Comparative Effectiveness and Safety of Intra-articular Injection of High versus Low Molecular Weight Hyaluronic Acid in Idiopathic Adhesive Capsulitis; A Randomized Clinical Trial

Comparative Effectiveness and Safety of Intra-articular Injection of High versus Low Molecular Weight Hyaluronic Acid in Idiopathic Adhesive Capsulitis; A Randomized Clinical Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comparative Effectiveness and Safety of Intra-articular Injection of High versus Low Molecular Weight Hyaluronic Acid in Idiopathic Adhesive Capsulitis; A Randomized Clinical Trial Mahshad Mir, Rezvaneh Mohebbi, Ghader Mohammadnezhad, Ahmad Raeissadat, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4265513/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Adhesive capsulitis (AC) of the shoulder is an inflammatory condition with pain and limitation in range of motion (ROM) in the glenohumeral joint. The main goal in managing AC is pain reduction and returning the joint function. Intra-articular hyaluronic acid (HA) has recently been considered as a safe modality in AC. However, the clinical properties of HA are associated with its molecular weight. This study aimed to compare the effectiveness of intra-articular injection of low molecular weight (LMW) with high molecular weight (HMW) HA in patients with AC. Methods: Fifty-six eligible patients with AC were randomized in this triple-blinded clinical trial. All patients underwent standard physical therapy as a baseline care. The follow-up visits were at 4, 12, and 24 weeks after LMW-HA or HMW-HA injection. The primary outcome was the visual analog scale (VAS) and others were the Oxford shoulder score (OSS), active ROM, and patient satisfaction. Results: No significant differences were detected in between-group variables at baseline. Within-group analysis showed VAS, OSS, and active ROM were markedly improved over time in both groups, also between-group analysis showed VAS and OSS decreased significantly ( P <0.001). Four-week follow-up showed the LMW-HA group had lower pain ( P = 0.049), conversely, the trend of VAS at 12 weeks and 24 weeks favors HMW-HA ( P <0.001). Regarding satisfaction, this parameter had significantly improved in both groups between four-, 12-, and 24 weeks. And there was no significant difference between groups. Conclusion: HMW-HA is a more effective intervention than LMW-HA in patients with AC. Adhesive capsulitis Hyaluronic acid Physical therapy Ultrasound-guided injection Frozen shoulder Introduction Adhesive capsulitis (AC) is a chronic inflammatory condition of the shoulder, characterized by deliberate progress in pain and stiffness of the glenohumeral joint ( 1 , 2 ). AC is a common ailment of the shoulder in 3–5% of the general population ( 3 , 4 ). The main goal in managing AC is reducing pain and returning to the natural function of the shoulder ( 5 ). Physical therapy (PT), physiotherapy, pharmacotherapy, and surgical interventions are the choices considered in the AC cases. The mainstays of pharmacotherapy interventions are non-steroidal anti-inflammatory drugs (NSAIDs), oral analgesics, and systemic or intra-articular corticosteroid (CS) injections ( 6 – 11 ). Intra-articular injection of HA has recently been considered as a safe modality in AC and common tendinopathies ( 12 – 14 ). The viscoelastic properties of HA have enabled the molecule to provide a suitable lubrication for proper movement while trapping the mechanical forces applied to the joint components ( 15 – 18 ). It also has anti-inflammatory properties, which are desirable in inflammatory conditions. However, there are differences between the effects of different HA products based on their molecular weight. Low molecular weight (LMW)-HA is those that weigh between 500 to 730 kDa, while those that are high in molecular weight, weigh over 2,000 kDa ( 12 , 16 , 19 , 20 ). Clinical studies on intra-articular injection of HA suggest that LMW-HA has greater penetration into the tissue, and high molecular weight (HMW)-HA has greater anti-inflammatory and longer duration of action ( 21 , 22 ). Up to now, there has been no study comparing the effectiveness of HMW-HA products with LMW-HA in AC. We hypothesize that the effects of these two products on pain, function, range of motion (ROM), patient satisfaction, and side effects are different. This clinical comparative study aimed to assess this hypothesis, this longitudinal study was designed to compare the clinical efficacy of HMW-HA and LMW-HA in two groups of patients with idiopathic AC. Methods Design and Setting This randomized, triple-blinded parallel clinical trial was conducted to clarify whether the clinical HMW-HA has more clinical benefits or LMW-HA, adhering to the consolidated standards of reporting trials 2022 (CONSORT) ( 23 ). Patients with idiopathic AC were selected from patients who visited the special physical medicine and rehabilitation clinic of Shahid Modarres Hospital between November 2018 and March 2022. The hospital is a referral center with a well-equipped setting in a rehabilitation clinic in Tehran, Iran. Ethical Considerations This study was performed following the Declaration of Helsinki ( 24 ). The study protocol received approval from the Institutional Review Board of Shahid Beheshti University of Medical Sciences (Code: IR.SBMU.PHARMACY.1397.084). The trial protocol was registered at the Iranian Registry of Clinical Trials (IRCT), a WHO Primary Register setup (registration No: IRCT20170608034390N4; First registration date: 01/01/2020), and was updated in October 2022. Eligibility Assessment and Recruitment Adults (18–65 years) with one-sided AC were included in this study. All patients underwent magnetic resonance imaging (MRI) and if they had AC for at least 3 months from the onset of pain were invited to be included. Pregnant or lactating women were not included. Patients with a history of traumatic injury to the shoulder, active tendonitis, and a history of rotator cuff (RC) tear in the last six months were excluded. In addition, patients who had used NSAIDs during the last week, and systemic or peri-articular injection of CS in the affected shoulder during the last two months were excluded. Participants with shoulder pain were selected from people who came to the clinic. All patients received verbal and in-print information about the process and purpose of the study. Patients were assured they could be excluded from the study at any time. In addition, all their questions were answered. When the physician made sure of the agreement of patients with the study protocol, asked them to fill out a written informed consent with a signature or fingerprint. A general practitioner and a resident of physical medicine and rehabilitation performed full physical examinations on the shoulders. Patients filled out a questionnaire for their medical and supplement history. According to eligibility criteria, an MRI scan of medical records was ordered. A blinded radiologist read all the scans. Then, the individual files were reviewed by two qualified physicians for a final decision on whether to enroll in the study. Interventions At first, the site of intra-articular shoulder injection was identified. The injection zone was disinfected with 10% polyvinylpyrrolidone iodine solution, and then one milliliter (mL) of HMW-HA (> 2000 kDa) (Viscor ®; Nikan Teb Kimia Pharmaceutical Co., Ltd. Iran) or LMW-HA (500–700 kDa) (Hyalgan®; Fidia Farmaceutici, Abano Terme, Italy) were injected. To decrease the pain at the injection site, 2 mL lidocaine 2% was injected in combination with the HAs. Outcome Measures and Follow-ups • Visual Analog Scale (VAS) The primary outcome was the VAS, which contains a straight line. The endpoints describe limits as “no pain” to “pain as bad as it could be”. Patients marked their pain level on the line between the two extremes. • Range of Motion (ROM) To evaluate the ROM of the affected joint, the angle of active abduction, flexion, internal rotation, and external rotation were measured by a standard goniometer. Patients move their arms in different directions and their movement angle is measured by the physician. • Oxford shoulder score (OSS) To investigate the function of patients, the OSS questionnaire was utilized, OSS contains 12 items, designed and developed for measuring the shoulder function. • Satisfaction Patients’ satisfaction was assessed based on the Likert numerical rating scale between one and five points. (One = Not satisfied at all, five = Completely satisfied). • Rigidity & Inflammation of Injection Site Patients were examined for rigidity, bruising, swelling, inflammation, and tenderness at the injection site one week after injection. • Follow-ups All participants were evaluated at baseline, 4, 12, and 24 weeks after injection. Sample Size Hao et al. reported that the minimum difference for a perceived improvement in pain score of shoulder disorders is 15% in a systematic review ( 25 ). Also, Tashjian et al. reported similar results about the minimum perceptible difference in pain of patients treated for RC disease ( 26 ). According to these reports, our research team decided to perform sample size calculations based on standardized effect sizes for a longitudinal research scenario. We calculated our study sample size for repeated-measures analysis of variance (ANOVA) of VAS data, including within-group and between-group analyses. Considering an average effect size of 20% for the F test, a 2-tailed P value of less than 0.05 as a statistically significant difference, a power of 80%, and a correlation between repeated measures of 0.3, and 4 times of measurement, we need 25 participants in each group. To ensure that the study would be sufficiently powered in the case of a 10% loss to follow-up samples three more subjects were added to each group and a total of 56 cases were allocated to be randomized with a 1:1 ratio. Randomization Patients were divided into two groups and to minimize covariate differences