Adhesive capsulitis (AC), commonly referred to as frozen shoulder, is a painful disorder characterized by restricted shoulder movement due to fibrotic adhesions within the joint and contraction of the joint capsule [1]. Affecting 2%-5% of the general population, AC is predominantly observed in middle-aged individuals, with a higher prevalence in females compared to males [1-3]. The chronic nature of AC and the diverse therapeutic interventions necessitated for its management impose a substantial economic burden on patients [4]. A recent survey, for instance, revealed that the yearly insurance cost for AC management in Switzerland amounted to 78 million Swiss francs [5].

The etiology of AC is hypothesized to stem from an inflammatory healing response initiated by minor injuries, potentially resulting in an excessive accumulation and proliferation of fibroblasts that secrete type I and type III collagen, thereby causing limitations in shoulder joint mobility and inducing shoulder pain [6,7]. Primary treatment approaches can be divided into non-surgical and surgical modalities. Non-surgical modalities encompass conservative treatment, physiotherapy (PT), pharmacological therapy, and injections (including intra-articular corticosteroids or sodium hyaluronate injections, botulinum toxin type A, and suprascapular nerve blocks). Surgical treatment modalities consist of intra-articular distension, manipulation under anesthesia to promote adhesion tears and facilitate inferior capsule release, and arthroscopic capsulotomy [8]. However, surgical modalities are correlated with certain adverse reactions, such as inferior glenoid rim fractures, anterior subluxation, alterations in serum glucose levels, and vasovagal responses [9-11]. Consequently, the development of more effective treatment paradigms is critical to minimize unnecessary surgery, avert excessive use of anesthetics and analgesics, and prevent potential addiction to pain-relief medications.

Pharmacopuncture therapy, rooted in traditional Korean medicine, combines acupuncture and herbal medicine by injecting fluid herbal extracts into acupoints [12]. This method is predominantly utilized for treating various diseases, particularly musculoskeletal disorders [13,14]. Furthermore, the therapy has been linked to minimal adverse events. A retrospective analysis revealed that out of 80,523 musculoskeletal patients who underwent pharmacopuncture therapy, adverse events were exceedingly rare (infection in 0.002% of patients; anaphylactic shock in 0.019% of patients) [15]. Despite its widespread use for musculoskeletal diseases and high satisfaction ratings among patients and Korean medicine practitioners, as evidenced by a 2018 self-reported online survey [16], pharmacopuncture therapy is not currently covered by national health insurance [17].

A prior review identified only two studies examining the impact of pharmacopuncture therapy on adhesive capsulitis in South Korea [18]. These studies consisted of one randomized controlled trial (RCT) evaluating the efficacy of bee venom pharmacopuncture [19] and one non-RCT investigating the effectiveness of scolopendrid pharmacopuncture on AC [20]. While the RCT demonstrated that bee venom pharmacopuncture significantly alleviated pain compared to the normal saline injection group, no RCTs have been conducted on other types of pharmacopuncture, nor have any studies compared pharmacopuncture therapy to an active control group. Consequently, there is a pressing need for a well-designed RCT reflecting clinical practice in South Korea and employing various pharmacopuncture types. As a result, this manuscript introduces the first protocol for a pragmatic RCT aimed at assessing the effectiveness and safety of pharmacopuncture therapy for AC by comparing pharmacopuncture and physical therapy strategies at multiple centers in South Korea.

1. Study design

This investigation will be carried out at Jaseng Hospital of Korean Medicine, South Korea; Deajeon Jaseng Hospital of Korean Medicine, South Korea; Bucheon Jaseng Hospital of Korean Medicine, South Korea; and Haeundae Jaseng Hospital of Korean Medicine, South Korea. The study protocol adheres to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines [21] (Supplementary Appendix 1) and the principles outlined by the Consolidated Standards of Reporting Trials (CONSORT) [22]. Institutional Review Board (IRB) approval was obtained under approval numbers JASENG 2022-02-013, JASENG 2022-02-014, JASENG 2022-02-015, and JASENG 2022-02-016. This study is structured as a multi-center, parallel-group, pragmatic randomized controlled trial, which compares pharmacopuncture therapy to PT using a 1:1 allocation ratio. A total of 50 participants will be randomly assigned to either the intervention or control group. Participants in the intervention group will undergo pharmacopuncture therapy targeting the shoulder region, while those in the control group will receive PT. The trial will encompass six weeks of treatment involving twelve visits, followed by a six-week follow-up period. A schematic representation of the study can be found in Fig. 1.

