy of Orthopaedic Surgeons (AAOS) 2013 clinical practice guideline strongly recommended against the injection of hyaluronic acid and did not recommend for or against platelet rich plasma injections in symptomatic knee OA. Intra-articular corticosteroid injection has been widely applied and showed to reduce deformity and improve pain relief and physical function. Raynauld et al[ indicated that the beneficial effects of intra-articular steroid injections could last as long as 24 weeks. He et al[ concluded that corticosteroid was found to be an effective and safe therapy in the treatment of knee OA compared with other intra-articular injections. Methylprednisolone is a synthetic glucocorticoid which has a higher receptor affinity and little mineralocorticoid activity.[ It is widely distributed in the tissue. Diffusion of MPA from a knee joint following an intra-articular injection, reflecting its duration of local action, has been found to continue for between 7 and 21 days. Intra-articular administration makes it possible to enhance local anti-inflammatory while mitigating systemic response. Based on the obvious advantages, methylprednisolone was thought to be more effective in reducing pain and local inflammatory response. However, there was a lack of reliable evidence due to the small published articles. Thus, we performed the meta-analysis from RCTs and demonstrated that intra-articular methylprednisolone was associated with a further reduced pain up to 24 weeks.

The pathogenesis of osteoarthritis contains stress-induced mechanisms, phenotype shifts, and abnormal cellular activities in cartilage and synovium.[ As a result, intra- and extracellular proinflammatory mediators is activated. Then aseprtic inflammatory reaction of knee joints may cause cartilage degeneration and hyperosteogeny, which results in twist, unstable, and stiffness and develops into deformity ultimately. Methylprednisolone have powerful anti-inflammatory and immunosuppressive effects by inhibiting inflammatory mediators and immune responses. Minimizing inflammatory response can alleviate the progression of the pathological changes and then maintain physical function of knee joints. Popma et al[ concluded that there was a significant difference in terms of range of motion between triamcinolone and control groups. However, McAlindon et al[ reported that no benefits results from intra-articular triamcinolone was observed regarding physical function in knee OA. In our study, WOMAC physical function was used for evaluating the functional restoration. The present meta-analysis revealed that intra-articular injection of methylprednisolone was associated with a significant improvement in knee function.

Currently, there remains controversial regarding the intra-articular glucocorticoid due to the destructive effects on cartilage and synovium. Previous studies in animal and human have showed mixed results. Wernecke et al[ reported a dose and time effect that low dose and duration showed protective effect, while high dose cause chondrotoxicity and cell damage. All included patients received 40 mg intra-articular methylprednisolone injection; therefore we did not perform a dose-response analysis. The overall incidence of adverse effects was 5/378 in the methylprednisolone groups compared 1/361 in control groups (P = .180). Intra-articular methylprednisolone administration was not related to an increased risk of adverse effects. Additionally, no severe adverse effects were observed. We recommend an intra-articular of 1 mL (40 mg) of methylprednisolone for routine clinical practice because all included studies used following this instructions. However, more RCTs with long term follow up were required to explore the optimal dose of methylprednisolone and potential adverse effects.

Several potential limitations of this study should be noted. Only 4 RCTs with small sample size are included, which may influence the results; type of opioid differed from each other, due to the limited studies, we did not perform a subgroup analysis; heterogeneity among the included studies was unavoidable due to different grade of OA. Heterogeneity was also caused by a variety of other factors such as age, gender and BMI; methodological weakness in the included studies should be considered which may influence our results; short duration of follow-up can cause the underestimation of the adverse effects. Another limitation is the publication bias among articles, which is also common in previous reviews; although we applied the GRADE system to assess the evidence level and recommendation strengths, judgment was still necessary.

Despite the aforementioned limitations, this is the first meta-analysis from RCTs to assess the efficacy and safety of intra-articular methylprednisolone injection for pain management in knee OA. High-quality RCTs with large sample size are required to study the optimal dose and potential adverse effects in the future investigation.

Conclusion

Intra-articular methylprednisolone injection was associated with an improved pain relief and physical function in patients with knee OA. Additionally, no severe adverse effects were observed. Due to the limited quality of the evidence currently available, higher quality RCTs were required.

Author contributions

HC and KC conceived of the design of the study. JZ performed and collected the data and contributed to the design of the study. KT finished the manuscript.

Conceptualization: Ke Chen.

Data curation: Huiguang Cheng.

Formal analysis: Jiangtao Zhang.

Writing – original draft: Kewei Tian.