Efficacy of ultrasound-guided botulinum toxin type A in shoulder pain: a meta-analysis on randomized controlled trials

Efficacy of ultrasound-guided botulinum toxin type A in shoulder pain: a meta-analysis on randomized controlled trials | 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 Efficacy of ultrasound-guided botulinum toxin type A in shoulder pain: a meta-analysis on randomized controlled trials Shiying Zhuang, Xiaoli Zhang, Cheng Lin, Zhizhuo Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4400796/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Jan, 2026 Read the published version in BMC Musculoskeletal Disorders → Version 1 posted 4 You are reading this latest preprint version Abstract Background Shoulder pain is a very common symptom. A number of studies have demonstrated that botulinum toxin type A is effective in relieving shoulder pain. Therefore, this systematic review and meta-analysis aimed to synthesize scientific evidence and quantify the combined effects of ultrasound-guided botulinum toxin type A on shoulder pain. Methods A comprehensive literature search was conducted in databases such as PubMed, Embase, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), China National Knowledge Information Database (CNKI), Wanfang database, and VIP database (VIP) using the keywords "ultrasound", "Botulinum toxin type A", and "shoulder pain". Two reviewers independently reviewed the studies, extracted data from eligible studies, and assessed the risk of bias. A random-effects model was used to calculate the standardized mean difference (SMD) and 95% confidence interval (CI) for Visual Analog Scale (VAS), Upper Extremity Fugl-Meyer assessment (UEFMA), Range of Motion (ROM), Modified Barthel Index (MBI). Funnel plots and sensitivity analyses were also employed to evaluate the six outcome indicators above. Results Out of retrieved 854 records, ten studies (involving 533 patients) were finally included. Pooled analysis showed that ultrasound-guided botulinum toxin type A was associated with moderate improvements in shoulder pain (SMD = -0.96; 95% CI -1.37 to -0.55; P < 0.001), UEFMA score (SMD = 1.43; 95% CI 0.49 to 2.37; P = 0.003), ROM of shoulder flexion (SMD = 1.28; 95% CI 0.63 to 1.93; P < 0.001) and external rotation (SMD = 1.66; 95%CI, 0.83 to 2.48; P < 0.001). Mild improvements were observed in ROM of shoulder abduction (SMD = 0.8; 95%CI 0.18 to 1.43; P = 0.01) and MBI score (SMD = 1.33; 95% CI 0.22 to 2.43; P = 0.02). Conclusions Ultrasound-guided BoNT-A injections are beneficial for reducing pain and enhancing the upper limb function, shoulder ROM and quality of life. More high-quality studies with large sample sizes are needed to assess long-term efficacy, strengthening the evidence that ultrasound-guided BoNT-A facilitates the reduction of shoulder pain. Ultrasound-guided BoNT-A injection shoulder pain ROM upper limb function quality of life meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Background Shoulder pain is a very common condition and is estimated to be the third most common musculoskeletal presentation following low back pain and knee pain in primary care [ 1 ]. Shoulder pain, a costly health care encumbrance in the United States, increases social and economic burdens. In 2010, the value of lost productivity due to pain ranged from $ 299 to $ 335 billion [ 2 ]. Shoulder disease may lead to dysfunction of upper limb motor function and mobility, leading to depressive states and poor health-related quality of life [ 3 ]. If not well addressed, negative functional performance further increases negative psychology and quality of survival. Moreover, severe disability and morbidity may occur. Therefore, the treatment of shoulder pain is highly of importance. There are many different treatments for shoulder pain, such as physical therapy [ 4 , 5 ], medication [ 6 ], intra-articular injection of steroids [ 6 ], dexamethasone [ 7 ] and transection of the subscapular nerve block [ 8 ]. However, these treatments are not always effective, and some have even been associated with adverse effects [ 9 ]. Waldron et al reported that dexamethasone injection caused an increase in blood glucose within 24 hours [ 10 ]. Puzzitiello et al indicated that steroid injections may affect tendon repair [ 11 ]. In addition, Karen et al suspected that nerve block may be associated with a risk of nerve damage [ 12 ]. Overall, it is indispensable to find the safe and effective analgesic therapies. In recent years, botulinum toxin injection has been used for analgesia. The first randomized controlled study to demonstrate the efficacy of botulinum toxin in the treatment of shoulder pain was in 1994, and William et al performed botulinum toxin injection in patients with sarcolemmal pain syndrome [ 13 ]. To their surprise, patients experienced reduction in pain of at least 30% [ 13 ]. Evidence from a meta-analysis on the effectiveness of Botulinum toxin for shoulder pain treatment revealed that the experimental group experienced more effective pain relief and a greater increase in joint mobility [ 14 ]. Then, in a randomized controlled study of hemiplegic shoulder pain, group 1 received Botulinum toxin type A (BoNT-A) injection into the pectoralis major and teres major, and group 2 received suprascapular nerve block (SSNB) [ 15 ]. The results showed that BoNT-A injection into the pectoralis major and teres major muscles was as effective as SSNB in the short term but superior to SSNB in the medium term. However, the beneficial effects of BoNT-A were not always observed across studies. For example, several randomized controlled studies failed to confirm that botulinum toxin injection has better benefits than placebo for stroke shoulder pain [ 16 , 17 , 18 ]. Several factors contribute to these conflicting results, including study quality, patient factors and injection technique. Among the aforementioned factors, the technique of injection may be a key factor. Ultrasound guidance has been shown to improve the delivery accuracy and clinical outcomes of injectable therapies. One of its outstanding advantages is real-time scanning of targeted muscles and adjacent structures [ 19 ]. By observing these images, doctors can improve the precision of controlling the depth of the needle. Therefore, some people believe that ultrasound-guided injection is a viable solution that can improve accuracy, efficacy and safety, reducing the possibility of adverse events caused by improper injection [ 20 ]. By comparing the efficacy of ultrasound-guided injection with that of blind injections, a meta-analysis revealed that ultrasound-guided injections had greater accuracy for all shoulder girdle injections, except for those in subacromial space [ 21 ]. Similarly, Bae et al [ 22 ] injected the BoNT-A (24 U) into the masseter of each volunteer using conventional blind and ultrasound-guided injection techniques on the left and right sides. There was greater facial contour reduction in the ultrasound-guided group than in the blind injection group after one month. In contrast, Riggs et al [ 23 ] and Cole et al [ 24 ] reported that there was no difference between skin-tagged microinjections and ultrasound guidance in terms of pain. To date, several meta-analyses on the treatment of botulinum toxin have reached a consensus that compared with conventional (steroid or placebo injection) therapy, Botulinum toxin injections have beneficial effects on patients with shoulder pain, but the efficacy values for ultrasound-guided injection of BoNT- A have not been fully understood. Based on our literature search, no meta-analyses have summarized the efficacy of the BoNT-A on shoulder pain via ultrasound guidance so far. Thus, the current study aimed to synthesize the scientific evidence and qualify the pooled effect of the ultrasound-guided BoNT-A injection in individuals with shoulder pain. Method A meta-analysis was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) declaration and the Cochrane Handbook [ 25 ]. Our protocol was registered in the Prospective Register of Systematic Reviews (Ref: CRD42023493074, available at: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=493074 ). Eligibility criteria In accordance with the PICOS guidelines, the following inclusion criteria were established [ 26 ]: (i) Participants (P): Patients who suffered from shoulder pain; (ii) Intervention (I): Ultrasound-guided BoNT-A injections; (iii) Comparison (C): All relevant studies with placebo and other active control groups were included; (iv) Outcome (O): First, shoulder pain was measured by the visual analog scale (VAS) and/or simple McGill pain score. Second, shoulder function was assessed by the passive range of motion (PROM), upper extremity Fugl-Meyer assessment (UEFMA) and/or modified Ashworth scale (MAS). Third, quality of life was assessed by the quality of life (QoL) scale, and ADL (activities of daily living) ability was assessed by the Modified Barthel Index (MBI) score. Lastly, the therapeutic effect was evaluated for clinical efficacy evaluation. (v) Study design (S): Randomized controlled trials (RCTs). Search strategy An extensive search strategy was used for the seven data sources, including PubMed, Cochrane Library, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, WanFang database, China National knowledge Information Database (CNKI) and VIP database (VIP) from database inception to December 2023 without any language restrictions. These databases were used to identify ultrasound-guided BoNT-A injections for shoulder pain of diverse etiologies. We used the following terms in various combinations: “ultrasound’’, “BoNT-A’’, “shoulder’’, “pain’’ (detailed in supplementary file 1). Study selection and data extraction The research results were exported to Endnote 20.0. The duplicates were identified and removed automatically. Two reviewers (S.Y.Z and X.L.Z) independently examined all titles and abstracts, followed by a full-text review by the same two reviewers. Any discrepancies were settled through a full examination and discussion. If necessary, a third reviewer (Z.Z.W) was invited to reach a consensus. The following information was extracted from each study: (i) characteristics of the study (i.e., authors, city, year of publication); (ii) characteristics of the population (i.e., sample size, age); (iii) characteristics of the intervention (i.e., treatment setting, duration, injection dose, number of injections and points); (iv) characteristics of the outcomes (i.e., means and standard deviations of the above indicators). If the extracted data were not reported in the article, we emailed the first/corresponding