Effectiveness and Safety of Ultrasound-Guided Pharmacopuncture for Carpal Tunnel Syndrome: Protocol for A Multicenter, Randomized, Assessor-Blinded, Waiting-List-Controlled Clinical Trial

Abstract

Introduction

Carpal tunnel syndrome (CTS) is a common compressive neuropathy caused by entrapment of the median nerve within the carpal tunnel. Although conventional treatments such as injections and surgery are used, Korean medicine interventions, including pharmacopuncture, are also used in clinical practice. However, clinical evidence from randomized controlled trials of pharmacopuncture for CTS remains limited. Ultrasound-guided pharmacopuncture may improve procedural precision by enabling real-time identification of the median nerve and surrounding anatomical structures.

Objective

To evaluate the effectiveness and safety of a pragmatic ultrasound-guided pharmacopuncture as an additional treatment to lifestyle management and exercise education in patients with carpal tunnel syndrome.

Methods and Analysis

This is a multicenter, randomized, assessor-blinded, waiting-list-controlled clinical trial registered with the Clinical Research Information Service (CRIS; KCT0011180). A total of 64 participants with clinically diagnosed CTS will be enrolled at two Korean medicine hospitals and randomly allocated in a 1:1 ratio to either the intervention group or the waiting-list control group. The intervention group will receive ultrasound-guided pharmacopuncture once weekly for 3 weeks in addition to lifestyle management and exercise education, whereas the waiting-list control group will receive lifestyle management and exercise education only during the study period. The primary outcome is the change in hand numbness and pain visual analog scale score from baseline to Visit 4 (Week 4). Secondary outcomes include the Boston Carpal Tunnel Questionnaire, median nerve cross-sectional area measured by ultrasound, maximum grip strength of the affected hand, and Patient Global Impression of Change. The primary effectiveness outcome will be evaluated in the full analysis set using a mixed-effects model for repeated measures.

Conclusion

This trial will provide comparative effectiveness and safety evidence for ultrasound-guided pharmacopuncture added to lifestyle management and exercise education in patients with carpal tunnel syndrome.

Introduction

Carpal tunnel syndrome (CTS) is a common compressive neuropathy resulting from entrapment of the median nerve within the carpal tunnel. This condition is associated with hand numbness, pain, and muscle weakness, and can substantially affect daily activities and work performance.¹ CTS is associated with repetitive wrist use and other occupational and individual risk factors, and it often requires ongoing symptom management.²

According to healthcare big data from the South Korean Health Insurance Review and Assessment Service (HIRA), more than 160,000 patients per year received treatment for CTS between 2020 and 2023, and approximately 73% of patients in 2023 were female. Annual treatment costs associated with CTS in South Korea increased from 48.8 billion KRW in 2020 to 51.2 billion KRW in 2023.³ Thus, CTS is a highly prevalent condition associated with a significant socioeconomic burden, highlighting the need for more effective and standardized treatment strategies.

Current management of CTS includes conventional medical approaches such as pharmacotherapy, physiotherapy, injections, and surgery,⁴ as well as Korean medicine interventions such as acupotomy, pharmacopuncture, and chuna manual therapy.⁵ Pharmacopuncture is a therapeutic modality that combines acupuncture theory with the administration of herbal medicine–derived or other medicinal extracts by injection into acupuncture points or affected sites.⁵ However, although a randomized comparative study of pharmacopuncture has been reported,⁶ the number and scale of available studies remain limited, and the clinical evidence regarding its effectiveness and safety is insufficient. Ultrasound-guided pharmacopuncture may improve procedural precision by allowing real-time visualization of the target and adjacent anatomical structures, and procedural guidance for its application to upper-extremity nerve entrapment, including CTS, has been described.⁷ The Daling (PC7) region was selected because the Korean medicine clinical practice guideline identifies PC7 among treatment sites along the median nerve for CTS, including pharmacopuncture.⁵ Ultrasound-guided perineural injection may facilitate hydrodissection, mechanically separating the median nerve from the transverse carpal ligament and flexor tendons, whereas anti-inflammatory activity has been reported for the pharmacopuncture preparations used in this trial or their principal constituents.^8–12 The present trial evaluates these procedural and solution-related components together and is not designed to determine their relative contributions. Meanwhile, randomized studies of ultrasound-guided perineural injection for CTS have compared dextrose with normal saline placebo and with corticosteroid, and broader evidence on ultrasound-guided CTS injections has also been reviewed.^8,13,14 These studies provide relevant clinical context but involve different injectates and comparator designs and therefore do not directly establish the effectiveness of ultrasound-guided pharmacopuncture for CTS. Accordingly, its comparative effectiveness and safety remain to be established in a randomized controlled trial.

