Shoulder pain is a common musculoskeletal complaint in primary care, following lumbar and knee pain [1], affecting approximately 18-26% of adults at any point in life [2-5]. A painful shoulder is not associated with mortality; however, it is associated with substantial morbidity [6]. In addition, symptoms affect an individual’s ability to perform daily activities both at home and in the workplace [7,8]. Consequently, managing shoulder pain consumes a significant proportion of medical resources [9,10].

Shoulder disorders may involve impingement, shoulder muscle rupture, and calcific tendinitis; however, the terms describing rotator cuff disorder associated with shoulder pain are not standardized [11]. The term 'rotator cuff disease' has been used to describe rotator cuff disorder at any anatomical location and due to any cause [12,13].

Treatment of rotator cuff disease is divided into surgical and conservative types. Surgery should be considered only after conservative therapy has failed [14]. Some evidence suggests that pain- and disability-related outcomes of surgical and non-surgical treatments are comparable [1].

Korean Medicine offers conservative treatments, including acupuncture and pharmacopuncture. Acupuncture may reduce shoulder pain [15,16] even in chronic pain cases [17]. In fact, acupuncture can offer immediate pain relief and improve shoulder function in adhesive capsulitis [18].

Pharmacopuncture combines acupuncture with herbal medicine [19]. First introduced to Korea in 1960s, it is frequently used in Korean Medicine [20,21]. Research on pharmacopuncture began in the 1990s, with randomized controlled trials (RCTs) launched in the 2000s. Pharmacopuncture has been used for musculoskeletal, neurological, and circulatory disorders, among others; musculoskeletal disorders are the most common indication [19,22]. Pharmacopuncture may involve bee venom, Hominis placenta, and Aconitum ciliare Decaisne solutions [23,24]. A study on pharmacopuncture for musculoskeletal diseases in South Korea found that 32,947 (98.6%) of 33,145 inpatients at 12 Korean Medicine hospitals and clinics received pharmacopuncture treatment, and 289,860 (77.6%) of 373,755 outpatients received pharmacopuncture treatment. In addition, 6,710 outpatients presented with shoulder-related diseases, which is the leading indication for pharmacopuncture [25]. Pharmacopuncture alone and in combination with acupuncture is more effective at reducing pain and improving the quality of life than acupuncture monotherapy or other conservative treatments [26]. In addition, among 29 randomized controlled trials on pharmacopuncture, five studies reported side effects that included local pain, fatigue, and redness, which disappeared in a short period of time without any additional treatment [27]. Pharmacopuncture is relatively safe and is unlikely to cause serious adverse effects.

However, despite its widespread use, clinical evidence on the safety and effectiveness of pharmacopuncture for rotator cuff disease is lacking. To date, few studies have compared pharmacopuncture with acupuncture, which is another treatment of Korean Medicine. Therefore, this pilot study aimed to evaluate the effectiveness and safety of pharmacopuncture combined with acupuncture for rotator cuff disease.

1. Objective

This study focuses on patients with rotator cuff disease. The aims of this study are as follows:

• 1)

  To confirm the difference in pain levels, functional outcomes, and consumed medicine dose between the intervention group receiving pharmacopuncture therapy and acupuncture treatment, and the control group receiving only acupuncture treatment.

• 2)

  To compare the rates of adverse events between the groups.

This is a practical clinical study that is not aimed to determine the details of pharmacopuncture therapy or acupuncture treatment. The treatment details will be determined for each session. All matters regarding the procedure will be recorded on case report forms (CRFs) and reviewed retrospectively.

2. Study design

This study is a two-group, parallel, single-center, pragmatic, randomized controlled, assessor-blinded trial. A total of 40 patients will be recruited based on the eligibility criteria from among the patients presenting at Daejeon University Daejeon Korean Medicine Hospital between July and December 2022.

