Knee osteoarthritis (KOA) is a common bone and joint disorder characterized by gradual cartilage degeneration, often accompanied by local pain, joint deformity, swelling, and motor impairment (1). Due to the complexity of KOA, there is still no effective treatment to date (2). For KOA, the primary treatment goal is to relieve pain, improve joint function, slow disease progression, and enhance patients' quality of life (3). The management of KOA encompasses basic treatment, pharmacotherapy, and surgical intervention, with intra-articular drug injection typically reserved for cases where oral or topical medications yield insufficient therapeutic effects (4). Compared with systemic administration, intra-articular delivery offers numerous advantages, including improving local bioavailability, reducing systemic exposure and the incidence of adverse reactions, and lowering treatment costs (5).

In recent years, intra-articular injection of multi-drug regimens for KOA treatment has garnered considerable attention. The involved drugs or pharmaceutical preparations encompass sodium hyaluronate, glucocorticoids, platelet-rich plasma, ozone, local anesthetics, and vitamins (6). Additionally, tension in the nerves and muscles surrounding the knee joint is another key contributor to pain (6). Notably, there are no unified standards for drug formulation and dosage, and the clinical efficacy remains to be further validated. This study aims to assess the clinical efficacy and safety of the “triple injection” (0.3 mL betamethasone +0.7 mL lidocaine +2 mL sodium hyaluronate) regimen.

KOA is a prevalent degenerative joint disease characterized by joint pain, disability, and loss of function (12). Currently, there is no curative treatment for KOA in clinical practice. For KOA patients who respond poorly to oral analgesics or anti-inflammatory drugs and suffer from moderate to severe pain, intra-articular drug injection into the knee joint is a viable therapeutic option. In recent years, the application of intra-articular drug injection in KOA treatment has gained increasing popularity (13). Compared with systemic administration and surgical treatment, intra-articular drug injection offers advantages such as high bioavailability, fewer systemic adverse reactions, and lower treatment costs (14).

The injection protocol used in this study was the “triple injection,” consisting of 0.3 mL compound betamethasone, 0.7 mL lidocaine, and 2 mL sodium hyaluronate. Sodium hyaluronate is composed of hyaluronic acid (HA), for which there are relatively few studies. It is widely distributed in both humans and animals, exerting multiple biological functions, including chondroprotection, anti-inflammatory effects, and joint lubrication, as well as protective effects on the meniscus (15). Intra-articular injection of sodium hyaluronate for KOA treatment improves joint lubrication, and reduces friction between articular cartilages, thereby alleviating joint pain, improving joint mobility. This therapy demonstrates significant efficacy in patients with early and mid-stage KOA (16–18). A single 5-week course of intra-articular sodium hyaluronate injection can relieve pain and improve joint function in KOA patients for up to 6 months, without serious side effects or complications (19). However, in clinical practice, it is commonly observed that the therapeutic effect of single-agent sodium hyaluronate injection is not significant in patients with more severe KOA, and combination injection with other drugs is usually required for intervention (19). However, in clinical practice, it is commonly observed that the therapeutic effect of single-agent sodium hyaluronate injection is not significant in patients with more severe KOA, and combination injection with other drugs is usually required for intervention.

Notably, primary KOA is typically associated with aseptic inflammation, which is the primary factor contributing to pain symptoms and disease progression (20). Studies have shown that intra-articular administration of lidocaine can reduce pain transmission in damaged peripheral nerves, thereby inhibiting pain sensitization, protecting already sensitized peripheral nerves in the injured area, and stabilizing neuronal cell membranes (21, 22). Literature reports indicate that a single intra-articular injection of 5 mL of 2% lidocaine into the knee joint cavity does not compromise chondrocyte viability, whether in healthy cartilage or KOA-affected cartilage (23). Intra-articular injection of local anesthetics is therefore widely used in the treatment of patients with painful knee KOA (24).

Regarding steroids, the “Management Guidelines for Hand, Hip and Knee Osteoarthritis (2019)” published by the American College of Rheumatology/Arthritis Foundation (25), recommends intra-articular steroid injections for KOA patients. Within the joint cavity, steroids exert a potent anti-inflammatory effect, aiding in alleviating KOA-related pain and promoting the recovery of knee function. They are indicated for the treatment of acute joint effusion and non-specific inflammation of surrounding soft tissues in KOA (26). The mechanism of action of glucocorticoids primarily involves inhibiting the production and release of inflammatory mediators, suppressing immune cell activity, and reducing the immune response (27). Studies have reported that the duration of pain relief following intra-articular glucocorticoid injection in the knee joint is at least 1 week (28), and can last up to 6 weeks (29), which is consistent with the findings of the present study. In a double-blind, randomized controlled trial, intra-articular injection of triamcinolone acetonide (10 mg) was found to be non-inferior to 40 mg triamcinolone acetonide in improving pain in KOA patients. Both doses significantly relieved pain and improved quality of life in symptomatic KOA patients. Compound betamethasone is a long-acting glucocorticoid with strong anti-inflammatory activity; additionally, intra-articular injection of 0.5–2 mL compound betamethasone can alleviate OA-related pain and stiffness within 2–4 h (30), which was the primary rationale for selecting betamethasone in this study. Andzie-Mensah et al. (31) conducted a single-blind randomized controlled study to compare the efficacy of betamethasone dipropionate and methylprednisolone acetate in the treatment of primary knee osteoarthritis [Kellgren-Lawrence (K-L) stages 2–4]. The results showed that both steroid injections alleviated symptoms; however, betamethasone dipropionate exhibited superior long-term efficacy compared with methylprednisolone acetate, providing sustained pain relief for more than 8 weeks. Wattanasirisombat et al. (32) performed a single-center, double-blind, randomized controlled trial to compare the efficacy of a single injection of long-acting corticosteroid (betamethasone) and medium-acting corticosteroid (triamcinolone) in KOA treatment. The results demonstrated that both the betamethasone and triamcinolone groups exhibited a significant reduction in resting Visual Analog Scale (VAS) pain scores starting from day 1, which persisted for up to 6 months. However, no significant differences were observed between betamethasone and triamcinolone in terms of resting VAS pain scores, functional scores, or performance-based outcomes at 6 months, highlighting the need for longer-term follow-up in the present study.