Figure 1. Flow chart of the study design.

2. Patients

1) Inclusion criteria

To be eligible for enrollment in the study, participants must satisfy all of the following criteria:

• 1)

  Be aged between 19 and 70 years.

• 2)

  Exhibit noticeable limitations in passive or active shoulder range of motion.

• 3)

  Have a shoulder pain numeric rating scale (NRS) score greater than 5.

• 4)

  Experience symptom duration exceeding 1 month.

• 5)

  Possess no other clinical or radiological findings pertinent to the aforementioned symptoms.

• 6)

  Voluntarily agree to participate in this clinical trial and provide written consent to comply with the study protocol after receiving and comprehending a detailed explanation of the clinical trial procedures.

2) Exclusion criteria

Patients will be excluded from the study if they:

• 1)

  Suffer from shoulder pain resulting from specific medical conditions such as acute fractures or shoulder dislocation.

• 2)

  Experience pain originating from non-shoulder diseases, including tumors, fibromyalgia, rheumatoid arthritis, gout, or cervical disc herniation.

• 3)

  Have any disease that could potentially impact the assessment of outcomes or therapeutic effects, such as stroke, myocardial infarction, kidney disease, diabetic neuropathy, dementia, or epilepsy.

• 4)

  Are currently taking medications that may interfere with the evaluation of outcomes, including steroids, immunosuppressants, and psychiatric medications.

• 5)

  Are unsuitable for safely receiving pharmacopuncture therapy, such as those with hemorrhagic diseases, individuals on anticoagulant drugs, or those with severe diabetes.

• 6)

  Possess a history of pharmacopuncture therapy or usage of medications like non-steroidal anti-inflammatory drugs.

• 7)

  Are pregnant, planning to become pregnant, or breastfeeding.

• 8)

  Have undergone shoulder surgery within 3 months prior to the trial.

• 9)

  Are participating in other clinical trials within 1 month of termination or plan to participate in other clinical trials during this study or within 6 months of the selection date.

3. Randomization and allocation concealment

An independent statistician will employ the block randomization method using RStudio 1.1.463 (© 2009-2018 RStudio, Inc.) with block sizes of two and four, followed by a 1:1 allocation ratio for the experimental and control groups within each block. This statistician will generate the random numbers and assign the randomized codes to the respective groups prior to the study commencement. To ensure allocation concealment, sealed opaque envelopes will be utilized. All eligible participants will be assigned to either the intervention or control group based on the randomization code.

4. Blinding

Due to the distinct nature of the interventions, blinding of physicians and participants in this study is not feasible. However, outcome assessors, data managers, and statisticians will remain blinded to the outcome assignment.

5. Interventions

Participants will be divided into two groups according to the randomization code. Over the course of six weeks, those in the experimental group will undergo two pharmacopuncture therapy sessions per week, while the control group will receive two PT sessions per week. Therapists will determine the acupoint, PT selection, and treatment duration after evaluating each patient’s symptoms and radiographic examination results.

1) Experimental group

Participants in the experimental group will receive treatment twice weekly for six weeks. A trained doctor of Korean medicine will determine the acupoint selection based on the patient’s symptoms, shoulder X-ray examination results, and the extent of improvement. All procedures involving acupoints will be documented.

2) Control group

The control group will undergo two PT sessions per week for a six-week period. The PT regimen will encompass various modalities, such as superficial heat therapy, deep heat therapy, and electrotherapy, which will be integrated into clinical practice depending on each individual’s symptoms. Physicians will determine the specific type, point, and duration of PT based on the patient’s symptoms, shoulder radiographic findings, and the extent of improvement. All details regarding the types, durations, and points of PT will be recorded in the patient’s chart for assessment.

6. Outcome measurements

All participants will be subjected to a series of evaluations before, during, and after the study by the designated outcome assessors. The enrollment, intervention, and measurement schedules for participants are detailed in Table 1.

EQ-5D-5L = EuroQol-5 Dimension; NRS = Numeric rating scale; PGIC = Patients’ Global Impression of Change; ROM = Range of motion; SPADI = Shoulder pain and disability index; SF-12, v2 = Short Form-12 Health Survey Version 2; VAS = Visual analogue scale..

&md=tbl&idx=1' data-target="#file-modal"">Table 1

Planned schedule of the trial.