within groups, a web-based software ( www.sealedenvelope.com ) was applied for stratified block randomization ( 27 ). Diabetes considered as matching factor. Blinding Even though HMW-HA and LMW-HA were filled in the same shape syringes, the viscosity of the solutions was different. To solve this issue which could disturb the blinding of the study, it was decided to exclude the injecting physician from the process of eligibility assessments, treatment, and follow-ups. So eligible patients received a sealed envelope with a code written on it and, the injecting physician opened the envelope and did the injections. Physical Therapy All patients were trained to do specific stretching exercises of the shoulder at home. In this regard, Codman and posterior capsular stretch, arm overhead, twisting outward, hand behind back exercises twice a day with 10 repetitions each time. Patients with AC were in observation for 30 minutes after the injection in the clinic to monitor any important adverse events, including hypersensitivity and bleeding. Patients were advised to limit the use of the shoulder joint for 72 hours and not take a shower for 24 hours. Patients were only allowed to take acetaminophen 325 mg tablets as a painkiller if needed; however, they were not allowed to take any painkiller 24 hours before each follow-up visit. Injection Technique The need for proper needle placement in the intra-articular space for capsular dilation increases the importance of injection accuracy ( 28 ). Interventions guided with an ultrasound (US) are valuable because the needle can be followed in real-time during the procedure and no radiation or contrast agent is involved ( 29 ). In this study, the US-guided injections were performed from behind the shoulder with a 22-gauge spinal needle. The alpinion-E-cube 7 US device was used with a 3–12 MHz linear probe. The patient was sitting in such a way that the patient's involved hand was relaxed on his thigh. Injections were performed into the posterior surface of the humerus. S.A.R. did the injections, he has more than 10 years’ experience of intra-articular injection in the shoulder under US guidance. Figure 1 represents the injection site and US guidance. Statistical Analyses All statistical analyses were performed using SPSS software version 25. Parametric results were presented as the mean ± SD. Shapiro-Wilk test was used to assess the normal distribution of results. Paired sample t-tests were used to compare paired results. For non-parametric data, the Mann-Whitney signed rank test was used instead. To compare the pre-and post-injection data, within and between groups, repeated-measures ANOVA was used. Mauchly tests were utilized to assess the sphericity of the data for ANOVA, and if the violation of sphericity was assumed, for correcting the degrees of freedom, Lower-bound correction was used. Two-tailed P values of less than 0.05 ( P < 0.05) were interpreted as significant. Results In this study, 94 patients with unilateral shoulder pain were assessed based on the recruitment protocol, within them 56 patients were randomized to participate in HMW-HA or LMW-HA groups and 51 patients finalized the study per the designed protocol after 24 weeks’ follow-up. Figure 2 shows the CONSORT flow chart from the eligibility assessment to the week 24 visit. In this trial, the youngest participant was 37 and the oldest one was 65 years old. Table 1 shows and compares the baseline characteristics of patients in more detail. No significant difference was observed in the demographic characteristics of the patients at baseline. Table 1 Baseline characteristics of the participants in the groups. Feature Group P HMW-HA LMW-HA (n = 26) (n = 25) Women (%) 16 (64%) 18 (69%) 0.692 Duration (Month) 5.08 ± 1.38 4.77 ± 1.63 0.662 Age (Year) 51.84 ± 7.47 52.19 ± 8.29 0.715 Diabetes (%) 6(24%) 5 (19%) 0.679 CAD (%) 2 (8%) 3 (11%) 0.671 Right Affected side (%) 18 (76%) 19 (73%) 0.931 Hypothyroidism (%) 4 (15%) 4 (16%) 0.952 Tendonitis (%) 5 (19%) 5 (20%) 0.945 HMW-HA: High Molecular Weight Hyaluronic Acid, LMW-HA: Low Molecular Weight Hyaluronic Acid, CAD: Coronary Arterial Disease • Comparative Outcomes All parameters had improved significantly throughout the time in both groups. Table 2 compares within and between groups for VAS, active ROM (abduction, flexion, internal rotation, and external rotation), OSS, and patients’ satisfaction at baseline, 4-, 12- and 24 weeks after injection. Evaluation of shoulder pain showed that both interventions significantly healed the pain in a six-month time horizon. However, the results of pairwise comparisons show that the improvement of the pain index in six months is greater for HMW-HA than for LMW-HA, which does not have a statistically significant difference in the 4th and 12th -week follow-ups. Assessment of shoulder function and ability with OSS showed that HMW-HA was more effective in AC in all initial and long-term follow-ups. Concerning ROM indices only in abduction and flexion HMW-HA produced clinical advantages and in other subsets, no conclusive difference was observed in six-month follow-up in pairwise comparison analyses. Table 2 Between- and within-group analyses for changes in outcomes. HMW-HA (n = 26) LMW-HA (n = 25) Between Group Analysis ( P ) VAS (mean ± SD) Follow-ups Baseline 6.83 ± 1.30 6.64 ± 1.26 0.524 4th week 4.74 ± 1.05 3.91 ± 1.38 0.006 12th week 2.85 ± 1.03 3.05 ± 0.72 0.056 24th week 1.35 ± 0.93 2.73 ± 0.7 < 0.001 Within Group Analysis ( P ) < 0.001 0.001 Estimated Marginal Means 3.86 ± 0.13 4.26 ± 0.12 0.035 OSS (mean ± SD) Follow-ups Baseline 20.87 ± 1.60 20.59 ± 1.44 0.543 4th week 17.35 ± 1.40 17.95 ± 1.73 0.202 12th week 15.13 ± 1.32 16.23 ± 1.48 0.012 24th week 13.00 ± 1.24 14.23 ± 0.92 > 0.001 Within Group Analysis ( P ) < 0.001 < 0.001 Pairwise Comparisons Baseline to 4th week -3.52 ± 1.34 -2.64 ± 1.26 0.028 Baseline to 12th week -5.74 ± 2.03 -4.36 ± 1.43 0.012 Baseline to 24th week -7.87 ± 1.84 -6.36 ± 1.47 0.004 Estimated Marginal Means 16.59 ± 1.06 17.25 ± 1.07 0.044 Abduction Follow-ups Baseline 84.83 ± 12.63 85.55 ± 14.86 0.862 4th week 108.3 ± 7.95 112.01 ± 9.73 0.168 12th week 132.74 ± 10.49 130.0 ± 11.48 0.408 24th week 160.74 ± 9.26 148.68 ± 11.96 < 0.001 Within Group Analysis ( P ) < 0.001 < 0.001 Pairwise Comparisons Baseline to 4th week 23.48 ± 11.11 26.46 ± 11.70 0.385 Baseline to 12th week 47.91 ± 15.99 44.45 ± 18.39 0.504 Baseline to 24th week 75.91 ± 14.35 63.14 ± 18.40 0.013 Estimated Marginal Means 121.65 ± 7.87 119.06 ± 7.87 0.275 Flexion Follow-ups Baseline 94.22 ± 11.92 94.23 ± 15.01 0.998 4th week 118.48 ± 14.72 120.27 ± 13.69 0.675 12th week 138.35 ± 13.09 134.27 ± 13.06 0.302 24th week 166.70 ± 7.32 157.0 ± 11.80 0.002 Within Group Analysis ( P ) < 0.001 < 0.001 Pairwise Comparisons Baseline to 4th week 24.26 ± 12.15 26.05 ± 12.44 0.629 Baseline to 12th week 44.13 ± 13.10 40.05 ± 16.77 0.366 Baseline to 24th week 72.48 ± 11.10 62.77 ± 15.21 0.018 Estimated Marginal Means 129.43 ± 10.62 126.44 ± 10.62 0.35 Internal Rotation Follow-ups Baseline 27.26 ± 6.31 25.50 ± 7.46 0.425 4th week 34.26 ± 7.57 35.59 ± 9.62 0.395 12th week 43.17 ± 10.45 45.41 ± 11.47 0.72 24th week 58.48 ± 9.30 57.55 ± 10.96 0.42 Within Group Analysis ( P ) < 0.001 < 0.001 Pairwise Comparisons Baseline to 4th week 7.00 ± 5.34 10.09 ± 5.39 0.06 Baseline to 12th week 15.91 ± 8.50 19.91 ± 10.15 0.159 Baseline to 24th week 31.22 ± 7.63 32.05 ± 10.13 0.758 Estimated Marginal Means 40.79 ± 8.18 40.01 ± 8.17 0.929 External Rotation Follow-ups Baseline 26.57 ± 5.71 27.41 ± 7.27 0.667 4th week 38.52 ± 7.51 41.50 ± 9.84 0.259 12th week 54.04 ± 10.59 53.27 ± 11.28 0.814 24th week 68.91 ± 9.95 69.50 ± 12.58 0.863 Within Group Analysis ( P ) < 0.001 < 0.001 Pairwise Comparisons Baseline to 4th week 11.96 ± 5.80 14.09 ± 5.89 0.227 Baseline to 12th week 27.48 ± 9.09 25.86 ± 10.78 0.589 Baseline to 24th week 42.35 ± 9.71 42.09 ± 12.16 0.938 Estimated Marginal Means 47.01 ± 7.88 47.92 ± 7.88 0.701 Satisfaction Follow-ups 4th week 3.30 ± 1.02 3.41 ± 1.10 0.742 12th week 3.70 ± 1.18 3.68 ± 1.29 0.97 24th week 4.56 ± 0.84 4.14 ± 1.09 0.144 Within Group Analysis ( P ) < 0.001 < 0.001 Pairwise Comparisons Baseline to 12th week 0.39 ± 0.66 0.27 ± 0.77 0.58 Baseline to 24th week 1.26 ± 0.69 0.73 ± 0.63 0.01 Estimated Marginal Means 3.85 ± 0.95 3.74 ± 1.09 0.713 VAS: Visual analog scale/ OSS: Oxford shoulder score. Based on the evaluation of the 5-point Likert spectrum, in both groups, patients were highly satisfied with the intervention performed to manage AC, and intergroup analyzes did not reveal any difference between LMW-HA and HMW-HA. After 24 weeks, there was a significant improvement in VAS and OSS in the HMW-HA group compared with the LMW-HA group. Figure 3 and Fig. 4 visualize improvement in the primary outcome and OSS which show the positive impact of molecular weight of the HA on pain and disability reduction in idiopathic AC. • Adverse Events (AEs) One week after injection six patients (four in the HMW-HA and two in the LMW-HA group) reported rigidity ( P = 0.413) and seven participants (five in the HMW-HA and two in the LMW-HA group) described inflammation in the injection site ( P = 0.242). There were no serious AEs reported in either group. Three patients in HMW-HA and one in LMW-HA had more than 2 weeks of rigidity or swelling, however, they became better 4 weeks after injection ( P = 0.317). Discussion This study is the first clinical trial that compares the efficacy of US-guided intra-articular injection of HMW-HA and LMW-HA in idiopathic AC. To find any discrepancies in clinical outcomes, shoulder pain, disability, ROM, and patient satisfaction were assessed in both groups. In this study, results show that in all parameters, there were no significant differences between the HMW-HA group and the LMW-HA group at baseline. In addition, between the HMW-HA group and the LMW-HA group, there were significant differences in reducing shoulder pain and disability and achieving normal performance