Prospective participants will be asked to provide written informed consent to participate in the trial. Study eligibility will be determined based on demographic and clinical characteristics, including medical history, questionnaire-based assessments, shoulder radiographic examinations, physical examinations, blood tests, electrocardiogram (ECG) examinations, and urine human chorionic gonadotropin levels for women that may be pregnant. Eligible participants will be randomized to the acupuncture-pharmacopuncture combination therapy group or acupuncture monotherapy group at a 1:1 ratio. As a pragmatic trial, this study does not prospectively prescribe treatment, which is at the discretion of the Korean Medicine doctor and subject to patient symptoms. The participants will complete a total of nine hospital visits, including eight treatment sessions (twice per week for 4 weeks). Outcome assessments will be performed at weeks two, four, and eight. Table 1 shows schedule of this clinical trial.

Table 1

Schedule for the treatment and the outcome measurements.

	Study Period
	Enrollment	Treatment phase								Follow-up phase	Unscheduled visit
Visit	Screening	1	2	3	4	5	6	7	8	9	-
Week	0	1		2		3		4		8	-
Enrollment
Informed consent	●
Inclusion/Exclusion criteria	●
Vital signs	●	●	●	●	●	●	●	●	●	●	●
Demographic characteristics	●
Medical history	●
Physical examination	●										●
Clinical laboratory test	●									●	●
Electrocardiography	●
Radiography of shoulder	●
Random allocation		●
Intervention
Intervention group: acupuncture-pharmacopuncture combination therapy		◉	◉	◉	◉	◉	◉	◉	◉
Control group: acupuncture monotherapy		○	○	○	○	○	○	○	○
Assessments
VAS	●	●			●				●	●
SPADI		●			●				●	●
ROM	●	●			●				●	●
EQ-5D		●			●				●	●
PGIC					●				●	●
No worse than mild pain					●				●	●
Drug consumption					●				●	●
Change of medical history		●	●	●	●	●	●	●	●	●	●
Check withdrawal and dropout		●	●	●	●	●	●	●	●	●	●
Safety assessment		●	●	●	●	●	●	●	●	●	●
Visit schedule training	●	●	●	●	●	●	●	●	●	●	●

3. Inclusion criteria [28,29]

• 1)

  Age range of 19-75 years, both sexes.

• 2)

  Diagnosis of rotator cuff disease made by the study principal investigator or another specialist prior to study enrolment.

• 3)

  Visual Analogue Scale (VAS) shoulder pain score of ≥ 40 points.

• 4)

  Capacity and willingness to provide informed consent.

4. Exclusion criteria

• 1)

  Shoulder surgery within the previous 3 months [30].

• 2)

  Diagnosis of malignancy or fracture, among others, which may account for shoulder pain.

• 3)

  Anticipating shoulder surgery within the study period.

• 4)

  Underlying diseases (stroke, myocardial infarction, kidney disease, severe diabetes, dementia, epilepsy, severe hemorrhagic disease, etc.) that may interfere with the treatment effect or result interpretation.

• 5)

  Treatment with steroids, immunosuppressants, psychotropic medication, or any other drug that may affect outcomes within the previous 3 months.

• 6)

  Severe abnormalities in blood test results, such as aspartate aminotransferase (AST) or alanine transferase (ALT) levels three-times the upper normal range limit, or blood creatinine level twice the upper normal range limit, among others.

• 7)

  Treatment with nonsteroidal anti- inflammatory drugs (NSAIDs) or pharmacopuncture, acupuncture, physical therapy within 1 week [31].

• 8)

  Present or planned pregnancy, and lactation.

• 9)

  Active or planned participation in another clinical trial within 1 month or during the follow-up period, respectively.

• 10)

  Unsuitability for the trial, as judged by the principal investigator.

5. Sample size

This is a preliminary pilot study designed to assess the feasibility of a larger study. The sample included the minimum number of participants required to evaluate the treatment effectiveness. The sample size is based on similar pilot studies [31,32] rather than on statistical calculations. Therefore, the number of subjects was set to 20 per group for a total a 40.

6. Randomization and allocation concealment

Randomization helps eliminate assessment bias in both participants and assessors. A statistician not involved in the study is responsible for participant randomization using a random number table created using SAS^® Version 9.4 (SAS Institute. Inc., Cary, NC). The randomization results are delivered to the investigators in sealed opaque envelopes, which are then stored in a double-locked cabinet. All participants will be informed about the study aims and procedures before signing a consent form. After baseline assessments, an investigator will open a randomization envelope. The investigator will write the day and time of opening on the envelope and sign it before entering group allocation into the participant’s electronic record.