Time point	Screening	Enrollment allocation	Active treatment post-allocation			Follow-up
Week	–1	0	1	2	3,4,5,6	7	13
Visit window	0-7		± 3	± 3	± 3	± 4	± 7
Enrollment	O	O
Written informed consent	O
Vital signs	O	O	O	O	O	O	O
Sociodemographic characteristics	O
Medical history	O	O	O
Shoulder X-ray	O
Randomized allocation		O
Interventions
Treatment in pharmacopuncture groups (experimental group)			← 2 times/ week →
Treatment in physiotherapy group (control group)			← 2 times/ week →
Assessment
Drug consumption	O	O	O	O	O	O	O
Adverse events			O	O	O	O	O
NRS of shoulder pain	O		O	O	O	O	O
VAS of shoulder pain			O	O	O	O	O
ROM of shoulder	O		O	O	O	O	O
SPADI			O			O	O
SF-12			O			O	O
EQ-5D-5L			O			O	O
PGIC						O	O
Physical examination	O
Credibility and expectancy	O
Evaluation of medical costs			O	O	O	O	O
Evaluation of time cost				O
Evaluation of lost work productivity			O	O	O	O	O
Blood analysis	O					O
Compliance						O

EQ-5D-5L = EuroQol-5 Dimension; NRS = Numeric rating scale; PGIC = Patients’ Global Impression of Change; ROM = Range of motion; SPADI = Shoulder pain and disability index; SF-12, v2 = Short Form-12 Health Survey Version 2; VAS = Visual analogue scale..

1) Primary outcome

Numerical Rating Scale (NRS) score: The NRS is an 11-point tool used to assess pain intensity over a one-week period. Pain intensity scores range from 0 to 10, with 0 indicating no pain and 10 representing unbearable pain. Throughout this study, participants will be asked to rate their pain intensity using the NRS at each assessment prior to commencing the intervention.

2) Secondary outcomes

Visual Analog Scale (VAS) score for shoulder pain: Participants in this study will quantify their pain intensity on a 100-mm VAS, with 0 denoting no pain and 100 signifying the most severe pain imaginable. Participants will provide their scores before each intervention.

Range of motion (ROM): Participants’ ROM will be assessed by evaluating their lateral flexion. Participants will stand upright and be instructed to extend their arms as far as possible without bending their knees. Assessors will then measure the distance between the tip of the middle finger and the floor. Participants will report their scores before the study begins and after the intervention concludes.

Shoulder Pain and Disability Index (SPADI): The SPADI is a 13-item self-administered assessment tool comprising five pain and eight disability items. Higher SPADI scores indicate more severe disability. Participants will report their scores before the initial intervention and during follow-up.

Patients’ Global Impression of Change: This questionnaire evaluates patients’ perceived health status using a seven-point scale ranging from 1 to 7 as follows: 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. The questionnaire will be administered during the follow-up phase.

Short Form-12 Health Survey Version 2 (SF-12v2): The SF-12v2 is a clinically relevant and reliable instrument for measuring patient well-being. This self-administered, health-related quality of life questionnaire contains 12 items across eight physical and mental health domains, including physical function, role-physical, bodily pain, general health, vitality, social function, role-emotional, and mental health. Completion takes less than five minutes, with higher scores indicating better health-related quality of life. Participants will report their scores before the initial intervention and during follow-up.

EuroQol-5 Dimension (EQ-5D-5L): The EQ-5D-5L is a widely-utilized method for indirectly estimating health quality status using predetermined preference scores for each functional level. This tool encompasses five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each item is weighted based on the level of each component. The preference score calculation equation is provided, complete with weights and constants. Participants will report their scores before the first intervention and during follow-up.

7. Sample size calculation

The present study posits that a significant difference in outcomes will be observed between the experimental and control groups. However, no previous studies have directly compared the efficacy of pharmacopuncture therapy and PT for treating AC patients. Based on the pilot study [23], a minimum of 15 patients per group is deemed necessary. Factoring in a 25% withdrawal rate and accounting for subgroup analysis, we aim to recruit a total of 50 patients.

8. Recruitment

To recruit participants, we will employ online media releases in conjunction with promotional posters displayed both inside and outside the study center.

9. Statistical methods

An independent statistician, blinded to group allocation, will perform the statistical analysis using SAS 9.4 (SAS Institute Inc., Cary, NC, USA) or RStudio 1.1.463 (© 2009-2018 RStudio, Inc.). Sociodemographic characteristics and treatment expectancy will be evaluated for each group. A p-value less than .05 will be established as the level of statistical significance. An interim analysis will be conducted following the primary endpoint for validity analysis.