with slight AEs. There were no significant differences in increasing the range of internal and external rotation between the HMW-HA and the LMW-HA group. Results showed that the HMW-HA and the LMW-HA group similarly increased satisfaction. Although participants had just one injection, both HMW-HA and LMW-HA were effective for the treatment of AC after 6 months based on all monitored parameters. While proving part of our hypothesis that the HMW-HA and LMW-HA are significantly different in improving pain and function, the results refute the part that includes the difference between them in ROM, patient satisfaction, and the incidence of AEs. Evidence also suggested that AEs including pain, stiffness, and inflammation at the injection site were less common in LMW-HA. Some trials confirm the results of this study. Most of them did not report the molecular weight of HA or just declare the high or low molecular weight terms. Hsieh et al. compared the effect of HA with PT and PT alone for the management of AC. A total of 70 patients were randomly allocated to 2 groups of 35 participants. All participants had one-hour training for 12 weeks (3 sessions per week) and HA with PT group received 20mg HA injection for 3 times (one per week). Disability was decreased significantly in both groups 3 months after injection. In 3 months after treatment ROM (abduction, flexion, internal rotation, external rotation) was improved significantly however, there were no significant differences between groups. In a randomized clinical trial and placebo-controlled, 90 patients (95 shoulders) with AC were included. They were randomly divided into 4 groups. Patients in group 1 received 30mg of HA (1000–2900 kDa) weekly for 2 weeks. In the CS group, patients received 40mg of triamcinolone acetonide once. In the PT group, participants had a hot pack for 20 minutes, ultrasonic therapy for 5 minutes, and transcutaneous electrical nerve stimulation (TENS) for 20 minutes. They received this pack for 10 days. The control group and all participants had Stretching and Codman exercises at home. After 3 months, pain reduced significantly in the HA group compared with the control group. In addition, abduction was significantly increased in the HA group compared with the control group after 3 months ( 30 ). In Rovetta and Monteforte trial, 30 participants were randomly divided into two groups; one group received a combination of 20mg HA and CS (20mg Triamcinolone acetonide) intra-articular injection with PT (for 4–12 weeks) and the other group received CS with PT. After 6 months, pain and joint motion in all patients especially in the HMW-HA group. They reported no severe AEs ( 31 ). This study shows that with one injection of HA over 6 months, the parameters of pain, shoulder joint function, ROM, and satisfaction improved significantly. Therefore, injection of HA in the intra-articular space is effective in reducing pain and improving the function of patients with AC. By analyzing the amount of side effects, it was observed that no specific long-term, no-return, or debilitating side effects of HA were reported. There was no significant difference in the rigidity and inflammation, but the small amount of inflammation and stiffness observed were higher in the HMW-HA group. It is probably due to its viscosity. Declarations Ethics approval The Ethics Committee approved this study of the Faculty of Pharmacy of Shahid Beheshti University of Medical Sciences with the ethics code IR.SBMU.PHARMACY.1397.084. a. Ethics approval and consent to participate This clinical study was approved by the institutional review board of ethics of our Shahid Beheshti Medical University, Tehran, Iran, on September 2021 (IR.SBMU.PHARMACY.1397.084). Also, the study was registered in the Iranian Registry of Clinical Trials database (https://irct.behdasht.gov.ir/trial/37113; IRCT registration number: IRCT20170608034390N9) b. Consent for publication Not applicable. c. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. d. Competing interests The authors did not declare any competing interests related to the study results. e. Funding This study was financially supported by the research committee of Shahid Beheshti University of Medical Sciences, Tehran, Iran. f. Authors' contributions H.E. and R.M. generated a novel idea and presented a proposal, A.R. and M.M. recruited the eligible patients, G.M., A.R. and H.E. analyzed and interpreted the data, H.E. and R.M. drafted an initial report, M.M. and A.R. wrote the main manuscript text and H.E. prepared figures 1-3. All authors reviewed the manuscript. g. Acknowledgments We thank the research committee of Shahid Beheshti University of Medical Sciences for the financial support of this study. References Papalexis N, Parmeggiani A, Facchini G, Miceli M, Carbone G, Cavallo M et al. 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The Effect of Intra-articular Injection of Hyaluronic Acid in Frozen Shoulder: a Systematic Review and Meta-analysis of Randomized Controlled Trials. J Orthop Surg Res [Internet]. 2022 Dec 1 [cited 2024 Apr 8];17(1):1–10. https://link.springer.com/articles/ 10.1186/s13018-022-03017-4 . Rezasoltani Z, Esmaily H, Dadarkhah A, Rousta M, Mohebbi R, Vashaei F. Low Molecular-weight Hyaluronic Acid Versus Physiotherapy for the Treatment of Supraspinatus Tendinopathy: A Randomized Comparative Clinical Trial. Journal of the American Academy of Orthopaedic Surgeons [Internet]. 2021 Oct 1 [cited 2024 Apr 8];29(19):E979–92. https://journals.lww.com/jaaos/fulltext/2021/10010/low_molecular_weight_hyaluronic_acid_versus.11.aspx . Migliore A, Blicharski T, Plebanski R, Zegota Z, Gyula G, Rannou F et al. Knee Osteoarthritis Pain Management with an Innovative High and Low Molecular Weight Hyaluronic Acid Formulation (HA-HL): A Randomized Clinical Trial. 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Journal of Functional Morphology and Kinesiology. 2022, Vol 7, Page 3 [Internet]. 2021 Dec 29 [cited 2024 Apr 8];7(1):3. https://www.mdpi.com/2411-5142/7/1/3/htm . Butcher NJ, Monsour A, Mew EJ, Chan AW, Moher D, Mayo-Wilson E et al. Guidelines for Reporting Outcomes in Trial Reports: The CONSORT-Outcomes 2022 Extension. JAMA [Internet]. 2022 Dec 13 [cited 2023 Aug 19];328(22):2252–64. https://jamanetwork.com/journals/jama/fullarticle/2799401 . WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects – WMA. – The World Medical Association [Internet]. [cited 2022 Jan 28]. https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/ . Hao Q, Devji T, Zeraatkar D, Wang Y, Qasim A, Siemieniuk RAC et al. Minimal important differences for improvement in shoulder condition patient-reported outcomes: a systematic review to inform a BMJ Rapid Recommendation. BMJ Open [Internet]. 2019 Feb 1 [cited 2024 Apr 8];9(2):e028777. https://bmjopen.bmj.com/content/9/2/e028777 . Tashjian RZ, Shin J, Broschinsky K, Yeh CC, Martin B, Chalmers PN et al. Minimal clinically important differences in the American Shoulder and Elbow Surgeons, Simple Shoulder Test, and visual analog scale pain scores after arthroscopic rotator cuff repair. J Shoulder Elbow Surg [Internet]. 2020 Jul 1 [cited 2024 Apr 8];29(7):1406–11. https://pubmed.ncbi.nlm.nih.gov/32081634/ . Sealed Envelope |. Randomisation (randomization) and online databases for clinical trials [Internet]. [cited 2023 Sep 24]. https://www.sealedenvelope.com/ . Andrén L, Lundberg BJ. Treatment of rigid shoulders by joint distension during arthrography. Acta Orthop. 1965;36(1):45–53. Zwar RB, Read JW, Noakes JB. Sonographically guided glenohumeral joint injection. Am J Roentgenol 183(1):48–50. Calis M, Demir H, Ulker S, Kirnap M, Duygulu F, Calis HT. Is intraarticular sodium hyaluronate injection an alternative treatment in patients with adhesive capsulitis? Rheumatol Int. 2006;26(6):536–40. Rovetta G, Monteforte P. Intraarticular injection of sodium hyaluronate plus steroid versus steroid in adhesive capsulitis of the shoulder. Int J Tissue React. 1998;20(4):125–30. Park KD, Nam HS, Lee JK, Kim YJ, Park Y. Treatment effects of ultrasound-guided capsular distension with hyaluronic acid in adhesive capsulitis of the shoulder. Arch Phys Med Rehabil. 2013;94(2):264–70. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4265513","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":296813982,"identity":"c693e8cd-69e1-47fb-b2e5-d8d2279bd348","order_by":0,"name":"Mahshad Mir","email":"","orcid":"","institution":"Shahid Beheshti University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Mahshad","middleName":"","lastName":"Mir","suffix":""},{"id":296813983,"identity":"6e28519f-9369-457f-807b-c200a7ea5e6b","order_by":1,"name":"Rezvaneh Mohebbi","email":"","orcid":"","institution":"Shahid Beheshti University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Rezvaneh","middleName":"","lastName":"Mohebbi","suffix":""},{"id":296813984,"identity":"716ae70f-c612-48b4-8e4d-cc514e1fae75","order_by":2,"name":"Ghader Mohammadnezhad","email":"","orcid":"","institution":"Shahid Beheshti University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Ghader","middleName":"","lastName":"Mohammadnezhad","suffix":""},{"id":296813985,"identity":"5209cda9-320f-4e14-88ab-34f8ee5460a2","order_by":3,"name":"Ahmad Raeissadat","email":"","orcid":"","institution":"Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Ahmad","middleName":"","lastName":"Raeissadat","suffix":""},{"id":296813986,"identity":"a5992a65-cc44-4eac-8946-4b5f4da1c90c","order_by":4,"name":"Alireza Parhizgar","email":"","orcid":"","institution":"The University of Texas, MD Anderson Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Alireza","middleName":"","lastName":"Parhizgar","suffix":""},{"id":296813990,"identity":"d5291b62-65ef-4ea9-981e-10534b012fa1","order_by":5,"name":"Hadi Esmaily","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA60lEQVRIiWNgGAWjYBAC+wYgkVDAwGAARAc+ANkEtRiAiAQDiJaDM4jWwgDVwsxDlBb+04kfHhgcZjBnP7zxsG2bXR4/ewPjh485ePwikbtZIgGoxbInreBwbltysWTPAWbJmdvw2CLBuwGsxeBAjgFQC3PihhsJbMy8+LTwn938A6zl/BuDw5Zt9URoYcjdBrHlBtAWxrbDRGiRyN1mkWCQDtTyrOBgz7njiTN7Djbj9Yt9/9nNN39UWAMdlrz5w4+y6sR+9uaDHz7i0QIFzfUNIIqRDUw2EFQPBHVQ+g8xikfBKBgFo2CkAQAVWFiCSAFB6AAAAABJRU5ErkJggg==","orcid":"","institution":"Shahid Beheshti University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Hadi","middleName":"","lastName":"Esmaily","suffix":""}],"badges":[],"createdAt":"2024-04-14 15:14:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4265513/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4265513/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57658409,"identity":"4c79aafe-2b56-4386-b32c-cfd767956265","added_by":"auto","created_at":"2024-06-04 02:31:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1133583,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4265513/v1/5b690784-b611-467d-b888-6fcb447d25c3.