7. Blinding

The characteristics of the treatments used in this study precluded participant and administrator blinding; however, study assessors are blinded to group allocation and are not involved in the intervention. All evaluations and analyses will be performed at a site different from the treatment site.

8. Intervention group: acupuncture-pharmacopuncture combination therapy

Acupuncture-pharmacopuncture combination therapy will be performed eight times in total, twice weekly for 4 weeks as standard; it may be performed 1-3 times per week, as required. A licensed Korean Medicine doctor, with at least two years of clinical experience in acupuncture and pharmacopuncture, will conduct the therapy, interacting with the participants as normal, which is characteristic of a pragmatic clinical trial. The treatment protocol is not pre-determined and will be determined at the specialist’s discretion, depending on patient presentation and changes over time. The intervention details will be reported in the CRFs and reviewed retrospectively.

9. Control group: acupuncture monotherapy

Acupuncture monotherapy involves dry needling without additional intervention. The course involves eight treatments, delivered twice a week for 4 weeks in general; this treatment may be delivered 1-3 times a week, as required. A licensed Korean Medicine doctor, with at least two years of clinical experience in acupuncture, will deliver all treatments and will interact with the patient as normal, which is characteristic of a pragmatic clinical trial. The acupuncture protocol is not pre-determined, and the treatment remains at the administrators’ discretion, depending on patient symptoms and changes over time. The intervention details will be recorded in the CRFs and reviewed retrospectively.

10. Co-interventions

All participants may receive other treatments for shoulder pain relief at other treatment centers in cases of severe pain onset during the study, including physical and exercise therapy. Invasive treatments, including medication and surgery, are not permitted during the trial. Finally, the participants may not undergo any other Korean medical treatments for shoulder pain during the study period.

Acetaminophen with a maximum dose of ≤ 4,000 mg (8T/day) [33,34] per day is provided as a rescue drug at visits 1, 4, and 8, in cases of intolerable pain; drug consumption must be reported. Intervention assessments will be performed without the drug administration on assessment days 4, 8, and 9.

At every visit, the type and frequency of treatments received elsewhere will be recorded on the CRFs. In cases where treatments taken by the participants may interfere with the study, these participants may be excluded.

Assessments of treatment safety and effectiveness will be performed at baseline and weeks 2, 4, and 8.

11. Primary outcome: VAS shoulder pain score

The VAS score helps to evaluate pain levels. Subjects mark the point representing their pain level on a straight 100-mm line, which represents a range from “no pain at all” to “maximum imaginable pain”. VAS scores will be the primary outcomes in the study [35].

12. Shoulder pain and disability index (SPADI)

The SPADI helps estimate shoulder pain and dysfunction caused by musculoskeletal pathology. It involves a pain and disability subscale of five and eight items, respectively. A score of 0 points indicates ‘best’ and 100 points indicates ‘worst’ outcomes. It uses an average of 13 subscale items with higher scores indicating a greater degree of disability [36].

13. Shoulder motion range

The active range of motion represents shoulder function. An assessor measures the angle of flexion, extension, abduction, external rotation, and internal rotation using a goniometer, considering spinal movement [37,38].

14. EuroQol 5-Dimension 5-Level (EQ-5D-5L)

The EQ-5D-5L is an instrument for measuring the quality of life using five levels of severity across five dimensions. Each dimension has five response categories corresponding to absent, slight, moderate, severe, and extreme problems. The vertical VAS score helps evaluate overall health on the day of assessment on a vertical line marked from 0-100 points [39].

15. Patient Global Impression of Change (PGIC)

The PGIC score reflects treatment efficacy by evaluating changes in pain levels as ‘very much improved’, ‘much improved’, ‘minimally improved’, ‘no change’, ‘minimally worse’, ‘much worse’, or ‘very much worse’ relative to baseline values [40].

16. ‘No worse than mild pain’

Reducing pain to levels of ‘no worse than mild pain’ has economic and health benefits. Although treating pain is challenging, maintain the levels mild and below may be considered effective pain control [41].

17. Drug consumption

Acetaminophen is provided to participants experiencing uncontrolled severe shoulder pain during the study period. The consumption of the drugs reflects the analgesic effects of the intervention. Participants will be required to complete a dosing diary and bring the remaining drug amounts to the assessment [42-44].

