FS is associated with continuous shoulder pain and loss of ROM, and can lead to shoulder disability and disrupted sleep[27]. Despite the current retrospective study[28] considering FS as a self-limited disease, treatments aimed at relieving pain and restoring shoulder motion and function was recommended [29]with favorable choice remained. In addition to nonsteroidal anti-inflammatory drugs, intra-articular corticosteroid administration and physical therapy, intra-articular injection of HA is gaining growing popularity in comparison with other conventional therapies. Some studies have compared different treatments for FS, whereas none involved intra-articular injection of HA[12, 30]. Hence, the current study aimed to quantitatively evaluate the effect of intra-articular HA injection on FS patients concerning pain relief and functional improvements.
Our results showed favorable outcomes in intra-articular HA injection, but failed to exert superior effect compared to other conventional therapy in pain relief. Since FS is a self-limited disease involving 3 phases. A constant pain appears early in painful freezing phase, and gradually subsides in adhesive phase. And the reduction of glenohumeral movements starts to improve until resolution phase. the between-approaches comparisons of pain-relieving effect might be complicated to make when FS turns into adhesive phase, in which the pain naturally relieves[2]. According to the assessing timepoints, pain might decrease spontaneously in both experimental and control groups leading to no statistical significance between groups. In addition, combination of treatments in controls may also affect the analysis. Lim[22] and Park[23] used intra-articular injection of corticosteroid as control, while Rovetta[11] used HA as an adjunctive therapy to corticosteroid plus physical therapy. Since corticosteroid is characterized with strong analgesic effect, studies enrolling usage of corticosteroid may suppress symptomatic pain manifestation[12, 30]. Some studies proved that corticosteroid contributed to anti-inflammation earlier than HA[31]. The pain-relieving effect of HA might be prominent in long-term control, which was supported by some studies[17, 32, 33]. Akhtar et al. confirmed the effect of HA in pain relief by UCLA pain scale[21] by conducting a RCT. An animal experiments also suggested that HA could reduce the concentration of inflammatory mediators such as prostaglandins, fibronectin, and cyclic adenosine monophosphate[34]. According to our results, HA has a comparable effect of pain relief with corticosteroid injection, though not superior. Given the side-effects of corticosteroid resulting in periarticular calcification, cutaneous atrophy, cutaneous depigmentation, tendon rupture and avascular necrosis[35–37], we suggested that intra-articular injection of HA is a favorable option in pain relief for FS patients.
The results of functional assessments, as shown in Fig. 4, clearly imply that the patients with HA interventions tend to have higher ROM values in external rotation than the control. When evaluating the remaining ROM aspects, we did not find statistical significances concerning ROM in abduction and flexion. Given the mixed results on the efficacy of HA in functional improvements, its application in patients with restricted ROM should be discussed. The ROM calculations, varied in individual studies, that Cails[25] and Park[23] assessed passive ROM and Hsieh[24] and Sang-Hong[26] assessed both active and passive ROM. Lim[22] and Rovetta[11] haven’t mentioned it but we can judge from their context that they also used passive ROM, too. Therefore, the passive ROM data were calculated to perform data synthesis. The follow-up time was 3 months for most studies,[22, 24, 25] while Rovetta[11] assessed at 6 weeks and Park[23] and Sang-Hong[26] assessed at 6 months, so the follow up time were all less than 6 months. Except for Hsieh’s, all studies used corticosteroid in controls. may also affect the performances of HA as discussed above[11, 22, 23, 25]. Overall, the eligible individual studies in the current meta-analysis presented low heterogeneity, which may suggest the credibility of the results. All individual study included for quantitative analysis reported improved ROM in external rotation, and eventually achieved a result favor for HA. From the perspective of directions of ROM, external rotation was well-established as the most important and sensitive direction in the motion of shoulder[3, 25], which also frequently selected as the representative of movements of shoulder[4, 38]. The superior improvement in external rotation suggested HA have a superior effect in functional recovery. The reason why significance was not found in abduction and flexion may be the limited sample size or a low sensitivity of these two directions. In addition, corticosteroid usage in control groups may also affect the comparison results. Therefore, the higher external rotation ROM values led us to considered HA injection as the better qualified treatment in improving ROM of shoulder in FS patients, compared to the existing therapy.