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparative Effectiveness and Safety of Intra-articular Injection of High versus Low Molecular Weight Hyaluronic Acid in Idiopathic Adhesive Capsulitis; A Randomized Clinical Trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAdhesive capsulitis (AC) is a chronic inflammatory condition of the shoulder, characterized by deliberate progress in pain and stiffness of the glenohumeral joint (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). AC is a common ailment of the shoulder in 3\u0026ndash;5% of the general population (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). The main goal in managing AC is reducing pain and returning to the natural function of the shoulder (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Physical therapy (PT), physiotherapy, pharmacotherapy, and surgical interventions are the choices considered in the AC cases. The mainstays of pharmacotherapy interventions are non-steroidal anti-inflammatory drugs (NSAIDs), oral analgesics, and systemic or intra-articular corticosteroid (CS) injections (\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIntra-articular injection of HA has recently been considered as a safe modality in AC and common tendinopathies (\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). The viscoelastic properties of HA have enabled the molecule to provide a suitable lubrication for proper movement while trapping the mechanical forces applied to the joint components (\u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). It also has anti-inflammatory properties, which are desirable in inflammatory conditions. However, there are differences between the effects of different HA products based on their molecular weight. Low molecular weight (LMW)-HA is those that weigh between 500 to 730 kDa, while those that are high in molecular weight, weigh over 2,000 kDa (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Clinical studies on intra-articular injection of HA suggest that LMW-HA has greater penetration into the tissue, and high molecular weight (HMW)-HA has greater anti-inflammatory and longer duration of action (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eUp to now, there has been no study comparing the effectiveness of HMW-HA products with LMW-HA in AC. We hypothesize that the effects of these two products on pain, function, range of motion (ROM), patient satisfaction, and side effects are different. This clinical comparative study aimed to assess this hypothesis, this longitudinal study was designed to compare the clinical efficacy of HMW-HA and LMW-HA in two groups of patients with idiopathic AC.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDesign and Setting\u003c/h2\u003e \u003cp\u003eThis randomized, triple-blinded parallel clinical trial was conducted to clarify whether the clinical HMW-HA has more clinical benefits or LMW-HA, adhering to the consolidated standards of reporting trials 2022 (CONSORT) (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Patients with idiopathic AC were selected from patients who visited the special physical medicine and rehabilitation clinic of Shahid Modarres Hospital between November 2018 and March 2022. The hospital is a referral center with a well-equipped setting in a rehabilitation clinic in Tehran, Iran.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEthical Considerations\u003c/h2\u003e \u003cp\u003eThis study was performed following the Declaration of Helsinki (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). The study protocol received approval from the Institutional Review Board of Shahid Beheshti University of Medical Sciences (Code: IR.SBMU.PHARMACY.1397.084). The trial protocol was registered at the Iranian Registry of Clinical Trials (IRCT), a WHO Primary Register setup (registration No: IRCT20170608034390N4; First registration date: 01/01/2020), and was updated in October 2022.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eEligibility Assessment and Recruitment\u003c/h2\u003e \u003cp\u003eAdults (18\u0026ndash;65 years) with one-sided AC were included in this study. All patients underwent magnetic resonance imaging (MRI) and if they had AC for at least 3 months from the onset of pain were invited to be included. Pregnant or lactating women were not included. Patients with a history of traumatic injury to the shoulder, active tendonitis, and a history of rotator cuff (RC) tear in the last six months were excluded. In addition, patients who had used NSAIDs during the last week, and systemic or peri-articular injection of CS in the affected shoulder during the last two months were excluded.\u003c/p\u003e \u003cp\u003eParticipants with shoulder pain were selected from people who came to the clinic. All patients received verbal and in-print information about the process and purpose of the study. Patients were assured they could be excluded from the study at any time. In addition, all their questions were answered. When the physician made sure of the agreement of patients with the study protocol, asked them to fill out a written informed consent with a signature or fingerprint. A general practitioner and a resident of physical medicine and rehabilitation performed full physical examinations on the shoulders. Patients filled out a questionnaire for their medical and supplement history. According to eligibility criteria, an MRI scan of medical records was ordered. A blinded radiologist read all the scans. Then, the individual files were reviewed by two qualified physicians for a final decision on whether to enroll in the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eInterventions\u003c/h2\u003e \u003cp\u003eAt first, the site of intra-articular shoulder injection was identified. The injection zone was disinfected with 10% polyvinylpyrrolidone iodine solution, and then one milliliter (mL) of HMW-HA (\u0026gt;\u0026thinsp;2000 kDa) (Viscor \u0026reg;; Nikan Teb Kimia Pharmaceutical Co., Ltd. Iran) or LMW-HA (500\u0026ndash;700 kDa) (Hyalgan\u0026reg;; Fidia Farmaceutici, Abano Terme, Italy) were injected. To decrease the pain at the injection site, 2 mL lidocaine 2% was injected in combination with the HAs.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eOutcome Measures and Follow-ups\u003c/h2\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003ch2\u003e\u0026bull; Visual Analog Scale (VAS)\u003c/h2\u003e \u003cp\u003eThe primary outcome was the VAS, which contains a straight line. The endpoints describe limits as \u0026ldquo;no pain\u0026rdquo; to \u0026ldquo;pain as bad as it could be\u0026rdquo;. Patients marked their pain level on the line between the two extremes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003e\u0026bull; Range of Motion (ROM)\u003c/h2\u003e \u003cp\u003eTo evaluate the ROM of the affected joint, the angle of active abduction, flexion, internal rotation, and external rotation were measured by a standard goniometer. Patients move their arms in different directions and their movement angle is measured by the physician.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e\u0026bull; Oxford shoulder score (OSS)\u003c/h2\u003e \u003cp\u003eTo investigate the function of patients, the OSS questionnaire was utilized, OSS contains 12 items, designed and developed for measuring the shoulder function.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e\u0026bull; Satisfaction\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003ePatients\u0026rsquo; satisfaction was assessed based on the Likert numerical rating scale between one and five points. (One\u0026thinsp;=\u0026thinsp;Not satisfied at all, five\u0026thinsp;=\u0026thinsp;Completely satisfied).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e\u0026bull; Rigidity \u0026amp; Inflammation of Injection Site\u003c/h2\u003e \u003cp\u003ePatients were examined for rigidity, bruising, swelling, inflammation, and tenderness at the injection site one week after injection.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e\u0026bull; Follow-ups\u003c/h2\u003e \u003cp\u003eAll participants were evaluated at baseline, 4, 12, and 24 weeks after injection.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eSample Size\u003c/h2\u003e \u003cp\u003eHao et al. reported that the minimum difference for a perceived improvement in pain score of shoulder disorders is 15% in a systematic review (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Also, Tashjian et al. reported similar results about the minimum perceptible difference in pain of patients treated for RC disease (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). According to these reports, our research team decided to perform sample size calculations based on standardized effect sizes for a longitudinal research scenario. We calculated our study sample size for repeated-measures analysis of variance (ANOVA) of VAS data, including within-group and between-group analyses. Considering an average effect size of 20% for the F test, a 2-tailed P value of less than 0.05 as a statistically significant difference, a power of 80%, and a correlation between repeated measures of 0.3, and 4 times of measurement, we need 25 participants in each group. To ensure that the study would be sufficiently powered in the case of a 10% loss to follow-up samples three more subjects were added to each group and a total of 56 cases were allocated to be randomized with a 1:1 ratio.