author of that article to secure the missing data. Quality assessment and strength of recommendations S.Y.Z and C.L., two independent reviewers, assessed the quality of the eligible studies, and any differences were reconciled through a thorough examination and discussion until a consensus was reached. The revised Cochrane risk-of-bias tool for randomized trials encompasses seven domains [ 27 ]: (i) Random sequence generation (selection bias); (ii) Allocation concealment (selection bias); (iii) Blinding of participants and personnel (performance bias); (iv) Blinding of outcome assessment (detection bias); (v) Incomplete outcome data (attrition bias); (vi) Selective reporting (reporting bias); (vii) Other bias. Each study's risk of bias was classified as "low risk," "some concerns," or "high risk". The Strength of Recommendation Taxonomy (SORT) was employed to classify each study into three levels of evidence and recommendation, ranging from 1 to 3 [ 28 ]. Level 1 was based on good-quality patient-oriented evidence, Level 2 was based on limited-quality patient-oriented evidence, and Level 3 was based on other evidence. The three strengths of recommendation were A to C, with Recommendation A: Based on consistent and good-quality patient-oriented evidence; Recommendation B: Based on evidence of varying or inadequate patient-oriented quality; Recommendation C: A recommendation based on consensus, customary practice, opinion, disease-related data, or case studies for diagnosis, treatment, prevention, or screening. Low-quality (Recommendation C) studies were excluded. Statistical analysis A random-effects model was employed by RevMan 5. 4. 1 to assess the effect of ultrasound-guided BoNT-A injection interventions on the alleviation of pain in patients, with standardized mean differences (SMD) and 95% confidence intervals (CI) [ 29 ]. The SMD was classified as either small (from 0.2 to 0.49), moderate (from 0.50 to 0.79), or large (equal to or above 0.80) [ 30 ]. The I 2 statistic among studies was utilized to assess heterogeneity, with the I 2 index level being either low, medium, or high when the level was > 25%, > 50% or > 75%, respectively [ 31 ]. In addition, a sensitivity analysis will be performed by removing them on a case-by-case basis. Funnel plots were also generated to evaluate publication bias. The publication bias was considered when the funnel plot was clearly asymmetric. P < 0.05 was considered to indicate statistical significance. Results Study selection Out of the 854 articles initially obtained through the database, 221 were eliminated due to duplication, and 587 were excluded after the titles and abstracts read. Of the 203 records, 46 were deemed suitable for full-text screening. Ultimately, only 10 of the 46 eligible to read the full text were included. The other 36 studies were excluded for the following reasons: not RCTs (n = 5), missing data (n = 2), missing full text (n = 3), and ineligible interventions (n = 26). The qualitative analysis was satisfactory for a total of 10 articles (Fig. 1 ). Characteristics of the included studies A qualitative review of 533 participants was conducted. Nine studies were reported in Chinese [ 32 , 33 , 35 – 40 ], except for one in English [ 34 ]. All selected articles were RCTs published from 2017 through 2023. The interventions were not identical across the 10 studies. One study used BoNT-A alone without other therapies [ 35 ], three studies [ 31 , 36 , 40 ] used BoNT-A with conventional rehabilitation and one study used BoNT-A with physiotherapy [ 34 ]. Five studies combined BoNT-A with other reagents. Of these five studies, two used BoNT-A with lidocaine [ 33 , 38 ], two used BoNT-A with lidocaine and kinesitherapy [ 32 , 34 ], and one conducted mixed injections of BoNT-A and triamcinolone acetonide supplemented with conventional rehabilitation [ 39 ]. Nine out of ten studies agreed on the number of injections only once [ 31 , 32 , 34 – 40 ]. In the remaining study, the drug was injected two times [ 34 ]. For the total injectable dose, one study injected 200 U [ 33 ], another study injected 200–400 U [ 40 ], and eight studies injected 100 U [ 31 , 32 , 34 – 39 ]. The follow-up periods spanned from 4 to 12 weeks for all studies. Regarding outcome measures, ten indicators were included in the eligible studies. The VAS score was commonly used in nine studies [ 31 – 34 , 36 – 40 ], the UEFMA score was eight [ 31 , 33 , 34 36 – 40 ], the MBI score was two [ 39 , 40 ], and the ROM of shoulder during flexion, abduction, and external rotation was measured in five studies [ 32 , 33 , 37 – 39 ]. However, three articles reported shoulder range of motion in two rather than three directions [ 34 , 36 , 40 ]. Specifically, one study measured the ROM of flexion and abduction [ 36 ], while two studies measured the ROM of abduction and external rotation [ 34 , 40 ]. The MAS score and QoL score were measured in the study by Tan et al [ 34 ]. Similarly, the Brief McGill Pain score and Clinical Efficacy Assessment were only applied in the article by Wang et al (2021) [ 35 ] (Supplementary file 2: Table S1 ). Assessment of bias The overall risk of bias in the 10 studies is of concern. Specifically, the detailed information about the randomization was not reported in all studies. Seven studies explicitly explained the use of the random number table method for allocation concealment [ 31 , 33 , 35 , 36 , 38 – 40 ], while three did not clarify the specific methods [ 32 , 34 , 37 ]. Blinding is another prominent concern, and only one trial evidently emphasized the process of double blinding [ 34 ]. Two articles were lost to follow-up, so there may be a risk of attrition bias [ 37 , 38 ]. In general, the strength of the recommendation in two trails was classified as B, the remaining eight trials were classified as grade A (Supplementary file 2: Table S2 ) (Fig. 2 , Fig. 3 ). VAS score As shown in Fig. 4 , nine RCTs analyzed the VAS score, including a total of 591 participants (245 in the BoNT-A group and 246 in the control group) [ 31 – 34 , 36 – 40 ]. A pooled mean standard deviation difference of -0.96 (95% CI -1.37 to -0.55; P < 0.001) was revealed to favor of the BoNT-A group. There was a high heterogeneity across the studies (I 2 = 77%; P = 0.0001), which may be partly explained by the subjective self-rating of pain measured from VAS (Fig. 4 ). To analyze heterogeneity, subgroup analyses were performed according to the follow-up period. Of the 9 studies, 6 reported VAS scores at one-week post-injection [ 31 , 33 , 34 , 36 – 38 ], 2 reported scores at 2 weeks [ 38 , 40 ], 7 reported scores at 4 weeks [ 32 – 34 , 36 – 38 , 40 ], 2 reported scores at 8 weeks [ 33 , 37 ], and 2 reported scores at 12 weeks [ 31 , 34 ]. The results showed that pain relief was most pronounced at 4 weeks (SMD = -1.46; 95% CI -2 to -0.92; P < 0.001). Minimal improvement was observed at 12 weeks [ 31 , 34 ], although this difference was not statistically significant (SMD = -0.5; 95% CI -1.34 to 0.35; P = 0.05). Overall, there were significant differences in outcomes at 1, 2, 4, 6, 8, 12, and 24 weeks of follow-up ( P < 0.0001) (Fig. 5 ). UEFMA score The UEFMA score was reported in eight studies with a total sample size of 451 (225 in the BoNT-A group and 226 in the control group). For analysis, a random-effect model was employed, due to the considerable heterogeneity (I 2 = 94%, P = 0.003). The use of different injection routes may be a factor contributing to the high heterogeneity. Four studies used intra-articular injections [ 32 , 33 , 37 , 38 ], two used intramuscular injections [ 34 , 40 ], and two used injections into the tendon sheaths and bursa [ 36 , 39 ]. The pooled results revealed a significant improvement of BoNT-A on upper limb functional recovery (SMD = 1.43; 95% CI 0.49 to 2.37; P = 0.003) (Fig. 6 ). To explore the sources of heterogeneity, we performed subgroup analysis based on different injection routes. The results also showed that the most significant improvement was achieved using a combined injection of tendon and bursa, although it was also not statistically significant (SMD = 4.22; 95% CI -1.5 to 9.93; P = 0.15) (Supplementary file 2: Fig. S1 ). ROM of the Shoulder The ROM of shoulder flexion A total sample size of 365 (183 in the BoNT-A group and 182 in the control group) was reported in six studies [ 32 , 33 , 36 – 39 ], revealing a significant heterogeneity among them (I 2 = 87%; P < 0.001) in the ROM of shoulder flexion. The pooled analysis of these six trials showed that a bigger flexion angle was associated with the BoNT-A group than the control group (SMD = 1.28; 95%CI 0.63 to 1.93; P < 0.001) (Fig. 7 ). The different injection doses may be responsible for the high heterogeneity (I 2 = 87%), so a subgroup analysis was performed. Of the six included studies, only one had a single-site injection dose of less than 100 U [ 39 ]. According to the subgroup meta-analysis, the ROM of shoulder abduction differed between subgroup1 (Single -point injection dose < 100 U) and subgroup 2 (Single point injection dose = 100 U) ( P = 0.0002) (Fig. 8 ). The ROM of shoulder abduction A total sample size of 431 (215 in the BoNT-A group and 216 in the control group) was reported in eight studies [ 32 – 34 , 36 – 40 ]. The heterogeneity with 89% of shoulder abduction ROM was high ( P < 0.001). The pooled analysis of these eight trials revealed that a higher abduction angle was associated than BoNT-A group compared to the control group (SMD = 0.8; 95%CI 0.18 to 1.43; P = 0.01) (Fig. 9 ). The sample size of the experimental group varied for each study, with a maximum of 54 and a minimum of 14. Two studies had an experimental group sample size of more than 30 people [ 33 , 37 ] and six had no more than 30 people [ 32 , 34 , 36 , 38 – 40 ]. In the subgroup meta-analysis, the ROM of shoulder abduction was different between subgroup 1 (experimental group ≤ 30 people) and subgroup 2 (experimental group > 30 people) ( P = 0.01) (Supplementary file 2: Fig. S2 ). The ROM of external rotation There were seven trials with 381 patients who compared the control group to the BoNT-A group in terms of external rotation (190 in the BoNT-A group and 191 in the control group) [ 32 – 34 , 37 – 40 ]. Although the result is conducive to BoNT-A group in improvement of shoulder external rotation mobility (SMD = 1.66; 95%CI 0.83 to 2.48; P < 0.001), a high heterogeneity was observed in the pooled analysis (I 2 = 91%; P < 0.001) (Fig. 10 ). To explore the sources of heterogeneity the seven studies were grouped according to study quality assessment. Two articles were classified as Grade