Waiting-list control designs have been used as an alternative approach to minimize ethical concerns while maintaining the structure of a randomized clinical trial, since the control group receives the same intervention after a defined delay rather than immediately.¹⁵ In particular, when evaluating interventions that are not suited for placebo control because of ethical or practical limitations, a waiting-list control design offers all participants the opportunity to receive treatment while still enabling a controlled comparison of clinical outcomes. In addition, this design may improve participant acceptability and better reflect the continuity of routine clinical practice. Therefore, a waiting-list control group was selected in this study as a pragmatic comparator to evaluate the clinical effectiveness of US-guided pharmacopuncture in patients with CTS.¹⁵

The objective of this study is to evaluate the comparative effectiveness and safety of a pragmatic treatment strategy involving ultrasound-guided pharmacopuncture combined with lifestyle management and exercise education, compared with lifestyle management and exercise education alone, in patients with CTS. Accordingly, the primary hypothesis is that participants receiving US-guided pharmacopuncture in addition to lifestyle management and exercise education will show a greater reduction in the combined hand numbness and pain VAS score from baseline to Visit 4 (Week 4) than those receiving lifestyle management and exercise education alone.

Materials and Methods

Study Design

This study is a multicenter, randomized, assessor-blinded, waiting-list-controlled clinical trial. The study will be conducted at Pusan National University Korean Medicine Hospital (PNUKH) and Woosuk University Korean Medicine Hospital (WSOH), with the Department of Korean Medicine Rehabilitation at PNUKH serving as the primary study center. Participants will be recruited through recruitment posters displayed in and around the participating clinical trial sites. Interested patients will be informed about the study by clinical research coordinators and will provide written informed consent before screening. The study protocol (version 1.3, dated 31 October 2025) was approved by the Institutional Review Board of Pusan National University Korean Medicine Hospital on 14 November 2025 (approval no. PNUKH IRB 2025–08-003-002) and by the Institutional Review Board of Woosuk University Korean Medicine Hospital on 17 November 2025 (approval no. WSOH IRB H2508-01-01). The trial was registered with the Clinical Research Information Service (CRIS) on 19 November 2025 under the registration number KCT0011180. Participants who provide written informed consent, undergo screening assessments, and meet the inclusion and exclusion criteria will be enrolled. Enrolled participants will be randomly assigned in a 1:1 ratio to either the intervention group or the waiting-list control group. Screening and Visit 1 assessments will be performed on the same day. The intervention group will receive US-guided pharmacopuncture, lifestyle management, and exercise education once weekly for 3 weeks. The waiting-list control group will receive lifestyle management and exercise education only during the same period. The total treatment period will be 3 weeks, followed by three follow-up visits after completion of treatment. Follow-up assessments at Weeks 4, 7, and 11 were prespecified to evaluate the initial post-treatment response and the persistence of treatment effects, with Week 11 occurring approximately 8 weeks after the final treatment. The SPIRIT schedule of enrollment, interventions, and assessments is presented in Table 1, and the study flow diagram is shown in Figure 1. This study protocol adheres to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2025 guidelines,¹⁶ and the completed SPIRIT checklist is provided as S1 File.

Table 1.

SPIRIT Participant Timeline: Schedule of Enrollment, Interventions, and Assessments

Timepoint	Trial Period
	Enrollment		Post-Randomization					Close-Out
	Screening	Allocation	Visit1a(Week1)	Visit2 (Week2)	Visit3 (Week3)	Visit4 (Week4)	Visit5 (Week7)	Visit6 (Week11)
Enrollment:
Informed consent	X
Vital signb	X			X	X	X	X	X
Body measurements	X
Demographic characteristics	X
Medical history and concomitant medication review	X
Physical examination	X
Skin testc			X
Eligibility assessment	X
Randomization		X
Intervention/ Comparator:
Ultrasound-guided pharmacopuncture (intervention group)			X	X	X
Lifestyle management and exercise education / adherence assessmentd			X	X	X
Assessments:
Hand numbness and pain VASe	X			X	X	X	X	X
BCTQ		X				X	X	X
Wrist ultrasound (median nerve CSA)		X				X	X	X
Maximum grip strength of the affected hand		X				X	X	X
PGIC						X		X
Safety/Follow-Up:
Concomitant medication and treatment assessmentf				X	X	X	X	X
Early withdrawal assessment			X	X	X	X	X	X
Adverse event assessment			X	X	X	X	X	X