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eRandomization\u003c/h2\u003e \u003cp\u003ePatients were divided into two groups and to minimize covariate differences within groups, a web-based software (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.sealedenvelope.com\" target=\"_blank\"\u003ewww.sealedenvelope.com\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.sealedenvelope.com\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) was applied for stratified block randomization (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Diabetes considered as matching factor.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eBlinding\u003c/h2\u003e \u003cp\u003eEven though HMW-HA and LMW-HA were filled in the same shape syringes, the viscosity of the solutions was different. To solve this issue which could disturb the blinding of the study, it was decided to exclude the injecting physician from the process of eligibility assessments, treatment, and follow-ups. So eligible patients received a sealed envelope with a code written on it and, the injecting physician opened the envelope and did the injections.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003ePhysical Therapy\u003c/h2\u003e \u003cp\u003eAll patients were trained to do specific stretching exercises of the shoulder at home. In this regard, Codman and posterior capsular stretch, arm overhead, twisting outward, hand behind back exercises twice a day with 10 repetitions each time. Patients with AC were in observation for 30 minutes after the injection in the clinic to monitor any important adverse events, including hypersensitivity and bleeding. Patients were advised to limit the use of the shoulder joint for 72 hours and not take a shower for 24 hours. Patients were only allowed to take acetaminophen 325 mg tablets as a painkiller if needed; however, they were not allowed to take any painkiller 24 hours before each follow-up visit.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eInjection Technique\u003c/h2\u003e \u003cp\u003eThe need for proper needle placement in the intra-articular space for capsular dilation increases the importance of injection accuracy (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). Interventions guided with an ultrasound (US) are valuable because the needle can be followed in real-time during the procedure and no radiation or contrast agent is involved (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). In this study, the US-guided injections were performed from behind the shoulder with a 22-gauge spinal needle. The alpinion-E-cube 7 US device was used with a 3\u0026ndash;12 MHz linear probe. The patient was sitting in such a way that the patient's involved hand was relaxed on his thigh. Injections were performed into the posterior surface of the humerus. S.A.R. did the injections, he has more than 10 years\u0026rsquo; experience of intra-articular injection in the shoulder under US guidance. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e represents the injection site and US guidance.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section3\"\u003e \u003ch2\u003eStatistical Analyses\u003c/h2\u003e \u003cp\u003eAll statistical analyses were performed using SPSS software version 25. Parametric results were presented as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD. Shapiro-Wilk test was used to assess the normal distribution of results. Paired sample t-tests were used to compare paired results. For non-parametric data, the Mann-Whitney signed rank test was used instead. To compare the pre-and post-injection data, within and between groups, repeated-measures ANOVA was used. Mauchly tests were utilized to assess the sphericity of the data for ANOVA, and if the violation of sphericity was assumed, for correcting the degrees of freedom, Lower-bound correction was used. Two-tailed \u003cem\u003eP\u003c/em\u003e values of less than 0.05 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) were interpreted as significant.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eIn this study, 94 patients with unilateral shoulder pain were assessed based on the recruitment protocol, within them 56 patients were randomized to participate in HMW-HA or LMW-HA groups and 51 patients finalized the study per the designed protocol after 24 weeks\u0026rsquo; follow-up. Figure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e shows the CONSORT flow chart from the eligibility assessment to the week 24 visit.\u003c/p\u003e\n\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\n\u003cp\u003eIn this trial, the youngest participant was 37 and the oldest one was 65 years old. Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e shows and compares the baseline characteristics of patients in more detail. No significant difference was observed in the demographic characteristics of the patients at baseline.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBaseline characteristics of the participants in the groups.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eFeature\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eGroup\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eHMW-HA\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eLMW-HA\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;25)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWomen (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16 (64%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (69%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.692\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDuration (Month)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.08\u0026thinsp;\u0026plusmn;\u0026thinsp;1.38\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.77\u0026thinsp;\u0026plusmn;\u0026thinsp;1.63\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.662\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge (Year)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e51.84\u0026thinsp;\u0026plusmn;\u0026thinsp;7.47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52.19\u0026thinsp;\u0026plusmn;\u0026thinsp;8.29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.715\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiabetes (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6(24%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (19%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.679\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCAD (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (11%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.671\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRight Affected side (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (76%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19 (73%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.931\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHypothyroidism (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (15%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (16%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.952\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTendonitis (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (19%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (20%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.945\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eHMW-HA: High Molecular Weight Hyaluronic Acid, LMW-HA: Low Molecular Weight Hyaluronic Acid, CAD: Coronary Arterial Disease\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec23\" class=\"Section3\"\u003e\n\u003ch2\u003e\u0026bull; Comparative Outcomes\u003c/h2\u003e\n\u003cdiv id=\"Sec24\" class=\"Section4\"\u003e\n\u003cp\u003eAll parameters had improved significantly throughout the time in both groups. Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e compares within and between groups for VAS, active ROM (abduction, flexion, internal rotation, and external rotation), OSS, and patients\u0026rsquo; satisfaction at baseline, 4-, 12- and 24 weeks after injection. Evaluation of shoulder pain showed that both interventions significantly healed the pain in a six-month time horizon. However, the results of pairwise comparisons show that the improvement of the pain index in six months is greater for HMW-HA than for LMW-HA, which does not have a statistically significant difference in the 4th and 12th -week follow-ups. Assessment of shoulder function and ability with OSS showed that HMW-HA was more effective in AC in all initial and long-term follow-ups. Concerning ROM indices only in abduction and flexion HMW-HA produced clinical advantages and in other subsets, no conclusive difference was observed in six-month follow-up in pairwise comparison analyses.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBetween- and within-group analyses for changes in outcomes.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eHMW-HA (n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eLMW-HA (n\u0026thinsp;=\u0026thinsp;25)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eBetween Group Analysis (\u003cem\u003eP\u003c/em\u003e)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eVAS (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-ups\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e6.83\u0026thinsp;\u0026plusmn;\u0026thinsp;1.30\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e6.64\u0026thinsp;\u0026plusmn;\u0026thinsp;1.26\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e0.524\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e4th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e4.74\u0026thinsp;\u0026plusmn;\u0026thinsp;1.05\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e3.91\u0026thinsp;\u0026plusmn;\u0026thinsp;1.38\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e0.006\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e12th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e2.85\u0026thinsp;\u0026plusmn;\u0026thinsp;1.03\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e3.