As for functional assessments, results of Constant and ASES showed no statistical significance between HA and control group. Interestingly, HA group showed worse outcomes than control group in SPADI, which is a self-rating scale consisting of pain scale and disability scale[39]. The result in SPADI was pooled from three studies[23, 24, 26], while Park’s study weighted 87%. Among them, two studies used HA as an adjunctive therapy to the various treatments. In Park’s study, they used 0.5% lidocaine (18mL) for capsular distension before HA administration in HA group, while 0.5% lidocaine (4mL) plus triamcinolone (40mg/mL; 1mL) in control group without capsular distension. As reported, twelve patients in treatment group suffered pain during capsular distension, which may influence the functional exercise, thus affect the SPADI[23]. Since capsular distension is the main reason for the poor results in SPADI, the results may not be able to illustrate that the effect of HA injection was inferior to other treatments. After comprehensively analyzing the results of Constant and ASES score, we tend to conclude that HA injection may possess a similar effect than the existing treatments.
Some previous reviews[40, 41] have discussed the effect of HA on FS. Papalia et al.[40] stated that HA is effective, but not as effective as other conventional treatments. The study included two non-RCTs, which decreased its level of evidence. Lee et al. [41] included 4 trails and conducted a systematic review to compare the effect of HA and other conventional therapies on FS patients, which suggested that HA yielded limited effect, whether adopted individually or in combination. However, the absence of quantitative analysis in this study due to data limitation may further undermine its credibility. Comparing with the previous review, the current study enlarged samples with two recently published RCTs, and meta-analysis may contribute to more reliable results. Harris et al.[42] conducted a systematic review and concluded that HA injection into the glenohumeral joint significantly improved shoulder ROM, constant scores, and pain at short-term follow-up following treatment of FS while isolated intra-articular HA injection presented significantly better outcomes than control. Though we reached a similar conclusion, his study included too many low-level evidence studies, which made his conclusion less convincing, as well as meta-analysis was not performed by them. Our study confirmed his view with a more typical inclusion and exclusion criteria, and meta-analysis made the conclusion more reliable.
Overall, the present meta-analysis suggested that HA intra-articular injection displayed non-inferior effect in pain-relieving and superior performance in functional improvements compared with other conventional treatment. Some meta-analyses have investigated the optimal treatments of FS[12, 43], of which Challoumas’s is the latest well-designed study with largest samples. This net-work meta-analysis recommended corticosteroid intra-articular injection for FS patients within 1-year duration. Challoumas et al. argued for its earlier benefits in contrast to interventions with detailed comparisons regarding physiotherapy, intra-articular corticosteroid, subacromial corticosteroid, arthrographic distension plus intra-articular corticosteroid and no treatment or placebo[12]. However, the major concern is the absence of HA injection comparison. To the best of our knowledge, the current study is the first meta-analysis with the largest available samples investigating the effect on FS between HA injection and any other conservative interventions.
The HA molecule has properties of both viscous and elastic materials, and this property suggests that it may have lubricate effect, as well as anti-adhesion effect[44]. The adhesion of FS comes from the deposition of type I and type III collagen by fibroblasts and myofibroblasts. It is also widely believed to be caused by a synovial inflammation[2]. HA as a lubricant, directly increases the viscoelasticity of the joint, and promotes the release of adhesions. And HA improves synovial fluid concentrations and changes synovium abnormalities, which also reduces friction[45]. Besides, its effect in anti-inflammatory actions and protection of cartilage may also be helpful[7]. In summary, it is a result of comprehensive action that HA helps shoulder return to normal and promotes the release of adhesions.
There were several limitations in this meta-analysis. First, our meta-analysis was conducted without classifications concerning individual stages of FS, which may add to the confounding factors not stratified in the current analysis. However, we have attempted to search eligible studies, whereas the eligible studies did not recruit patients in accordance with specific criteria, and the participates varies in stages. Second, we failed to make stratified subgroup analyses to calculate separate conventional treatment comparisons. However, we have endeavored to calculated as much original data as much as possible, which was limited due to data absence. Third, potential bias may exist in the current study due to lack of ethnical issues, language of publications, and minor publication bias, which could be resolved by further meta-analysis based on larger samples included. Although these limitations exist, we believe that this high-level of evidence research is helpful for clinical decision-making.