B because some of participants dropped out [ 37 , 38 ]. Specifically, the study from Yu et al lost 6 cases [ 37 ] and the study from Wang et al lost 9 cases [ 38 ]. A significant difference was observed between the Grade A subgroup and Grade B subgroup ( P = 0.01) (Supplementary file 2: Fig. S3 ). MBI score Two trials with 80 patients that compared the BoNT-A group to the control group [ 39 , 40 ]. There was a notable heterogeneity among the BoNT-A and the control group (39 and 41 respectively) (I 2 = 79%; P = 0.03). However, subgroup analyses cannot be applied to explore sources of heterogeneity because of the limited number of studies. The results indicated that the MBI score of the BoNT-A group was greater than the control group (SMD = 1.33; 95% CI 0.22 to 2.43; P = 0.02) (Supplementary file 2: Fig. S4 ). Other outcomes One record reported the QoL scale score and MAS score [ 34 ]. Another study reported simple McGill pain score and clinical efficacy [ 35 ]. Because of the lack of studies on the four indexes mentioned above, this meta-analysis was unable to create forest plots for them. Sensitivity analysis The sensitivity analyses were performed by removing each trial and assessing how it affected the primary outcomes. No significant differences were found for the VAS score, UEFMA score and ROM of shoulder, confirming that all results are robust. Excluding the Lin et al [ 31 ], the heterogeneity of the VAS score was slightly reduced by 6%. The reason for this may be that the short-term and long-term efficacy of BoNT-A in reducing pain may be different, as most of the included studies had a follow-up period of 4 weeks, whereas the study by Lin et al had a follow-up period of 12 weeks. Mentioning the heterogeneity of ROM in flexion and abduction, a different degree of decrease was observed after excluding the study of Zhang et al [ 39 ]. However, this difference was not statistically significant, possibly because Zhang et al used three injection routes [ 39 ]. Publication bias An evaluation of publication bias was conducted using funnel plots, revealing a significant bias in the UEFMA score, ROM of flexion, abduction, and external rotation. Nevertheless, no significant publication bias was found for the VAS score or MBI score. Publication bias could not be assessed for the QoL scale score, MAS score, simple McGill pain score and clinical efficacy due to the limited number of included studies (Supplementary file 2: Fig. S5 ). Discussion Research on ultrasound-guided botulinum toxin injections has increased in recent years. A large body of literature proves that BoNT-A is a good choice for pain relief [ 13 – 15 ], because of its ability to inhibit of acetylcholine release and other neurological factors. The purpose of this meta-analysis was to investigate the efficacy of ultrasound-guided injection of BoNT-A for treating shoulder pain. Ten studies were included in this analysis (nine studies on hemiplegic shoulder pain [ 31 – 34 , 36 – 40 ] and one was on myofasciitis [ 40 ]), demonstrating that ultrasound-guided injections are significantly effective at decreasing pain. Furthermore, it’s also effective in increasing upper limb function and the ROM of shoulder. When the studies of Lin et al [ 31 ] and Zhang et al [ 39 ] were removed respectively from the VAS analysis and ROM of shoulder analysis, heterogeneity decreased but still remained high. Sensitivity analyses were performed by excluding one by one, and none of results were significantly altered. Therefore, all results were robust. Nevertheless, despite the inclusion of a total of 10 studies in the meta-analysis, we need to be cautious of the results due to the overall high risk of publication bias. The results showed that BoNT-A under ultrasound guidance can reduce shoulder pain greatly in the nine included studies, with a reduction of 1.04. This conclusion is consistent with the current literature [ 41 – 43 ]. Long-term follow-up facilitates more accurate assessment of efficacy and timely detection of adverse effects. The study by Wu et al [ 43 ] did not analyze the follow-up period in subgroups, whereas the study by Xie et al [ 42 ] included 1, 2, 4, and 12 weeks of follow-up. In this meta-analysis, the results at 1, 2, 4 ,6, 8, 12 and 24 weeks of follow-up were analyzed. Six studies documented results at 1 week of follow-up [ 31 , 33 , 34 , 36 – 38 ], but the period with the most documented follow-up results was at week 4, which was documented in seven studies [ 32 – 34 , 36 – 38 , 40 ]. The results showed a significant difference at 7 follow-up periods. The results also showed that it peaked at 4 weeks and then declined. In other words, the effect of BoNT-A is not lifelong as the pain-reducing effect of BoNT-A did not increase progressively over time. Therefore, BoNT-A injections should be used concurrently with other therapies during the period of optimal efficacy for pain relief in order to improve the efficiency of rehabilitation. In the past analyses, several clinical trials supported 4 weeks as a turning point in the efficacy of pain-relief [ 33 , 37 ]. Whereas some previous studies contrasted with our results, which showed the greatest improvement at 12 weeks [ 42 , 44 ]. Since only 2 studies had a follow-up time of 12 weeks in this study, further clinical studies are needed to determine the optimal period of efficacy, facilitating targeted treatment planning at different times. The meta-analysis showed that the ultrasound-guided BoNT-A group was superior to control group in terms of improvement in upper limb function in the eight studies (SMD = 1.44; 95% CI 0.49 to 2.38; P = 0.003). Multiple trials have also demonstrated that BoNT-A supports improved upper limb function [ 45 , 46 ], possibly due to the reduction in pain and spasticity. In the shoulder, BoNT-A is available via three routes of injection including intra-articular [ 31 – 33 , 37 , 38 ], intramuscular [ 34 , 40 ], tendon sheath and bursa injections [ 36 , 39 ]. However, the results of this meta-analysis showed no difference in efficacy between the three delivery routes. The reason may be that the patients in all 8 studies were in the stroke recovery phase (mostly in the synergy movement phase), and it was more difficult to achieve dissociated movement in a short period of time, therefore, long-term observation was needed. Only one study followed the UEFMA score for up to 12 weeks, meaning that the sample size for observation of long-term was small. There are few studies on the differences in the efficacy of the three BoNT-A routes, so more studies are still needed to explore this topic in the future. In terms of shoulder mobility, the ultrasound-guided increase in mobility in all three directions (i.e., flexion, abduction, and external rotation) was more favorable in the BoNT-A group. Specifically, external rotation had the largest increase at 1.66, while abduction had the smallest increase at 0.8. A previous meta-analysis supported that BoNT-A injections were beneficial for increasing the ROM of abduction and external rotation, but there was no difference in the ROM of flexion [ 42 ]. One possible reason for the different conclusions is that the previous analysis had a limited sample size of 103 people. In all included studies, the total dose was 100 U in all trials, except for one trial in which the total dose was 200 U-400 U and the other is 200 U. Based on the single-point injection dose for each subgroup, the results showed that ultrasound-guided BoNT-A was more effective at improving flexion when split-point injection was used (one point < 100 U) instead of single-point injection (one point = 100 U). The cause may be that split-point injections can extend the range of action and reduce localized effects, avoiding skeletal muscle injury from high dose BoNT-A [ 47 ]. In order to maximize the benefits, dose-response testing should be carried out further to improve the use of doses in clinical practice. The results showed that BoNT-A under ultrasound guidance can increase in abduction, with a small improvement of 0.8. Improvements in range of motion with BoNT-A have also been demonstrated in a national survey [ 48 ]. The study showed a statistically significant improvement in abduction in subgroup 1 ( experimental group ≤ 30 people), however subgroup 2 ( experimental group > 30 people) did not. Because of the small sample size of subgroup 2, the assessment of efficacy may be affected. Younger patients benefit less time relative to older patients when treated with BoNT-A injections [ 49 ]. Given that the mean age of studies included in subgroup 1 was greater than that of subgroup 2, older age may have led to a greater improvement in abduction in subgroup 1 than in subgroup 2. The results showed that BoNT-A under ultrasound guidance can increase in external rotation, with an improvement of 1.66. For external rotation, subgroup analyses were performed according to the quality of the studies. Two studies were classified as B because of the presence of loss to follow-up. Specifically, the loss-to-follow-up rate was 15.2% in the study by Wang et al [ 38 ], and 7.14% in the study from Yu et al [ 37 ]. Although neither study had a loss-to-follow-up rate of more than 20%, it may also have the risk of altering the outcomes [ 50 ]. In terms of the MBI score, the results showed that BoNT-A facilitated the improvement of MBI score under ultrasound guidance. Many studies have also proven that BoNT-A improves quality of life [ 51 , 52 ]. Shoulder pain, disability, and depression affect stress, then stress further affects quality of life [ 53 ]. Therefore, clinical treatment should be carried out from both physical and psychological perspective to improve the quality of life. Moreover, age may be a key factor in regulating quality of life. Disability increases with age, although older patients have better mental health than younger patients [ 54 ]. The strength of this study is that, to the best of our knowledge, this is the first retrospective meta-analysis of ultrasound-guided BoNT-A injections for shoulder pain. The current study provides evidence for the pain relief effect of ultrasound-guided BoNT-A on the shoulder. Next, all 10 studies included in this analysis used an RCT design, making the results relatively reliable. Finally, a sensitivity analysis was conducted by excluding each one and all results were found to be robust. The robust results further strengthen the credibility of this analysis. However, there are some limitations we need to address in this study. First, 10 articles were included in this study with a sample size of 533. The limited sample size