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.72\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e0.056\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e24th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e1.35\u0026thinsp;\u0026plusmn;\u0026thinsp;0.93\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e2.73\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eWithin Group Analysis (\u003c/strong\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePairwise Comparisons\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline to 4th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-2.09\u0026thinsp;\u0026plusmn;\u0026thinsp;1.16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-2.73\u0026thinsp;\u0026plusmn;\u0026thinsp;1.58\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.128\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline to 12th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-3.98\u0026thinsp;\u0026plusmn;\u0026thinsp;1.34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-3.59\u0026thinsp;\u0026plusmn;\u0026thinsp;1.44\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.105\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline to 24th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-5.48\u0026thinsp;\u0026plusmn;\u0026thinsp;1.68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-3.91\u0026thinsp;\u0026plusmn;\u0026thinsp;1.31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eEstimated Marginal Means\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.86\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.035\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eOSS (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-ups\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20.87\u0026thinsp;\u0026plusmn;\u0026thinsp;1.60\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20.59\u0026thinsp;\u0026plusmn;\u0026thinsp;1.44\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.543\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e4th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.35\u0026thinsp;\u0026plusmn;\u0026thinsp;1.40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.95\u0026thinsp;\u0026plusmn;\u0026thinsp;1.73\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.202\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e12th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15.13\u0026thinsp;\u0026plusmn;\u0026thinsp;1.32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.23\u0026thinsp;\u0026plusmn;\u0026thinsp;1.48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.012\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e24th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13.00\u0026thinsp;\u0026plusmn;\u0026thinsp;1.24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.92\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eWithin Group Analysis (\u003c/strong\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePairwise Comparisons\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline to 4th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-3.52\u0026thinsp;\u0026plusmn;\u0026thinsp;1.34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-2.64\u0026thinsp;\u0026plusmn;\u0026thinsp;1.26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.028\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline to 12th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-5.74\u0026thinsp;\u0026plusmn;\u0026thinsp;2.03\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-4.36\u0026thinsp;\u0026plusmn;\u0026thinsp;1.43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.012\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline to 24th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-7.87\u0026thinsp;\u0026plusmn;\u0026thinsp;1.84\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-6.36\u0026thinsp;\u0026plusmn;\u0026thinsp;1.47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.004\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eEstimated Marginal Means\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.59\u0026thinsp;\u0026plusmn;\u0026thinsp;1.06\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.25\u0026thinsp;\u0026plusmn;\u0026thinsp;1.07\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.044\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAbduction\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-ups\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e84.83\u0026thinsp;\u003cstrong\u003e\u0026plusmn;\u003c/strong\u003e\u0026thinsp;12.63\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e85.55\u0026thinsp;\u0026plusmn;\u0026thinsp;14.86\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.862\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e4th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e108.3\u0026thinsp;\u0026plusmn;\u0026thinsp;7.95\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e112.01\u0026thinsp;\u0026plusmn;\u0026thinsp;9.73\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.168\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e12th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e132.74\u0026thinsp;\u0026plusmn;\u0026thinsp;10.49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e130.0\u0026thinsp;\u0026plusmn;\u0026thinsp;11.48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.408\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e24th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e160.74\u0026thinsp;\u0026plusmn;\u0026thinsp;9.26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e148.68\u0026thinsp;\u0026plusmn;\u0026thinsp;11.96\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eWithin Group Analysis (\u003c/strong\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePairwise Comparisons\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline to 4th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23.48\u0026thinsp;\u0026plusmn;\u0026thinsp;11.11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26.46\u0026thinsp;\u0026plusmn;\u0026thinsp;11.70\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.385\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline to 12th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47.91\u0026thinsp;\u0026plusmn;\u0026thinsp;15.99\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e44.45\u0026thinsp;\u0026plusmn;\u0026thinsp;18.39\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.504\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline to 24th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e75.91\u0026thinsp;\u0026plusmn;\u0026thinsp;14.35\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e63.14\u0026thinsp;\u0026plusmn;\u0026thinsp;18.40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.013\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eEstimated Marginal Means\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e121.65\u0026thinsp;\u0026plusmn;\u0026thinsp;7.87\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e119.06\u0026thinsp;\u0026plusmn;\u0026thinsp;7.87\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.275\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFlexion\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-ups\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e94.22\u0026thinsp;\u0026plusmn;\u0026thinsp;11.92\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e94.23\u0026thinsp;\u0026plusmn;\u0026thinsp;15.01\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.998\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e4th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e118.48\u0026thinsp;\u0026plusmn;\u0026thinsp;14.72\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e120.27\u0026thinsp;\u0026plusmn;\u0026thinsp;13.69\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.675\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e12th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e138.35\u0026thinsp;\u0026plusmn;\u0026thinsp;13.09\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e134.27\u0026thinsp;\u0026plusmn;\u0026thinsp;13.06\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.302\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e24th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e166.70\u0026thinsp;\u0026plusmn;\u0026thinsp;7.32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e157.0\u0026thinsp;\u0026plusmn;\u0026thinsp;11.80\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.002\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eWithin Group Analysis (\u003c/strong\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePairwise Comparisons\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline to 4th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24.26\u0026thinsp;\u0026plusmn;\u0026thinsp;12.15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26.05\u0026thinsp;\u0026plusmn;\u0026thinsp;12.44\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.629\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline to 12th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e44.13\u0026thinsp;\u0026plusmn;\u0026thinsp;13.10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40.05\u0026thinsp;\u0026plusmn;\u0026thinsp;16.77\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.366\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline to 24th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e72.48\u0026thinsp;\u0026plusmn;\u0026thinsp;11.10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e62.77\u0026thinsp;\u0026plusmn;\u0026thinsp;15.21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.018\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eEstimated