Continuous data will be summarized using mean (standard deviation) or mean (quartiles) values. Differences between the two groups will be compared using either the Student’s t-test or the Wilcoxon rank-sum test, depending on the data distribution. Changes in each outcome value relative to the baseline will indicate effectiveness at the endpoint. For the primary analysis of continuous outcomes (NRS, VAS, SPADI, EQ-5D-5L, SF-12 scores, ROM, and blood test results), a linear mixed model will be developed using values of each variable that were statistically different between treatment groups at baseline as covariates, with the groups as a fixed factor. Analysis of covariance (ANCOVA) based on multiple imputations and the last observation carried forward will be employed. Moreover, we will calculate the area under the curve (AUC) at each time point post-randomized allocation to compare differences in each outcome at various treatment points and throughout the entire study period for both groups.

Categorical data will be expressed as frequency (%) and analyzed using the Chi-square test or Fisher’s exact test. We will compare and analyze the proportion of patients whose NRS and VAS scores for shoulder pain decreased by more than half of the baseline value. The time from randomization to shoulder pain improvement, as determined by a reduction in pain indices by less than half, will be assessed using the Kaplan-Meier survival analysis. The log-rank test will be used to compare the curves, and hazard ratios will be compared using the Cox proportional hazard model.

Intention-to-treat (ITT) analysis and per-protocol (PP) analysis will be employed for all data analysis, with ITT analysis serving as the primary method. For PP analysis, participants who complete nine or more treatment sessions during the 6-week treatment period will be analyzed separately. The primary ANCOVA will address missing data, multiple imputations will be used for the AUC analysis, and the linear mixed model will be implemented via the mixed model for repeated measures. For sensitivity analysis, the normality of distribution will be tested after imputing missing data using the last observation carried forward approach. In case of a nonparametric distribution, the main analysis will be repeated employing the Wilcoxon rank-sum test. If the superiority test fails, a non-inferiority test will be conducted. The non-inferiority margin is set at 1.4 (regarded as the VAS standard), which is half of the minimal clinically important difference for shoulder pain. If the lower boundary of the 95% confidence interval for the difference in VAS reduction between the two groups does not surpass the margin, pharmacopuncture will not be deemed inferior to PT.

10. Data monitoring

The IRB and an independent statistician will assess participant safety and the completeness of clinical data. The internal team at Jaseng Medical Foundation will monitor the trial through regular visits and calls. Investigators will promptly evaluate and address all adverse events.

11. Adverse events

Before initiating the study and after the final interventions, all participants will undergo a blood test to evaluate white blood cell, neutrophil, lymphocyte, monocyte, eosinophil, basophil, red blood cell, and platelet counts; hemoglobin and mean corpuscular hemoglobin concentrations; hematocrit, mean corpuscular volume, and erythrocyte sedimentation rate values. Biochemical assessments will be conducted to determine total protein, albumin, bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine transaminase, gamma-glutamyl transferase, blood urea nitrogen, and creatinine levels, as well as C-reactive protein concentration. Undesirable and unintended symptoms or adverse reactions will be documented, noting the duration of signs or symptoms. Patients will be asked to rate treatment safety using a six-grade scale in accordance with the causality assessment system of the Uppsala Monitoring Centre: certain, probable/likely, possible, unlikely, conditional/unclassified, and unassessable/unclassifiable.

12. Study discontinuation criteria

The principal investigator holds the ultimate authority to determine the study’s termination. Discontinuation will be deliberated in cases such as the identification of unforeseen, substantial, or intolerable risks to participants, the incidence of serious adverse events, or the emergence of adverse events associated with pharmacopuncture therapy or PT in over 25% of the participants.

13. Ethics considerations and dissemination

This study has been meticulously designed in adherence to the Korean Good Clinical Practices and the Declaration of Helsinki. All requisite documents (e.g., study protocol, case report form, informed consent form, and patient recruitment announcement) have been submitted to the IRB at each site, and approvals for the study have been granted. The approval numbers are as follows: JASENG 2022-02-013, JASENG 2022-02-014, JASENG 2022-02-015, and JASENG 2022-02-016. Any modifications to the documents will be implemented subsequent to IRB approval, and the revised documents will be updated on the trial registries. All researchers have undergone training in recruitment, screening, randomization, assessment of this study, the Declaration of Helsinki, and Korean Good Clinical Practices. Participants will be thoroughly informed about the study protocol. The investigator will procure written informed consent and furnish each participant with a copy of the consent form. Participants retain the right to withdraw from the trials at any moment, and all data collected during the study will be maintained in strict confidentiality.