Notes: X indicates that the corresponding intervention, procedure, or assessment is performed at the specified time point. ^a Screening and Visit 1 are performed on the same day. ^b Vital signs are measured at every on-site visit; for the waiting-list control group, measurements are omitted at Visit 2–3, when no on-site visit occurs. ^c If the pharmacopuncture type is changed at the clinician’s discretion, an additional skin test may be performed using the newly selected solution. ^d Lifestyle management and exercise education are provided to both groups at Visit 1, and exercise adherence is checked at Visits 2–3. ^e VAS is used at screening to confirm eligibility; in the intervention group, VAS is also assessed before each treatment session at Visit 2 and 3. ^f For the waiting-list control group, concomitant medication/treatment changes and early withdrawal are checked by telephone at Visits 2–3.

Abbreviations: BCTQ, Boston Carpal Tunnel Questionnaire; CSA, cross-sectional area; PGIC, Patient Global Impression of Change; VAS, Visual Analog Scale. Adapted from the SPIRIT 2025 participant timeline developed by Chan et al,¹⁶ under the Creative Commons Attribution 4.0 International License.

Figure 1.

Study flow diagram. Participants with carpal tunnel syndrome who provide informed consent and meet the eligibility criteria at screening will be randomized (n = 64) to either the intervention group (n = 32) or the waiting-list control group (n = 32). The intervention group will receive ultrasound-guided pharmacopuncture plus lifestyle management and exercise education (3 sessions over 3 weeks), whereas the waiting-list control group will receive lifestyle management and exercise education only during the study period. The primary endpoint will be assessed at Visit 4, followed by follow-up assessments at Visits 5 and 6. After completion of the study assessments, participants in the waiting-list control group will be offered ultrasound-guided pharmacopuncture.

Waiting-List Control Group

The waiting-list control group will receive the same lifestyle management and exercise education as the intervention group at Visit 1 but will not receive US-guided pharmacopuncture during the study assessment period. A waiting-list design was selected in consideration of the ethical and practical limitations of using a placebo control and the need to preserve participants’ opportunity to receive treatment. By differing only in the timing of pharmacopuncture delivery, this design allows comparison of clinical effectiveness under conditions reflecting routine clinical practice and may improve participant acceptability and adherence. After completing the Visit 6 assessments, participants in the waiting-list control group will be offered the same three once-weekly sessions of US-guided pharmacopuncture as the intervention group.

Sample Size

The required sample size was calculated based on a previous study by Wu, et al¹³ In that study, the difference in the mean change in visual analog scale (VAS) score was 2.16, and the standard deviations (SD) in each group were 1.64 (SD1) and 2.52 (SD2), respectively. On this basis, the pooled SD for the present study was estimated to be 2.12. Assuming a group allocation ratio of 1:1, a two-sided significance level of 0.05, and 95% power, the sample size was calculated using the following normal-approximation formula:

Here, n is the calculated sample size per group, δ is the assumed between-group difference, σ is the assumed common standard deviation, and w is the anticipated dropout proportion. After accounting for an anticipated dropout rate of 20% and rounding up, the target sample size was set at 32 participants per group, yielding a total of 64 participants. The calculation was performed directly using the formula without dedicated sample-size software.

Participants

Inclusion Criteria

Participants eligible for this study must meet the following criteria:

1. Symptoms of hand numbness and pain for ≥3 months, with a combined hand numbness and pain VAS score of ≥50 mm (out of 100 mm).

2. Male or female adults aged ≥19 years old and ≤70 years old.

3. Fulfill at least one of the following criteria (for bilateral symptoms, the side with more severe symptoms will be selected):

• Sensory abnormalities (eg, reduced sensation) in the distribution of the median nerve (palmar surface of the first, second, and third digits and radial half of the fourth digit; dorsal surface of the distal phalanges of the second and third digits and radial half of the fourth digit)

• Atrophy of the thenar eminence compared with the unaffected hand.

• Positive response to Phalen’s test and/or Tinel’s sign.

• 4.Ability to communicate normally.
• 5.Willingness to participate in the clinical trial and follow-up assessments, with voluntary provision of written informed consent approved by the institutional review board (IRB).