Marginal Means\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e129.43\u0026thinsp;\u0026plusmn;\u0026thinsp;10.62\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e126.44\u0026thinsp;\u0026plusmn;\u0026thinsp;10.62\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.35\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eInternal Rotation\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-ups\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27.26\u0026thinsp;\u0026plusmn;\u0026thinsp;6.31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25.50\u0026thinsp;\u0026plusmn;\u0026thinsp;7.46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.425\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e4th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34.26\u0026thinsp;\u0026plusmn;\u0026thinsp;7.57\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35.59\u0026thinsp;\u0026plusmn;\u0026thinsp;9.62\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.395\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e12th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e43.17\u0026thinsp;\u0026plusmn;\u0026thinsp;10.45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45.41\u0026thinsp;\u0026plusmn;\u0026thinsp;11.47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.72\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e24th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e58.48\u0026thinsp;\u0026plusmn;\u0026thinsp;9.30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e57.55\u0026thinsp;\u0026plusmn;\u0026thinsp;10.96\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.42\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eWithin Group Analysis (\u003c/strong\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePairwise Comparisons\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline to 4th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.00\u0026thinsp;\u0026plusmn;\u0026thinsp;5.34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.09\u0026thinsp;\u0026plusmn;\u0026thinsp;5.39\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.06\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline to 12th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15.91\u0026thinsp;\u0026plusmn;\u0026thinsp;8.50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19.91\u0026thinsp;\u0026plusmn;\u0026thinsp;10.15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.159\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline to 24th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31.22\u0026thinsp;\u0026plusmn;\u0026thinsp;7.63\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32.05\u0026thinsp;\u0026plusmn;\u0026thinsp;10.13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.758\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eEstimated Marginal Means\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40.79\u0026thinsp;\u0026plusmn;\u0026thinsp;8.18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40.01\u0026thinsp;\u0026plusmn;\u0026thinsp;8.17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.929\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eExternal Rotation\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-ups\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26.57\u0026thinsp;\u0026plusmn;\u0026thinsp;5.71\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27.41\u0026thinsp;\u0026plusmn;\u0026thinsp;7.27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.667\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e4th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e38.52\u0026thinsp;\u0026plusmn;\u0026thinsp;7.51\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41.50\u0026thinsp;\u0026plusmn;\u0026thinsp;9.84\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.259\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e12th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54.04\u0026thinsp;\u0026plusmn;\u0026thinsp;10.59\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e53.27\u0026thinsp;\u0026plusmn;\u0026thinsp;11.28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.814\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e24th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e68.91\u0026thinsp;\u0026plusmn;\u0026thinsp;9.95\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e69.50\u0026thinsp;\u0026plusmn;\u0026thinsp;12.58\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.863\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eWithin Group Analysis (\u003c/strong\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePairwise Comparisons\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline to 4th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.96\u0026thinsp;\u0026plusmn;\u0026thinsp;5.80\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14.09\u0026thinsp;\u0026plusmn;\u0026thinsp;5.89\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.227\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline to 12th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27.48\u0026thinsp;\u0026plusmn;\u0026thinsp;9.09\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25.86\u0026thinsp;\u0026plusmn;\u0026thinsp;10.78\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.589\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline to 24th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e42.35\u0026thinsp;\u0026plusmn;\u0026thinsp;9.71\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e42.09\u0026thinsp;\u0026plusmn;\u0026thinsp;12.16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.938\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eEstimated Marginal Means\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47.01\u0026thinsp;\u0026plusmn;\u0026thinsp;7.88\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47.92\u0026thinsp;\u0026plusmn;\u0026thinsp;7.88\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.701\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSatisfaction\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-ups\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e4th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.30\u0026thinsp;\u0026plusmn;\u0026thinsp;1.02\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.41\u0026thinsp;\u0026plusmn;\u0026thinsp;1.10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.742\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e12th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.70\u0026thinsp;\u003cstrong\u003e\u0026plusmn;\u003c/strong\u003e\u0026thinsp;1.18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.68\u0026thinsp;\u0026plusmn;\u0026thinsp;1.29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.97\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e24th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.84\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.14\u0026thinsp;\u0026plusmn;\u0026thinsp;1.09\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.144\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eWithin Group Analysis (\u003c/strong\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePairwise Comparisons\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline to 12th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.39\u0026thinsp;\u0026plusmn;\u0026thinsp;0.66\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.27\u0026thinsp;\u0026plusmn;\u0026thinsp;0.77\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.58\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline to 24th week\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.69\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.73\u0026thinsp;\u0026plusmn;\u0026thinsp;0.63\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.01\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eEstimated Marginal Means\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.85\u0026thinsp;\u0026plusmn;\u0026thinsp;0.95\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.74\u0026thinsp;\u0026plusmn;\u0026thinsp;1.09\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.713\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eVAS: Visual analog scale/ OSS: Oxford shoulder score.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eBased on the evaluation of the 5-point Likert spectrum, in both groups, patients were highly satisfied with the intervention performed to manage AC, and intergroup analyzes did not reveal any difference between LMW-HA and HMW-HA.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec25\" class=\"Section3\"\u003e\n\u003cp\u003eAfter 24 weeks, there was a significant improvement in VAS and OSS in the HMW-HA group compared with the LMW-HA group. Figure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e visualize improvement in the primary outcome and OSS which show the positive impact of molecular weight of the HA on pain and disability reduction in idiopathic AC.\u003c/p\u003e\n\u003cp\u003e\u0026bull; Adverse Events (AEs)\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cp\u003eOne week after injection six patients (four in the HMW-HA and two in the LMW-HA group) reported rigidity (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.413) and seven participants (five in the HMW-HA and two in the LMW-HA group) described inflammation in the injection site (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.242). There were no serious AEs reported in either group. Three patients in HMW-HA and one in LMW-HA had more than 2 weeks of rigidity or swelling, however, they became better 4 weeks after injection (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.317).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study is the first clinical trial that compares the efficacy of US-guided intra-articular injection of HMW-HA and LMW-HA in idiopathic AC. To find any discrepancies in clinical outcomes, shoulder pain, disability, ROM, and patient satisfaction were assessed in both groups.