18. Adverse events

Adverse events are undesirable and unintended effects of treatments and procedures, and they may not necessarily be related to trial intervention. Adverse events will be compiled into CRFs based on vital signs, medical history, and clinical evaluation at every visit. Serious adverse events will be reported to the institutional review board and monitored by a designated agent within 24 hours of reporting until resolution. Researchers will classify these events as treatment-related or unrelated, and examine their incidence.

19. Statistical analysis

The full analysis set will be utilized to compare the intervention and control groups. Statistical analysis will involve two-tailed tests, with a significance level of 5%. All analyses will be performed using SAS^® Version 9.4 (SAS instrument, Inc., Cary, NC). Missing data will be applied intent-to-treat with multiple imputation.

Demographic and clinical characteristics will be presented as descriptive statistics for each group, including sex, age, and medical and drug administration history. Continuous variables will be compared using the independent t-test or Wilcoxon rank sum test; summary statistics will be presented as means and standard deviations. A 95% confidence interval will be reported, as required. Categorical variables will be compared using the chi-squared test or Fisher’ exact test; summary statistics will be frequencies and percentiles.

The primary outcome measure will be the difference in VAS score at visit eight relative to the baseline value. This effect will be analyzed using covariance analysis, with baseline VAS values and age as covariates and fixed factors per group. If there is a clinical difference between each group among the demographic and pre-treatment characteristics, it will be added and stratified as a covariate, as necessary.

Secondary outcomes will be analyzed according to the primary protocol. Categorical variables will be examined using the chi-squared test or Fisher’s exact test. The paired t-test or Wilcoxon signified-rank test will be used for the first and second efficacy evaluation variables to analyze the difference in pre-treatment measurements within each group, and repeated measures analysis of variance will be performed to test the difference in trend changes after treatments. Dunnett's procedure will be used to correct for multiple comparisons. Safety evaluation will involve the analysis of adverse and serious event frequencies, provided the events are attributed to the study treatment.

20. Withdrawal and dropout

The investigators will record the reasons for study drop-out and treatment discontinuation. Participants enrolled in the study will be excluded from analyses despite not complying with the eligibility criteria. If serious adverse events attributable to the study treatment occur, the study may be discontinued.

21. Ethical approval and monitoring

This study was approved by the Institutional Review Board of Daejeon University Daejeon Korean Medicine Hospital (DJDSKH-22-BM-05) and was registered at the Clinical Research Information Service and International Clinical Trials Registry Platform of the World Health Organization (identifier, KCT0007416). The study protocol complies with the principles of the Declaration of Helsinki.

All participants will be provided with sufficient information about the study before being asked to sign an informed consent form. The participants may withdraw from the study at any time without any disadvantage; all participant data are confidential. After the study completion, an independent researcher will analyze the data compiled through CRFs and source documents stored separately, as stipulated by the Institutional Review Board (IRB) regulations of Daejeon University Daejeon Korean Medicine Hospital.

A clinical research associate will monitor study compliance with the trial protocol and the applicable standards and regulations. Monitoring is planned at a minimum of three timepoints: site initiation visit, interim monitoring visit, and site closing visit. Interim monitoring will be conducted when five participants are enrolled or once a month, and the schedule will be adjusted according to the recruitment situation.

22. Recruitment

Participants will be recruited through advertisements posted on hospital boards and online, as well as those posted on regional bulletin boards and public transportation. Study recruitment began in July 2022.

A pragmatic/practical clinical trial (PCT) is used to inform decisions in clinical practice [45]. PCT involves randomization into intervention and control groups, as does a randomized controlled trial. However, while a randomized trial assesses intervention efficacy in a perfect situation, PCT evaluates its effectiveness in routine care, which involves treatment personalization. In addition, PCT findings have high generalizability and can easily be translated into practical clinical situations [46].

In Korean Medicine research, trials are conducted to evaluate the treatment safety and effectiveness [39]. It has been suggested that PCTs should be conducted before performing randomized controlled trials [47]. A recent study compared outcomes of surgical and rehabilitation-based interventions for chronic low back pain [48]. In this study, surgery was recommended at the physician’s discretion rather than being prescribed by the study protocol. Other studies have evaluated the effectiveness of pharmacopuncture for cervical pain using PCTs [49].