However, studies have shown that repeated use of corticosteroids can have adverse effects on articular cartilage (33). Corticosteroid use can also induce various other physiological reactions in the body, including disrupting water, salt, sugar, protein, and fat metabolism, impairing the body's resistance, hindering tissue repair, and delaying tissue healing (34). Additionally, some studies have reported that multiple short-term corticosteroid injections may cause cartilage damage and increase the risk of exacerbating KOA progression (35). Wernecke et al. (36) conducted a study and found that intra-articular corticosteroid injections at low doses and low frequencies (≤2–3 mg per dose or total cumulative dose of 8–12 mg in the body) exerted beneficial effects, whereas higher doses and frequencies (>3 mg per dose or total cumulative dose of 18–24 mg in the body) caused chondrotoxic effects and cartilage damage. Whitaker et al. (37) evaluated the safety and tolerability of co-injecting 2.5% polyacrylamide hydrogel with betamethasone disodium phosphate and betamethasone acetate into the healthy metacarpophalangeal joints of horses. The results showed that injecting 1 mL of betamethasone (6 mg/mL) into horses was safe for articular cartilage. Davis et al. (38) investigated chondrocytes treated with a combination solution of betamethasone sodium phosphate and betamethasone acetate (without benzalkonium chloride) at concentrations of 0.2, 0.6, 1, 3, and 6 mg/mL for 30 min. They found that no significant chondrocyte death was observed in the above concentration groups within 7 days after treatment; intra-articular injection of a low dose of betamethasone (<2.1 mg per dose) did not cause obvious cartilage damage or cell death, whereas injection of a higher dose (>2.1 mg per dose) led to cartilage protein loss and subsequent cartilage damage. Therefore, to minimize potential articular cartilage damage caused by betamethasone, the “triple injection” used in the observation group of this study contained a single low dose of compound betamethasone (0.3 mL, containing 1.5 mg of betamethasone dipropionate and 0.6 mg of betamethasone sodium phosphate).

Consistent with Davis et al. (38), this study also did not find that the triple injection caused cartilage damage. In their systematic review, Pirri et al. (39) clearly pointed out the potential cartilage damage that glucocorticoids and lidocaine may induce. Due to the lack of standardization in injection protocols and dosages, definitive conclusions cannot be drawn, and clinicians must remain vigilant about their potential hazards at all times. Furthermore, in a clinical randomized controlled study (40), the observation group and the control group received intra-articular injections of triamcinolone acetonide and normal saline once every 3 months, respectively. After 2 years of continuous injections, magnetic resonance imaging (MRI) revealed a 0.11 mm difference in knee articular cartilage thickness between the two groups, indicating that corticosteroids cause an annual cartilage loss of approximately 0.055 mm. Given that the thickness of knee articular cartilage is 3–5 mm, continuous intra-articular injections of corticosteroids once every 3 months would require 10 years to reduce articular cartilage thickness by 12.5%, a change that has a relatively minor impact on KOA progression. Regarding the safety of glucocorticoids, no statistically significant differences in K-L scores or total knee replacement rates were observed between patients who received glucocorticoid injections and those who did not after 5 years of follow-up (41, 42). In the study by Baker et al. (43), the chondrotoxicity of the combined use of local anesthetics, glucocorticoids, and hyaluronic acid was investigated. The results showed that this combination could produce a synergistic anti-inflammatory effect and counteract, to some extent, the side effects associated with single-drug use. Consistent with this, the present study also found that the triple injection achieved significantly superior efficacy compared with sodium hyaluronate alone. However, it should be clearly noted that betamethasone alone exerts anti-inflammatory and analgesic effects, while lidocaine has anesthetic effects. Whether the triple injection combination is more effective than betamethasone or lidocaine alone requires further research.

This study has several limitations. First, the sample size included was relatively small, and this was a single-center study, which may introduce bias into the research results. Second, in this study, the observation group was treated with the “triple injection” (0.3 mL compound betamethasone + 0.7 mL lidocaine + 2 mL hyaluronic acid) for KOA, while the control group only received 2 mL of hyaluronic acid injection. The inconsistent injection doses between the two groups may potentially interfere with the evaluation of therapeutic efficacy. Third, WOMAC score, VAS score and HSS score used in this study are all subjective indicators. There are certain deviations in the assessment process of these scoring scales, and no objective indicators were included for comprehensive evaluation—for example, monitoring changes in inflammatory factors in knee synovial fluid before and after treatment, or conducting imaging assessments post-treatment. Fourth, this study adopted a single-blind design, which may lead to subjective bias in data collection by researchers. Fifth, the follow-up period of this study was relatively short, which may affect the stability of the results. Last but not least, it is worth noting that lidocaine and betamethasone were used as part of the intervention to mimic the typical clinical experience of patients; however, their use may affect the judgment of the triple injection's effectiveness.

Intra-articular injection of sodium hyaluronate and the “triple injection” are both effective therapeutic modalities for the early and mid-stage of KOA. Compared with sodium hyaluronate, the “triple injection” can more effectively relieve pain and improve knee joint function.