\u003c/p\u003e \u003cp\u003eIn this study, results show that in all parameters, there were no significant differences between the HMW-HA group and the LMW-HA group at baseline. In addition, between the HMW-HA group and the LMW-HA group, there were significant differences in reducing shoulder pain and disability and achieving normal performance with slight AEs. There were no significant differences in increasing the range of internal and external rotation between the HMW-HA and the LMW-HA group. Results showed that the HMW-HA and the LMW-HA group similarly increased satisfaction. Although participants had just one injection, both HMW-HA and LMW-HA were effective for the treatment of AC after 6 months based on all monitored parameters.\u003c/p\u003e \u003cp\u003eWhile proving part of our hypothesis that the HMW-HA and LMW-HA are significantly different in improving pain and function, the results refute the part that includes the difference between them in ROM, patient satisfaction, and the incidence of AEs.\u003c/p\u003e \u003cp\u003eEvidence also suggested that AEs including pain, stiffness, and inflammation at the injection site were less common in LMW-HA. Some trials confirm the results of this study. Most of them did not report the molecular weight of HA or just declare the high or low molecular weight terms.\u003c/p\u003e \u003cp\u003eHsieh et al. compared the effect of HA with PT and PT alone for the management of AC. A total of 70 patients were randomly allocated to 2 groups of 35 participants. All participants had one-hour training for 12 weeks (3 sessions per week) and HA with PT group received 20mg HA injection for 3 times (one per week). Disability was decreased significantly in both groups 3 months after injection. In 3 months after treatment ROM (abduction, flexion, internal rotation, external rotation) was improved significantly however, there were no significant differences between groups. In a randomized clinical trial and placebo-controlled, 90 patients (95 shoulders) with AC were included. They were randomly divided into 4 groups. Patients in group 1 received 30mg of HA (1000\u0026ndash;2900 kDa) weekly for 2 weeks. In the CS group, patients received 40mg of triamcinolone acetonide once. In the PT group, participants had a hot pack for 20 minutes, ultrasonic therapy for 5 minutes, and transcutaneous electrical nerve stimulation (TENS) for 20 minutes. They received this pack for 10 days. The control group and all participants had Stretching and Codman exercises at home. After 3 months, pain reduced significantly in the HA group compared with the control group. In addition, abduction was significantly increased in the HA group compared with the control group after 3 months (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). In Rovetta and Monteforte trial, 30 participants were randomly divided into two groups; one group received a combination of 20mg HA and CS (20mg Triamcinolone acetonide) intra-articular injection with PT (for 4\u0026ndash;12 weeks) and the other group received CS with PT. After 6 months, pain and joint motion in all patients especially in the HMW-HA group. They reported no severe AEs (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis study shows that with one injection of HA over 6 months, the parameters of pain, shoulder joint function, ROM, and satisfaction improved significantly. Therefore, injection of HA in the intra-articular space is effective in reducing pain and improving the function of patients with AC. By analyzing the amount of side effects, it was observed that no specific long-term, no-return, or debilitating side effects of HA were reported. There was no significant difference in the rigidity and inflammation, but the small amount of inflammation and stiffness observed were higher in the HMW-HA group. It is probably due to its viscosity.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cul\u003e\n\u003cli\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe Ethics Committee approved this study of the Faculty of Pharmacy of Shahid Beheshti University of Medical Sciences with the ethics code IR.SBMU.PHARMACY.1397.084.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea. Ethics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis clinical study was approved by the institutional review board of ethics of our Shahid Beheshti Medical University, Tehran, Iran, on September 2021 (IR.SBMU.PHARMACY.1397.084). Also, the study was registered in the Iranian Registry of Clinical Trials database (https://irct.behdasht.gov.ir/trial/37113; IRCT registration number:\u0026nbsp;IRCT20170608034390N9)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eb. Consent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ec. Availability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ed. Competing interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors did not declare any competing interests related to the study results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ee. Funding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was financially supported by the research committee of Shahid Beheshti University of Medical Sciences, Tehran, Iran.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ef. Authors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eH.E. and R.M. generated a novel idea and presented a proposal, A.R. and M.M. recruited the eligible patients, G.M., A.R. and H.E. analyzed and interpreted the data, H.E. and R.M. drafted an initial report, M.M. and A.R. wrote the main manuscript text and H.E. prepared figures 1-3. All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eg. Acknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the research committee of Shahid Beheshti University of Medical Sciences for the financial support of this study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePapalexis N, Parmeggiani A, Facchini G, Miceli M, Carbone G, Cavallo M et al. Current concepts in the diagnosis and treatment of adhesive capsulitis: role of diagnostic imaging and ultrasound-guided interventional procedures. 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Acta Orthop. 1965;36(1):45\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZwar RB, Read JW, Noakes JB. Sonographically guided glenohumeral joint injection. Am J Roentgenol 183(1):48\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCalis M, Demir H, Ulker S, Kirnap M, Duygulu F, Calis HT. Is intraarticular sodium hyaluronate injection an alternative treatment in patients with adhesive capsulitis? Rheumatol Int. 2006;26(6):536\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRovetta G, Monteforte P. Intraarticular injection of sodium hyaluronate plus steroid versus steroid in adhesive capsulitis of the shoulder. Int J Tissue React. 1998;20(4):125\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePark KD, Nam HS, Lee JK, Kim YJ, Park Y. Treatment effects of ultrasound-guided capsular distension with hyaluronic acid in adhesive capsulitis of the shoulder. Arch Phys Med Rehabil. 2013;94(2):264\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Adhesive capsulitis, Hyaluronic acid, Physical therapy, Ultrasound-guided injection, Frozen shoulder","lastPublishedDoi":"10.21203/rs.3.rs-4265513/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4265513/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Adhesive capsulitis (AC) of the shoulder is an inflammatory condition with pain and limitation in range of motion (ROM) in the glenohumeral joint. The main goal in managing AC is pain reduction and returning the joint function. Intra-articular hyaluronic acid (HA) has recently been considered as a safe modality in AC. However, the clinical properties of HA are associated with its molecular weight. This study aimed to compare the effectiveness of intra-articular injection of low molecular weight (LMW) with high molecular weight (HMW) HA in patients with AC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Fifty-six eligible patients with AC were randomized in this triple-blinded clinical trial. All patients underwent standard physical therapy as a baseline care. The follow-up visits were at 4, 12, and 24 weeks after LMW-HA or HMW-HA injection. The primary outcome was the visual analog scale (VAS) and others were the Oxford shoulder score (OSS), active ROM, and patient satisfaction.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e No significant differences were detected in between-group variables at baseline. Within-group analysis showed VAS, OSS, and active ROM were markedly improved over time in both groups, also between-group analysis showed VAS and OSS decreased significantly (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001). Four-week follow-up showed the LMW-HA group had lower pain (\u003cem\u003eP\u003c/em\u003e= 0.049), conversely, the trend of VAS at 12 weeks and 24 weeks favors HMW-HA (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001). Regarding satisfaction, this parameter had significantly improved in both groups between four-, 12-, and 24 weeks. And there was no significant difference between groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e HMW-HA is a more effective intervention than LMW-HA in patients with AC.\u003c/p\u003e","manuscriptTitle":"Comparative Effectiveness and Safety of Intra-articular Injection of High versus Low Molecular Weight Hyaluronic Acid in Idiopathic Adhesive Capsulitis; A Randomized Clinical Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-07 20:21:42","doi":"10.21203/rs.3.rs-4265513/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"846b4e0c-e318-4492-a56f-741af176b0a8","owner":[],"postedDate":"May 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-14T23:53:25+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-07 20:21:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4265513","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4265513","identity":"rs-4265513","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}