AC is a prevalent shoulder joint disease that can be classified into primary and secondary AC [24]. Primary AC is an idiopathic condition with no specific cause [25], while secondary AC results from trauma or surgery involving the shoulder joint [26]. AC is characterized by three stages: pain, frozen shoulder, and thawing. Pain levels can vary, with the painful stage lasting 3-9 months and the frozen stage potentially causing pain for 4-12 months. Pain improvement may occur over 1-3 years [27]. The prolonged disease course and frequent shoulder pain significantly affect patients’ quality of life. Consequently, developing more effective treatment approaches is crucial for pain reduction.

Traditional Korean medicine has demonstrated therapeutic benefits and plays a vital role in managing AC [28]. Pharmacopuncture therapy, a significant component of traditional Korean medicine, is considered a readily accessible complementary therapy for muscle relaxation, improved blood flow, and joint mobilization [29]. Various herbal medicine extracts are used in this therapy. In China, Ligusticum chuanxiong Hort, Angelica sinensis, and Salvia miltiorrhiza extracts have been employed to treat AC patients [18]. Ligusticum chuanxiong Hort inhibits TNF-α production and exhibits anti-inflammatory effects [30]. Angelica sinensis regulates MMP-1, MMP-3, COX-2 mRNA, protein expression, and PGE2 production, inhibiting rheumatoid synovial fibroblast proliferation [31]. Salvia miltiorrhiza extract modulates ERK1/2 phosphorylation to reduce inflammation in dextran-induced acute arthritis [32]. Furthermore, according to Korean clinical practice guidelines, Salvia miltiorrhiza has been combined with bee venom, centipede, and Juglandis semen for shoulder pain treatment [33]. Previous studies have shown that bee venom components possess anti-inflammatory, anti-nociceptive, and anti-arthritic properties [34]. However, no study has investigated other types of pharmacopuncture therapy for AC in South Korea. A well-designed clinical trial could promote the broader use of AC pharmacopuncture therapy for pain relief.

Pragmatic clinical trials are considered superior for guiding clinical decision-making and providing evidence for policy-making regarding treatment selection in real-world practice [35]. A pragmatic trial addresses the limitations of existing clinical trial designs and is valuable for determining treatment effects in real-world settings. Additionally, pragmatic trials are suitable for South Korean medical practice, as clinicians tend to apply medical techniques rather than develop new drugs or medical technologies. In this study, the inclusion criterion for age (19-70 years) was chosen to encompass the broadest age range possible. Furthermore, we will recruit patients with primary AC, exhibiting various disease stages for more than one month, and allow physicians to autonomously select the treatment type and acupoint within their respective treatment group. Outcome evaluations will include analyses to determine crucial measurements directly related to patients’ symptoms. We plan to conduct both ITT and PP analyses, utilizing data for noncompliance and values below expected levels.

The primary limitation of this study is incomplete blinding. Due to the intervention’s nature, successful blinding of physicians and patients is unachievable. To mitigate this limitation, a resident, blinded to group allocation and not involved in the intervention, will perform the outcome evaluation to minimize bias.

The outcomes of this investigation will contribute to a comprehensive understanding of the efficacy and safety of pharmacopuncture therapy, laying the groundwork for healthcare professionals to consider this innovative approach as an alternative treatment for patients with AC. Moreover, the insights gleaned from this study can offer valuable evidence to inform clinical decision-making and shape healthcare policy.

Supplementary data to this article can be found online at https://doi.org/10.51507/j.jams.2023.16.2.70

jams-16-2-70-supple.pdf

This trial is supported by the Korea Institute of Oriental Medicine (grant number: KSN1823211).

HYZ and CHH participated in the study concept and developed the first draft of the manuscript. CY, YJL, IHH, and KSP contributed to the trial design and study operation. KSP edited the final manuscript. All authors reviewed the final draft versions of this protocol and have read and approved the final manuscript.

The authors declare no conflict of interest.

The full data will be made available when the trial is finished and published. Application for the data should be made by contacting KSP.

This protocol has been approved by the medical ethics committees of Jaseng Hospital of Korean Medicine, South Korea; Deajeon Jaseng Hospital of Korean Medicine, South Korea; Bucheon Jaseng Hospital of Korean Medicine, South Korea; and Haeundea Jaseng Hospital of Korean Medicine, South Korea. The approval numbers are JASENG 2022-02-013, JASENG 2022-02-014, JASENG 2022-02-015, and JASENG 2022-02-016.

The recruitment for this study is ongoing. We anticipate that it will take 2 years to complete this trial. The first participant was enrolled on 20th April 2022, and the anticipated end of the trial date will be 30th June 2023.