prevented the analysis of many aspects (i.e., BoNT-A injection concentration, sex, disease duration, geographic area). Furthermore, high heterogeneity was found in most of the results, even through subgroup analyses were conducted. There are two possible reasons for the high heterogeneity: firstly, the different disease duration of the patients included in the study, which may affect the heterogeneity. Secondly, the outcome indicators included scale scores and ROM of the shoulder, which were measured with some subjectivity. Finally, the overall risk of publication bias was high in this study. Therefore, more high-quality studies need to be included in the future to strengthen the evidence supporting the use of ultrasound-guided BoNT-A injections for shoulder pain. Conclusion In conclusion, the results of this systematic review and meta-analysis suggest that ultrasound-guide injections of BoNT-A are more beneficial for reducing pain and enhancing the upper limb function, the ROM of the shoulder and quality of life. In the future, more high-quality studies with large sample sizes are needed to assess long-term efficacy, strengthening the evidence that ultrasound-guided BoNT-A facilitates the reduction of shoulder pain. Abbreviations BoNT-A: Botulinum Toxin Type A; SSNB: Suprascapular Nerve Block; VAS: Visual Analog Scale; ROM: Range of Motion; UEFMA: Upper Extremity Fugl-Meyer assessment; BI: Barthel Index; MBI: Modified Barthel Index; MAS: Modified Ashworth Scale; ADL: activities of daily living; QoL: Quality of Life scale; SMD: Standardized Mean Differences; CI: Confidence Intervals; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RevMan 5. 4. 1: Review Manager; RCT: Randomized Controlled Trial; SORT: Strength of Recommendation Taxonomy Declarations Acknowledgements Not applicable Authors’ contributions Shiying Zhuang and Xiaoli, Zhang are co-first authors of the article. ZZW designed and supervised the study. SYZ and XLZ conducted the data collection. CL and SYZ analyzed and interpreted the data. SYZ contributed to drafting the manuscript. ZZW critically revised the manuscript. All authors read and approved the final manuscript. 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Supplementary Files FigureS1.png FigureS2.png FigureS3.png FigureS4.png FigureS5.png TableS1.pdf TableS2.pdf Cite Share Download PDF Status: Published Journal Publication published 08 Jan, 2026 Read the published version in BMC Musculoskeletal Disorders → Version 1 posted Editorial decision: Revision requested 10 Jun, 2024 Submission checks completed at journal 02 Jun, 2024 Editor assigned by journal 02 Jun, 2024 First submitted to journal 10 May, 2024 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. We do this by developing innovative software and high quality services for the global research community. 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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-4400796","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":312835429,"identity":"d15ad9a4-d6b8-4905-8900-d909f285e771","order_by":0,"name":"Shiying Zhuang","email":"","orcid":"","institution":"Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shiying","middleName":"","lastName":"Zhuang","suffix":""},{"id":312835430,"identity":"9d78820b-6e78-4093-a99f-08598e7a1c44","order_by":1,"name":"Xiaoli Zhang","email":"","orcid":"","institution":"Fujian Medical 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16:41:59","extension":"pdf","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":157147,"visible":true,"origin":"","legend":"","description":"","filename":"TableS1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4400796/v1/56cd572c5650548e511f1d18.pdf"},{"id":58515841,"identity":"0d818e6c-332d-4a85-8f9c-2ad9680c9241","added_by":"auto","created_at":"2024-06-17 16:41:59","extension":"pdf","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":88913,"visible":true,"origin":"","legend":"","description":"","filename":"TableS2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4400796/v1/d19b50e44d4c360eaad50e53.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy of ultrasound-guided botulinum toxin type A in shoulder pain: a meta-analysis on randomized controlled trials","fulltext":[{"header":"Background","content":"\u003cp\u003eShoulder pain is a very common condition and is estimated to be the third most common musculoskeletal presentation following low back pain and knee pain in primary care [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Shoulder pain, a costly health care encumbrance in the United States, increases social and economic burdens. In 2010, the value of lost productivity due to pain ranged from \u003cspan\u003e$\u003c/span\u003e299 to \u003cspan\u003e$\u003c/span\u003e335\u0026nbsp;billion [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Shoulder disease may lead to dysfunction of upper limb motor function and mobility, leading to depressive states and poor health-related quality of life [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. If not well addressed, negative functional performance further increases negative psychology and quality of survival. Moreover, severe disability and morbidity may occur. Therefore, the treatment of shoulder pain is highly of importance.\u003c/p\u003e \u003cp\u003eThere are many different treatments for shoulder pain, such as physical therapy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], medication [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], intra-articular injection of steroids [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], dexamethasone [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] and transection of the subscapular nerve block [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, these treatments are not always effective, and some have even been associated with adverse effects [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Waldron et al reported that dexamethasone injection caused an increase in blood glucose within 24 hours [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Puzzitiello et al indicated that steroid injections may affect tendon repair [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In addition, Karen et al suspected that nerve block may be associated with a risk of nerve damage [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Overall, it is indispensable to find the safe and effective analgesic therapies. In recent years, botulinum toxin injection has been used for analgesia. The first randomized controlled study to demonstrate the efficacy of botulinum toxin in the treatment of shoulder pain was in 1994, and William et al performed botulinum toxin injection in patients with sarcolemmal pain syndrome [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. To their surprise, patients experienced reduction in pain of at least 30% [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Evidence from a meta-analysis on the effectiveness of Botulinum toxin for shoulder pain treatment revealed that the experimental group experienced more effective pain relief and a greater increase in joint mobility [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Then, in a randomized controlled study of hemiplegic shoulder pain, group 1 received Botulinum toxin type A (BoNT-A) injection into the pectoralis major and teres major, and group 2 received suprascapular nerve block (SSNB) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The results showed that BoNT-A injection into the pectoralis major and teres major muscles was as effective as SSNB in the short term but superior to SSNB in the medium term. However, the beneficial effects of BoNT-A were not always observed across studies. For example, several randomized controlled studies failed to confirm that botulinum toxin injection has better benefits than placebo for stroke shoulder pain [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Several factors contribute to these conflicting results, including study quality, patient factors and injection technique. Among the aforementioned factors, the technique of injection may be a key factor. Ultrasound guidance has been shown to improve the delivery accuracy and clinical outcomes of injectable therapies. One of its outstanding advantages is real-time scanning of targeted muscles and adjacent structures [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. By observing these images, doctors can improve the precision of controlling the depth of the needle. Therefore, some people believe that ultrasound-guided injection is a viable solution that can improve accuracy, efficacy and safety, reducing the possibility of adverse events caused by improper injection [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. By comparing the efficacy of ultrasound-guided injection with that of blind injections, a meta-analysis revealed that ultrasound-guided injections had greater accuracy for all shoulder girdle injections, except for those in subacromial space [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Similarly, Bae et al [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] injected the BoNT-A (24 U) into the masseter of each volunteer using conventional blind and ultrasound-guided injection techniques on the left and right sides. There was greater facial contour reduction in the ultrasound-guided group than in the blind injection group after one month. In contrast, Riggs et al [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] and Cole et al [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] reported that there was no difference between skin-tagged microinjections and ultrasound guidance in terms of pain.\u003c/p\u003e \u003cp\u003eTo date, several meta-analyses on the treatment of botulinum toxin have reached a consensus that compared with conventional (steroid or placebo injection) therapy, Botulinum toxin injections have beneficial effects on patients with shoulder pain, but the efficacy values for ultrasound-guided injection of BoNT- A have not been fully understood. Based on our literature search, no meta-analyses have summarized the efficacy of the BoNT-A on shoulder pain via ultrasound guidance so far. Thus, the current study aimed to synthesize the scientific evidence and qualify the pooled effect of the ultrasound-guided BoNT-A injection in individuals with shoulder pain.