Severe CTS is characterized by objective findings such as thenar atrophy, weakness of thumb abduction or opposition, and constant sensory loss.¹⁷ Thenar atrophy and sensory deficits in the median nerve distribution will be assessed during screening in this trial. When these or other clinical findings raise concern for severe CTS, the investigator will assess whether surgical evaluation should take priority over trial participation. Patients considered to require surgical management will not be enrolled and will be referred for appropriate surgical evaluation.

Exclusion Criteria

Individuals meeting one or more of the following criteria will be excluded from the study:

1. Neurological symptoms of the hand due to causes other than CTS, such as polyneuropathy, brachial plexopathy, thoracic outlet syndrome, or cervical disc herniation.

2. Sensory abnormalities of the hand due to systemic diseases, such as rheumatoid arthritis, diabetes, thyroid disease, or hormonal disorders.

3. Receipt of surgery, steroid injections, or other injection-based procedures (eg, local anesthetic injection) involving the hand within 1 month before screening.

4. Receipt of Korean medicine treatment (acupuncture, pharmacopuncture, moxibustion, or cupping) within 2 weeks before screening. However, based on the judgment of a sub-investigator, participation may be permitted if treatment received at another institution during this period was unrelated to the indication for this clinical trial.

5. Use of medications that may affect pain outcomes, including systemic steroids, antipsychotics, antidepressants, antiepileptics, or anxiolytics/sedative-hypnotics, within 1 month before screening. Participants receiving a stable dose of anxiolytics/sedative-hypnotics for at least 4 weeks at screening are exempt from this criterion. Other medications that could affect study results (eg, NSAIDs) are also exclusionary. These medication-related exclusion criteria were prespecified to minimize potential confounding of the patient-reported pain and numbness outcome by concomitant medications that may alter pain intensity or sensory symptoms.

6. Women who are currently pregnant or may be pregnant.

7. Internal medical conditions judged unsuitable for participation in this trial, such as severe systemic infection.

8. Wrist fracture, trauma, congenital deformity, or presence of a prosthesis at a relevant anatomical site.

9. Conditions in which pharmacopuncture is considered unsuitable or unsafe (eg, hemorrhagic disease or severe diabetes with increased infection risk).

10. Participation in another clinical trial completed within the previous 1 month, or planned participation in another clinical trial during the intervention or follow-up period of this study.

11. Inability to provide written informed consent.

12. Any other condition that the investigators judge to be unsuitable for participation in the clinical trial.

Eligibility for CTS will be based on the prespecified clinical criteria described above, together with exclusion of alternative neurological and systemic causes of hand symptoms. Electrodiagnostic confirmation and a predefined ultrasonographic threshold are not mandatory for enrollment, consistent with current clinical guidance supporting clinical diagnosis of CTS without routine NCV/EMG or ultrasonographic testing in all patients.⁴

Discontinuation and Dropout Criteria

Participants may withdraw from the study voluntarily at any time. Participation may also be discontinued or withdrawn at the investigator’s judgment. If intervention or observation is stopped, the investigator must assess and accurately document the primary reason for discontinuation or withdrawal.

The discontinuation and dropout criteria are as follows:

1. Participants found during the study to have violated the inclusion or exclusion criteria.

2. Participants who experience a serious adverse event (SAE), or when continuation in the study is judged difficult because of a non-serious adverse event (AE).

3. Participants with a disease not detected during pre-study testing but later identified and judged by the investigator to be capable of affecting the study results.

4. Participants who, directly or through a proxy, request discontinuation of the study or withdrawal of consent.

5. Participants confirmed to be pregnant during the study.

6. Participants unable to undergo medical treatment or procedures for CTS.

7. Participants requiring surgery or inpatient treatment for reasons such as an accident or another disease. This does not include hospitalization for simple observation unrelated to CTS, planned surgery, or examinations, including health check-ups or MRI scans.

8. Participants lost to follow-up during the study.

9. Any other condition that the investigators judge to be unsuitable for continued participation in the study.

For all cases of discontinuation or dropout, the reasons will be recorded in detail in the case report form (CRF). If discontinuation or dropout is due to an AE, the participant’s clinical course will continue to be monitored and recorded until the condition stabilizes or follow-up is no longer possible. If discontinuation or dropout is due to an AE related to the intervention, appropriate compensation will be provided in accordance with the relevant compensation policy. Additional participants will not be recruited to replace those who discontinue or withdraw.

Randomization and Blinding Methods

Randomization

This study will use block randomization with a 1:1 allocation ratio. The randomization list will be generated using SAS software (Version 9.4 or higher; SAS Institute Inc., Cary, NC, USA) by an independent statistician who is not directly involved in the trial. Using hospital as a stratification variable, the blocks will be randomly mixed. The generated randomization list will be stored and managed by staff independent of the study to prevent unauthorized disclosure.