Korean Medicine tends to customize treatments; this feature is difficult to represent in conventional randomized clinical trials, which require that treatment protocols be pre-specified regardless of participant needs. This design limitation precludes meaningful conclusions, given the high heterogeneity of pharmacopuncture. Accordingly, this pilot trial used a PCT design to reflect clinical practice.

Pragmatic Explanatory Continuum Indicator Summary (PRECIS) is a tool to help ascertain whether a trial is pragmatic or explanatory using a continuum [50]. This tool has been improved and validated to create PRECIS-2, which covers nine domains: eligibility criteria, recruitment, setting, organization, flexibility (delivery), flexibility (adherence), follow-up, primary outcome, and primary analysis, which are scored on a scale from 1 point (very explanatory) to 5 points (very pragmatic) [51].

Herein, the eligibility is given a score of 4 points, reflecting the recruitment of a broad spectrum of patients with limitations in age and VAS scores. Similarly, recruitment is given a score of 4 points, as diverse advertisements were used to reach diverse subjects. Setting could be given a score of 3 points due to the single-center nature of this study, which is based at a tertiary healthcare institution. Organization could be assigned a score of 4 points, as we planned imaging and laboratory evaluations, which are difficult to perform at other Korean Medicine clinics. Flexibility (delivery) is given a score of 5 points because this study lacks a predefined treatment, which is at the administrator’s discretion and determined by patient presentation. Flexibility (adherence) could be given a score of 4 points, as we recruit participants who can visit frequently during the study period. Follow-up could be given a score of 2 points because the participants are required to complete questionnaires and in-person assessments. The primary outcome domain could be given a score of 5 points, as the primary outcome of this study is VAS for shoulder pain, which captures patient symptoms. The primary analysis could be given a score of 5 points, as we planned an intent-to-treat analysis using data from the CRFs.

The National Institute for Korean Medicine Development [52] recommends conventional acupuncture along with warm acupuncture, cupping, pharmacopuncture, and chuna. Pharmacopuncture is a type of acupuncture that is performed in combination with other modalities rather than alone. Pharmacopuncture may be suitable for adults with shoulder pain. However, evidence of pharmacopuncture use is considered low, and the effectiveness of this treatment is unclear. Therefore, this study aims to compare outcomes of acupuncture alone and acupuncture combined with pharmacopuncture for rotator cuff disease. Both interventions will be performed, and the outcomes will be compared.

The limitations of this study include the small sample size and the short intervention period. Owing to the pragmatic nature of the research design, the participants and administrators will not be blinded to the interventions. However, blinded assessors will perform outcome evaluations to overcome bias. Moreover, the continuity and safety of the treatments can be evaluated by setting a 4-week treatment period and a 4-week follow-up period after the last treatment. This pragmatic, randomized controlled, parallel-group clinical study may help evaluate the contribution of acupuncture and pharmacopuncture to the non-surgical treatment of rotator cuff disease.

This study was financially supported by grants from the project KSN2022210 of the Korea Institute of Oriental Medicine (KIOM), Republic of Korea.

YIK and CHH determined the study design as principal investigators and were responsible for the final decision to submit the manuscript for publication. HJC, JHJ, HKK, CHH, and IHH designed the study. HJC drafted the manuscript. JHJ, JKJ and YIK conducted intervention. JHJ and JKJ revised the manuscript. BKK determined the statistical analysis procedures. BKK, MJK, YEC and CY provided technical advice and made critical revisions to the study. All the authors read and approved the final manuscript.

This study was approved by the Institutional Review Board of Daejeon University Daejeon Korean Medicine Hospital (DJDSKH-22-BM-05, 2022-04-29) and was registered at the Clinical Research Information Service and International Clinical Trials Registry Platform of World Health Organization (identifier: KCT0007416). The study protocol complies with the principles of the Declaration of Helsinki.

Informed consent will be obtained from all the subjects enrolled in the study.

The data from this trial will be accessible to other researchers upon reasonable request from the corresponding author. The trial findings will be disseminated through open-access journals and at national and international conferences.

The authors declare no conflict of interest.