\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003eA meta-analysis was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) declaration and the Cochrane Handbook [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Our protocol was registered in the Prospective Register of Systematic Reviews (Ref: CRD42023493074, available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=493074\u003c/span\u003e\u003cspan address=\"https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=493074\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEligibility criteria\u003c/h2\u003e \u003cp\u003eIn accordance with the PICOS guidelines, the following inclusion criteria were established [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]: (i) Participants (P): Patients who suffered from shoulder pain; (ii) Intervention (I): Ultrasound-guided BoNT-A injections; (iii) Comparison (C): All relevant studies with placebo and other active control groups were included; (iv) Outcome (O): First, shoulder pain was measured by the visual analog scale (VAS) and/or simple McGill pain score. Second, shoulder function was assessed by the passive range of motion (PROM), upper extremity Fugl-Meyer assessment (UEFMA) and/or modified Ashworth scale (MAS). Third, quality of life was assessed by the quality of life (QoL) scale, and ADL (activities of daily living) ability was assessed by the Modified Barthel Index (MBI) score. Lastly, the therapeutic effect was evaluated for clinical efficacy evaluation. (v) Study design (S): Randomized controlled trials (RCTs).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSearch strategy\u003c/h3\u003e\n\u003cp\u003eAn extensive search strategy was used for the seven data sources, including PubMed, Cochrane Library, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, WanFang database, China National knowledge Information Database (CNKI) and VIP database (VIP) from database inception to December 2023 without any language restrictions. These databases were used to identify ultrasound-guided BoNT-A injections for shoulder pain of diverse etiologies. We used the following terms in various combinations: \u0026ldquo;ultrasound\u0026rsquo;\u0026rsquo;, \u0026ldquo;BoNT-A\u0026rsquo;\u0026rsquo;, \u0026ldquo;shoulder\u0026rsquo;\u0026rsquo;, \u0026ldquo;pain\u0026rsquo;\u0026rsquo; (detailed in supplementary file 1).\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection and data extraction\u003c/h2\u003e \u003cp\u003eThe research results were exported to Endnote 20.0. The duplicates were identified and removed automatically. Two reviewers (S.Y.Z and X.L.Z) independently examined all titles and abstracts, followed by a full-text review by the same two reviewers. Any discrepancies were settled through a full examination and discussion. If necessary, a third reviewer (Z.Z.W) was invited to reach a consensus. The following information was extracted from each study: (i) characteristics of the study (i.e., authors, city, year of publication); (ii) characteristics of the population (i.e., sample size, age); (iii) characteristics of the intervention (i.e., treatment setting, duration, injection dose, number of injections and points); (iv) characteristics of the outcomes (i.e., means and standard deviations of the above indicators). If the extracted data were not reported in the article, we emailed the first/corresponding author of that article to secure the missing data.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eQuality assessment and strength of recommendations\u003c/h2\u003e \u003cp\u003e S.Y.Z and C.L., two independent reviewers, assessed the quality of the eligible studies, and any differences were reconciled through a thorough examination and discussion until a consensus was reached. The revised Cochrane risk-of-bias tool for randomized trials encompasses seven domains [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]: (i) Random sequence generation (selection bias); (ii) Allocation concealment (selection bias); (iii) Blinding of participants and personnel (performance bias); (iv) Blinding of outcome assessment (detection bias); (v) Incomplete outcome data (attrition bias); (vi) Selective reporting (reporting bias); (vii) Other bias. Each study's risk of bias was classified as \"low risk,\" \"some concerns,\" or \"high risk\". The Strength of Recommendation Taxonomy (SORT) was employed to classify each study into three levels of evidence and recommendation, ranging from 1 to 3 [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Level 1 was based on good-quality patient-oriented evidence, Level 2 was based on limited-quality patient-oriented evidence, and Level 3 was based on other evidence. The three strengths of recommendation were A to C, with Recommendation A: Based on consistent and good-quality patient-oriented evidence; Recommendation B: Based on evidence of varying or inadequate patient-oriented quality; Recommendation C: A recommendation based on consensus, customary practice, opinion, disease-related data, or case studies for diagnosis, treatment, prevention, or screening. Low-quality (Recommendation C) studies were excluded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eA random-effects model was employed by RevMan 5. 4. 1 to assess the effect of ultrasound-guided BoNT-A injection interventions on the alleviation of pain in patients, with standardized mean differences (SMD) and 95% confidence intervals (CI) [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The SMD was classified as either small (from 0.2 to 0.49), moderate (from 0.50 to 0.79), or large (equal to or above 0.80) [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. The I\u003csup\u003e2\u003c/sup\u003e statistic among studies was utilized to assess heterogeneity, with the I\u003csup\u003e2\u003c/sup\u003e index level being either low, medium, or high when the level was \u0026gt;\u0026thinsp;25%, \u0026gt;\u0026thinsp;50% or \u0026gt;\u0026thinsp;75%, respectively [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. In addition, a sensitivity analysis will be performed by removing them on a case-by-case basis. Funnel plots were also generated to evaluate publication bias. The publication bias was considered when the funnel plot was clearly asymmetric. \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered to indicate statistical significance.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection\u003c/h2\u003e \u003cp\u003eOut of the 854 articles initially obtained through the database, 221 were eliminated due to duplication, and 587 were excluded after the titles and abstracts read. Of the 203 records, 46 were deemed suitable for full-text screening. Ultimately, only 10 of the 46 eligible to read the full text were included. The other 36 studies were excluded for the following reasons: not RCTs (n\u0026thinsp;=\u0026thinsp;5), missing data (n\u0026thinsp;=\u0026thinsp;2), missing full text (n\u0026thinsp;=\u0026thinsp;3), and ineligible interventions (n\u0026thinsp;=\u0026thinsp;26). The qualitative analysis was satisfactory for a total of 10 articles (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of the included studies\u003c/h2\u003e \u003cp\u003eA qualitative review of 533 participants was conducted. Nine studies were reported in Chinese [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan additionalcitationids=\"CR36 CR37 CR38 CR39\" citationid=\"CR36\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e], except for one in English [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. All selected articles were RCTs published from 2017 through 2023. The interventions were not identical across the 10 studies. One study used BoNT-A alone without other therapies [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e35\u003c/span\u003e], three studies [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e] used BoNT-A with conventional rehabilitation and one study used BoNT-A with physiotherapy [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Five studies combined BoNT-A with other reagents. Of these five studies, two used BoNT-A with lidocaine [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e38\u003c/span\u003e], two used BoNT-A with lidocaine and kinesitherapy [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e], and one conducted mixed injections of BoNT-A and triamcinolone acetonide supplemented with conventional rehabilitation [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e39\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNine out of ten studies agreed on the number of injections only once [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan additionalcitationids=\"CR35 CR36 CR37 CR38 CR39\" citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. In the remaining study, the drug was injected two times [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. For the total injectable dose, one study injected 200 U [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e33\u003c/span\u003e], another study injected 200\u0026ndash;400 U [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e], and eight studies injected 100 U [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan additionalcitationids=\"CR35 CR36 CR37 CR38\" citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. The follow-up periods spanned from 4 to 12 weeks for all studies. Regarding outcome measures, ten indicators were included in the eligible studies. The VAS score was commonly used in nine studies [\u003cspan additionalcitationids=\"CR32 CR33\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan additionalcitationids=\"CR37 CR38 CR39\" citationid=\"CR37\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e], the UEFMA score was eight [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e \u003cspan additionalcitationids=\"CR37 CR38 CR39\" citationid=\"CR37\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e], the MBI score was two [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e], and the ROM of shoulder during flexion, abduction, and external rotation was measured in five studies [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan additionalcitationids=\"CR38\" citationid=\"CR38\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. However, three articles reported shoulder range of motion in two rather than three directions [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Specifically, one study measured the ROM of flexion and abduction [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e36\u003c/span\u003e], while two studies measured the ROM of abduction and external rotation [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. The MAS score and QoL score were measured in the study by Tan et al [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Similarly, the Brief McGill Pain score and Clinical Efficacy Assessment were only applied in the article by Wang et al (2021) [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e35\u003c/span\u003e] (Supplementary file 2: Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eAssessment of bias\u003c/h2\u003e \u003cp\u003eThe overall risk of bias in the 10 studies is of concern. Specifically, the detailed information about the randomization was not reported in all studies. Seven studies explicitly explained the use of the random number table method for allocation concealment [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan additionalcitationids=\"CR39\" citationid=\"CR39\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e], while three did not clarify the specific methods [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Blinding is another prominent concern, and only one trial evidently emphasized the process of double blinding [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Two articles were lost to follow-up, so there may be a risk of attrition bias [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. In general, the strength of the recommendation in two trails was classified as B, the remaining eight trials were classified as grade A (Supplementary file 2: Table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eVAS score\u003c/h2\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, nine RCTs analyzed the VAS score, including a total of 591 participants (245 in the BoNT-A group and 246 in the control group) [\u003cspan additionalcitationids=\"CR32 CR33\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan additionalcitationids=\"CR37 CR38 CR39\" citationid=\"CR37\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. A pooled mean standard deviation difference of -0.96 (95% CI -1.37 to -0.55; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) was revealed to favor of the BoNT-A group. There was a high heterogeneity across the studies (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;77%; \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.0001), which may be partly explained by the subjective self-rating of pain measured from VAS (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo analyze heterogeneity, subgroup analyses were performed according to the follow-up period. Of the 9 studies, 6 reported VAS scores at one-week post-injection [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan additionalcitationids=\"CR37\" citationid=\"CR37\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e38\u003c/span\u003e], 2 reported scores at 2 weeks [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e], 7 reported scores at 4 weeks [\u003cspan additionalcitationids=\"CR33\" citationid=\"CR33\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan additionalcitationids=\"CR37\" citationid=\"CR37\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e], 2 reported scores at 8 weeks [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e37\u003c/span\u003e], and 2 reported scores at 12 weeks [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. The results showed that pain relief was most pronounced at 4 weeks (SMD = -1.46; 95% CI -2 to -0.92; \u003cem\u003eP\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.001). Minimal improvement was observed at 12 weeks [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e], although this difference was not statistically significant (SMD = -0.5; 95% CI -1.34 to 0.35; \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.05). Overall, there were significant differences in outcomes at 1, 2, 4, 6, 8, 12, and 24 weeks of follow-up (\u003cem\u003eP\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.0001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eUEFMA score\u003c/h2\u003e \u003cp\u003eThe UEFMA score was reported in eight studies with a total sample size of 451 (225 in the BoNT-A group and 226 in the control group). For analysis, a random-effect model was employed, due to the considerable heterogeneity (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;94%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). The use of different injection routes may be a factor contributing to the high heterogeneity. Four studies used intra-articular injections [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e38\u003c/span\u003e], two used intramuscular injections [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e], and two used injections into the tendon sheaths and bursa [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. The pooled results revealed a significant improvement of BoNT-A on upper limb functional recovery (SMD\u0026thinsp;=\u0026thinsp;1.43; 95% CI 0.49 to 2.37; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003) (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo explore the sources of heterogeneity, we performed subgroup analysis based on different injection routes. The results also showed that the most significant improvement was achieved using a combined injection of tendon and bursa, although it was also not statistically significant (SMD\u0026thinsp;=\u0026thinsp;4.22; 95% CI -1.5 to 9.93; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.15) (Supplementary file 2: Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eROM of the Shoulder\u003c/h2\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003eThe ROM of shoulder flexion\u003c/h2\u003e \u003cp\u003eA total sample size of 365 (183 in the BoNT-A group and 182 in the control group) was reported in six studies [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan additionalcitationids=\"CR37 CR38\" citationid=\"CR37\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e39\u003c/span\u003e], revealing a significant heterogeneity among them (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;87%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) in the ROM of shoulder flexion. The pooled analysis of these six trials showed that a bigger flexion angle was associated with the BoNT-A group than the control group (SMD\u0026thinsp;=\u0026thinsp;1.28; 95%CI 0.63 to 1.93; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe different injection doses may be responsible for the high heterogeneity (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;87%), so a subgroup analysis was performed. Of the six included studies, only one had a single-site injection dose of less than 100 U [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. According to the subgroup meta-analysis, the ROM of shoulder abduction differed between subgroup1 (Single -point injection dose\u0026thinsp;\u0026lt;\u0026thinsp;100 U) and subgroup 2 (Single point injection dose\u0026thinsp;=\u0026thinsp;100 U) (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0002) (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eThe ROM of shoulder abduction\u003c/h2\u003e \u003cp\u003eA total sample size of 431 (215 in the BoNT-A group and 216 in the control group) was reported in eight studies [\u003cspan additionalcitationids=\"CR33\" citationid=\"CR33\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan additionalcitationids=\"CR37 CR38 CR39\" citationid=\"CR37\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. The heterogeneity with 89% of shoulder abduction ROM was high (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The pooled analysis of these eight trials revealed that a higher abduction angle was associated than BoNT-A group compared to the control group (SMD\u0026thinsp;=\u0026thinsp;0.8; 95%CI 0.18 to 1.43; \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.01) (Fig.\u0026nbsp;\u003cspan refid=\"Fig10\" class=\"InternalRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe sample size of the experimental group varied for each study, with a maximum of 54 and a minimum of 14. Two studies had an experimental group sample size of more than 30 people [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e37\u003c/span\u003e] and six had no more than 30 people [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan additionalcitationids=\"CR39\" citationid=\"CR39\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. In the subgroup meta-analysis, the ROM of shoulder abduction was different between subgroup 1 (experimental group\u0026thinsp;\u0026le;\u0026thinsp;30 people) and subgroup 2 (experimental group\u0026thinsp;\u0026gt;\u0026thinsp;30 people) (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.01) (Supplementary file 2: Fig. \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eThe ROM of external rotation\u003c/h2\u003e \u003cp\u003eThere were seven trials with 381 patients who compared the control group to the BoNT-A group in terms of external rotation (190 in the BoNT-A group and 191 in the control group) [\u003cspan additionalcitationids=\"CR33\" citationid=\"CR33\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan additionalcitationids=\"CR38 CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Although the result is conducive to BoNT-A group in improvement of shoulder external rotation mobility (SMD\u0026thinsp;=\u0026thinsp;1.66; 95%CI 0.83 to 2.48; \u003cem\u003eP\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.001), a high heterogeneity was observed in the pooled analysis (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;91%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig12\" class=\"InternalRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo explore the sources of heterogeneity the seven studies were grouped according to study quality assessment. Two articles were classified as Grade B because some of participants dropped out [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Specifically, the study from Yu et al lost 6 cases [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e37\u003c/span\u003e] and the study from Wang et al lost 9 cases [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. A significant difference was observed between the Grade A subgroup and Grade B subgroup (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.01) (Supplementary file 2: Fig. \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003eS3\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eMBI score\u003c/h2\u003e \u003cp\u003eTwo trials with 80 patients that compared the BoNT-A group to the control group [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. There was a notable heterogeneity among the BoNT-A and the control group (39 and 41 respectively) (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;79%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03). However, subgroup analyses cannot be applied to explore sources of heterogeneity because of the limited number of studies. The results indicated that the MBI score of the BoNT-A group was greater than the control group (SMD\u0026thinsp;=\u0026thinsp;1.33; 95% CI 0.22 to 2.43; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02) (Supplementary file 2: Fig. \u003cspan refid=\"MOESM4\" class=\"InternalRef\"\u003eS4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eOther outcomes\u003c/h2\u003e \u003cp\u003eOne record reported the QoL scale score and MAS score [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Another study reported simple McGill pain score and clinical efficacy [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Because of the lack of studies on the four indexes mentioned above, this meta-analysis was unable to create forest plots for them.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analysis\u003c/h2\u003e \u003cp\u003eThe sensitivity analyses were performed by removing each trial and assessing how it affected the primary outcomes. No significant differences were found for the VAS score, UEFMA score and ROM of shoulder, confirming that all results are robust.\u003c/p\u003e \u003cp\u003eExcluding the Lin et al [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], the heterogeneity of the VAS score was slightly reduced by 6%. The reason for this may be that the short-term and long-term efficacy of BoNT-A in reducing pain may be different, as most of the included studies had a follow-up period of 4 weeks, whereas the study by Lin et al had a follow-up period of 12 weeks. Mentioning the heterogeneity of ROM in flexion and abduction, a different degree of decrease was observed after excluding the study of Zhang et al [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. However, this difference was not statistically significant, possibly because Zhang et al used three injection routes [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e39\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003ePublication bias\u003c/h2\u003e \u003cp\u003eAn evaluation of publication bias was conducted using funnel plots, revealing a significant bias in the UEFMA score, ROM of flexion, abduction, and external rotation. Nevertheless, no significant publication bias was found for the VAS score or MBI score. Publication bias could not be assessed for the QoL scale score, MAS score, simple McGill pain score and clinical efficacy due to the limited number of included studies (Supplementary file 2: Fig. \u003cspan refid=\"MOESM5\" class=\"InternalRef\"\u003eS5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eResearch on ultrasound-guided botulinum toxin injections has increased in recent years. A large body of literature proves that BoNT-A is a good choice for pain relief [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], because of its ability to inhibit of acetylcholine release and other neurological factors. The purpose of this meta-analysis was to investigate the efficacy of ultrasound-guided injection of BoNT-A for treating shoulder pain. Ten studies were included in this analysis (nine studies on hemiplegic shoulder pain [\u003cspan additionalcitationids=\"CR32 CR33\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan additionalcitationids=\"CR37 CR38 CR39\" citationid=\"CR37\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e] and one was on myofasciitis [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e]), demonstrating that ultrasound-guided injections are significantly effective at decreasing pain. Furthermore, it\u0026rsquo;s also effective in increasing upper limb function and the ROM of shoulder. When the studies of Lin et al [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] and Zhang et al [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e39\u003c/span\u003e] were removed respectively from the VAS analysis and ROM of shoulder analysis, heterogeneity decreased but still remained high. Sensitivity analyses were performed by excluding one by one, and none of results were significantly altered. Therefore, all results were robust. Nevertheless, despite the inclusion of a total of 10 studies in the meta-analysis, we need to be cautious of the results due to the overall high risk of publication bias.\u003c/p\u003e \u003cp\u003eThe results showed that BoNT-A under ultrasound guidance can reduce shoulder pain greatly in the nine included studies, with a reduction of 1.04. This conclusion is consistent with the current literature [\u003cspan additionalcitationids=\"CR42\" citationid=\"CR42\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Long-term follow-up facilitates more accurate assessment of efficacy and timely detection of adverse effects. The study by Wu et al [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e43\u003c/span\u003e] did not analyze the follow-up period in subgroups, whereas the study by Xie et al [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e42\u003c/span\u003e] included 1, 2, 4, and 12 weeks of follow-up. In this meta-analysis, the results at 1, 2, 4 ,6, 8, 12 and 24 weeks of follow-up were analyzed. Six studies documented results at 1 week of follow-up [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan additionalcitationids=\"CR37\" citationid=\"CR37\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e38\u003c/span\u003e], but the period with the most documented follow-up results was at week 4, which was documented in seven studies [\u003cspan additionalcitationids=\"CR33\" citationid=\"CR33\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan additionalcitationids=\"CR37\" citationid=\"CR37\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. The results showed a significant difference at 7 follow-up periods. The results also showed that it peaked at 4 weeks and then declined. In other words, the effect of BoNT-A is not lifelong as the pain-reducing effect of BoNT-A did not increase progressively over time. Therefore, BoNT-A injections should be used concurrently with other therapies during the period of optimal efficacy for pain relief in order to improve the efficiency of rehabilitation. In the past analyses, several clinical trials supported 4 weeks as a turning point in the efficacy of pain-relief [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Whereas some previous studies contrasted with our results, which showed the greatest improvement at 12 weeks [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Since only 2 studies had a follow-up time of 12 weeks in this study, further clinical studies are needed to determine the optimal period of efficacy, facilitating targeted treatment planning at different times.\u003c/p\u003e \u003cp\u003eThe meta-analysis showed that the ultrasound-guided BoNT-A group was superior to control group in terms of improvement in upper limb function in the eight studies (SMD\u0026thinsp;=\u0026thinsp;1.44; 95% CI 0.49 to 2.38; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). Multiple trials have also demonstrated that BoNT-A supports improved upper limb function [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e46\u003c/span\u003e], possibly due to the reduction in pain and spasticity. In the shoulder, BoNT-A is available via three routes of injection including intra-articular [\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e38\u003c/span\u003e], intramuscular [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e40\u003c/span\u003e], tendon sheath and bursa injections [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. However, the results of this meta-analysis showed no difference in efficacy between the three delivery routes. The reason may be that the patients in all 8 studies were in the stroke recovery phase (mostly in the synergy movement phase), and it was more difficult to achieve dissociated movement in a short period of time, therefore, long-term observation was needed. Only one study followed the UEFMA score for up to 12 weeks, meaning that the sample size for observation of long-term was small. There are few studies on the differences in the efficacy of the three BoNT-A routes, so more studies are still needed to explore this topic in the future.\u003c/p\u003e \u003cp\u003eIn terms of shoulder mobility, the ultrasound-guided increase in mobility in all three directions (i.e., flexion, abduction, and external rotation) was more favorable in the BoNT-A group. Specifically, external rotation had the largest increase at 1.66, while abduction had the smallest increase at 0.8. A previous meta-analysis supported that BoNT-A injections were beneficial for increasing the ROM of abduction and external rotation, but there was no difference in the ROM of flexion [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. One possible reason for the different conclusions is that the previous analysis had a limited sample size of 103 people. In all included studies, the total dose was 100 U in all trials, except for one trial in which the total dose was 200 U-400 U and the other is 200 U. Based on the single-point injection dose for each subgroup, the results showed that ultrasound-guided BoNT-A was more effective at improving flexion when split-point injection was used (one point\u0026thinsp;\u0026lt;\u0026thinsp;100 U) instead of single-point injection (one point\u0026thinsp;=\u0026thinsp;100 U). The cause may be that split-point injections can extend the range of action and reduce localized effects, avoiding skeletal muscle injury from high dose BoNT-A [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. In order to maximize the benefits, dose-response testing should be carried out further to improve the use of doses in clinical practice.\u003c/p\u003e \u003cp\u003eThe results showed that BoNT-A under ultrasound guidance can increase in abduction, with a small improvement of 0.8. Improvements in range of motion with BoNT-A have also been demonstrated in a national survey [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. The study showed a statistically significant improvement in abduction in subgroup 1 ( experimental group\u0026thinsp;\u0026le;\u0026thinsp;30 people), however subgroup 2 ( experimental group\u0026thinsp;\u0026gt;\u0026thinsp;30 people) did not. Because of the small sample size of subgroup 2, the assessment of efficacy may be affected. Younger patients benefit less time relative to older patients when treated with BoNT-A injections [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. Given that the mean age of studies included in subgroup 1 was greater than that of subgroup 2, older age may have led to a greater improvement in abduction in subgroup 1 than in subgroup 2.\u003c/p\u003e \u003cp\u003eThe results showed that BoNT-A under ultrasound guidance can increase in external rotation, with an improvement of 1.66. For external rotation, subgroup analyses were performed according to the quality of the studies. Two studies were classified as B because of the presence of loss to follow-up. Specifically, the loss-to-follow-up rate was 15.2% in the study by Wang et al [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e38\u003c/span\u003e], and 7.14% in the study from Yu et al [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Although neither study had a loss-to-follow-up rate of more than 20%, it may also have the risk of altering the outcomes [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e50\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn terms of the MBI score, the results showed that BoNT-A facilitated the improvement of MBI score under ultrasound guidance. Many studies have also proven that BoNT-A improves quality of life [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. Shoulder pain, disability, and depression affect stress, then stress further affects quality of life [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. Therefore, clinical treatment should be carried out from both physical and psychological perspective to improve the quality of life. Moreover, age may be a key factor in regulating quality of life. Disability increases with age, although older patients have better mental health than younger patients [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e54\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe strength of this study is that, to the best of our knowledge, this is the first retrospective meta-analysis of ultrasound-guided BoNT-A injections for shoulder pain. The current study provides evidence for the pain relief effect of ultrasound-guided BoNT-A on the shoulder. Next, all 10 studies included in this analysis used an RCT design, making the results relatively reliable. Finally, a sensitivity analysis was conducted by excluding each one and all results were found to be robust. The robust results further strengthen the credibility of this analysis. However, there are some limitations we need to address in this study. First, 10 articles were included in this study with a sample size of 533. The limited sample size prevented the analysis of many aspects (i.e., BoNT-A injection concentration, sex, disease duration, geographic area). Furthermore, high heterogeneity was found in most of the results, even through subgroup analyses were conducted. There are two possible reasons for the high heterogeneity: firstly, the different disease duration of the patients included in the study, which may affect the heterogeneity. Secondly, the outcome indicators included scale scores and ROM of the shoulder, which were measured with some subjectivity. Finally, the overall risk of publication bias was high in this study. Therefore, more high-quality studies need to be included in the future to strengthen the evidence supporting the use of ultrasound-guided BoNT-A injections for shoulder pain.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, the results of this systematic review and meta-analysis suggest that ultrasound-guide injections of BoNT-A are more beneficial for reducing pain and enhancing the upper limb function, the ROM of the shoulder and quality of life. In the future, more high-quality studies with large sample sizes are needed to assess long-term efficacy, strengthening the evidence that ultrasound-guided BoNT-A facilitates the reduction of shoulder pain.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBoNT-A: Botulinum Toxin Type A; SSNB: Suprascapular Nerve Block; VAS: Visual Analog Scale; ROM: Range of Motion; UEFMA: Upper Extremity Fugl-Meyer assessment; BI: Barthel Index; MBI: Modified Barthel Index; MAS: Modified Ashworth Scale; ADL: activities of daily living; QoL: Quality of Life scale; SMD: Standardized Mean Differences; CI: Confidence Intervals; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RevMan 5. 4. 1: Review Manager; RCT: Randomized Controlled Trial; SORT: Strength of Recommendation Taxonomy\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eShiying Zhuang and Xiaoli, Zhang are co-first authors of the article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eZZW designed and supervised the study. SYZ and XLZ conducted the data collection. CL and SYZ analyzed and interpreted the data. SYZ contributed to drafting the manuscript. ZZW critically revised the manuscript. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere was no direct funding for performing this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study available from the corresponding author/first author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declared no potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Rehabilitation Medicine, School of Health, Fujian Medical University, No. 1 Xuefu North Road, University town, Fuzhou 350122, Fujian, China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eUrwin M, Symmons D, Allison T, Brammah T, Busby H, Roxby M, Simmons A, Williams G. 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Disabil Rehabil. 2014;36(4):313\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOh J, Lee MK. Shoulder pain, shoulder disability, and depression as serial mediators between stress and health-related quality of life among middle-aged women. Health Qual Life Outcomes. 2022;20(1):142.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWettstein M, Eich W, Bieber C, Tesarz J. Pain Intensity, Disability, and Quality of Life in Patients with Chronic Low Back Pain: Does Age Matter? Pain Med. 2019;20(3):464\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-musculoskeletal-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmsd","sideBox":"Learn more about [BMC Musculoskeletal Disorders](http://bmcmusculoskeletdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://author-welcome.nature.com/12891","title":"BMC Musculoskeletal Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Ultrasound-guided, BoNT-A, injection, shoulder pain, ROM, upper limb function, quality of life, meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-4400796/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4400796/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eShoulder pain is a very common symptom. A number of studies have demonstrated that botulinum toxin type A is effective in relieving shoulder pain. Therefore, this systematic review and meta-analysis aimed to synthesize scientific evidence and quantify the combined effects of ultrasound-guided botulinum toxin type A on shoulder pain.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA comprehensive literature search was conducted in databases such as PubMed, Embase, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), China National Knowledge Information Database (CNKI), Wanfang database, and VIP database (VIP) using the keywords \"ultrasound\", \"Botulinum toxin type A\", and \"shoulder pain\". Two reviewers independently reviewed the studies, extracted data from eligible studies, and assessed the risk of bias. A random-effects model was used to calculate the standardized mean difference (SMD) and 95% confidence interval (CI) for Visual Analog Scale (VAS), Upper Extremity Fugl-Meyer assessment (UEFMA), Range of Motion (ROM), Modified Barthel Index (MBI). Funnel plots and sensitivity analyses were also employed to evaluate the six outcome indicators above.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOut of retrieved 854 records, ten studies (involving 533 patients) were finally included. Pooled analysis showed that ultrasound-guided botulinum toxin type A was associated with moderate improvements in shoulder pain (SMD = -0.96; 95% CI -1.37 to -0.55; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), UEFMA score (SMD\u0026thinsp;=\u0026thinsp;1.43; 95% CI 0.49 to 2.37; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003), ROM of shoulder flexion (SMD\u0026thinsp;=\u0026thinsp;1.28; 95% CI 0.63 to 1.93; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and external rotation (SMD\u0026thinsp;=\u0026thinsp;1.66; 95%CI, 0.83 to 2.48; \u003cem\u003eP\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.001). Mild improvements were observed in ROM of shoulder abduction (SMD\u0026thinsp;=\u0026thinsp;0.8; 95%CI 0.18 to 1.43; \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.01) and MBI score (SMD\u0026thinsp;=\u0026thinsp;1.33; 95% CI 0.22 to 2.43; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eUltrasound-guided BoNT-A injections are beneficial for reducing pain and enhancing the upper limb function, shoulder ROM and quality of life. More high-quality studies with large sample sizes are needed to assess long-term efficacy, strengthening the evidence that ultrasound-guided BoNT-A facilitates the reduction of shoulder pain.\u003c/p\u003e","manuscriptTitle":"Efficacy of ultrasound-guided botulinum toxin type A in shoulder pain: a meta-analysis on randomized controlled trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-17 16:41:52","doi":"10.21203/rs.3.rs-4400796/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-06-10T20:46:19+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-02T12:00:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-02T12:00:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Musculoskeletal Disorders","date":"2024-05-10T12:51:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-musculoskeletal-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmsd","sideBox":"Learn more about [BMC Musculoskeletal Disorders](http://bmcmusculoskeletdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://author-welcome.nature.com/12891","title":"BMC Musculoskeletal Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"47a66fdc-88c2-4b80-b0f3-5a6d2d10bbce","owner":[],"postedDate":"June 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-12T16:06:26+00:00","versionOfRecord":{"articleIdentity":"rs-4400796","link":"https://doi.org/10.1186/s12891-025-09347-8","journal":{"identity":"bmc-musculoskeletal-disorders","isVorOnly":false,"title":"BMC Musculoskeletal Disorders"},"publishedOn":"2026-01-08 15:59:19","publishedOnDateReadable":"January 8th, 2026"},"versionCreatedAt":"2024-06-17 16:41:52","video":"","vorDoi":"10.1186/s12891-025-09347-8","vorDoiUrl":"https://doi.org/10.1186/s12891-025-09347-8","workflowStages":[]},"version":"v1","identity":"rs-4400796","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4400796","identity":"rs-4400796","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}