Each hospital will be provided with sequentially numbered, opaque, sealed, and tamper-evident allocation envelopes. These envelopes will be stored in a locked container. Participants will be assigned a screening number in the order in which they provide written consent. If they meet the inclusion and exclusion criteria, they will then be assigned a randomization number in the order of enrollment. An investigator will open the envelope with the corresponding number to confirm the participant’s group allocation. The investigator will sign and date the envelope before opening it. After the participant’s group allocation has been confirmed, the opened envelope will be stored separately. Randomization numbers that have already been used will not be reused.

Blinding

This will be an open-label trial because pharmacopuncture will be provided only to the intervention group; therefore, practitioners and participants cannot be blinded to group allocation. However, assessor blinding will be maintained, and the person responsible for outcome assessment will have no access to group allocation information. The same exercise and lifestyle management education will be provided to both groups. The educator responsible for this intervention will not be involved in pharmacopuncture and will have no knowledge of the participant group allocation. This design is intended to minimize unintentional bias during intervention delivery and outcome assessment. Effectiveness assessments will be performed according to a structured procedure, and the assessor will confirm only the items required to complete the CRF using standardized methods.

Interventions

The intervention group will receive US-guided pharmacopuncture in addition to lifestyle management and exercise education, whereas the waiting-list control group will receive lifestyle management and exercise education alone during the main study period and will be offered US-guided pharmacopuncture after completion of the study assessments. US-guided pharmacopuncture will be administered once weekly for 3 weeks, for a total of three sessions. Lifestyle management and exercise education will be provided identically to both groups.

US-Guided Pharmacopuncture

The procedure will be performed by Korean medicine doctors at each center with at least 2 years of clinical experience and prior experience in ultrasound-guided procedures. Before study initiation, all participating practitioners will undergo in-person training based on the same standard operating procedure (SOP), including demonstration of the standardized ultrasound-guided pharmacopuncture procedure and confirmation of procedural competency. To maintain consistency across centers, adherence to the SOP and procedural issues will be reviewed during monthly intersite videoconferences. Treatment fidelity will additionally be monitored through CRF documentation of the pharmacopuncture preparation and total injected volume and through regular monitoring of compliance with the protocol and SOP; any protocol deviations will be documented and reviewed.

The type of pharmacopuncture solution and injection site will be determined on the basis of prior examinations, ultrasound findings, and the clinician’s judgment. The type of pharmacopuncture solution used and the total injected volume will be recorded in the CRF. Allowing selection among multiple prespecified preparations reflects the individualized nature of the intervention and the pragmatic objective of evaluating US-guided pharmacopuncture as a clinical treatment approach rather than the efficacy of a single pharmacopuncture preparation. Procedural standards, safety monitoring, and restrictions on concomitant medications are prespecified in the protocol. The pharmacopuncture solutions used in this study will include melittin-containing bee venom pharmacopuncture, Hominis placenta pharmacopuncture, Hwangryun-haedok-tang pharmacopuncture, and Soyeom (anti-inflammatory) pharmacopuncture. Sweet BV and Soyeom pharmacopuncture will be prepared by the external herbal dispensary affiliated with Kirin Korean Medicine Clinic, whereas Hominis placenta and Hwangryun-haedok-tang pharmacopuncture will be prepared by the Jaseng External Herbal Dispensary. All preparations will be obtained from external herbal dispensaries certified to GMP or equivalent standards. Bee venom pharmacopuncture will be prepared using 0.5 mL of Sweet BV solution (1:10,000) and 2.5 mL of 5% dextrose solution, whereas Hominis placenta, Hwangryun-haedok-tang, and Soyeom pharmacopuncture will each be prepared using 1.5 mL of the respective solution and 1.5 mL of 5% dextrose solution. Before pharmacopuncture, the practitioner will review the participant’s history of allergy or previous adverse reactions to the components of the available pharmacopuncture preparations. Before the first treatment at Visit 1, a skin test will be performed using the selected pharmacopuncture solution. A 0.05 mL volume of the solution will be administered to the lateral aspect of the contralateral forearm, and the test site will be assessed after 15 minutes for signs of an allergic reaction, including erythema, wheal formation, and pruritus. If the findings are considered indicative of an allergic reaction, the selected solution will not be administered, and an alternative solution may be selected according to the same clinical decision-making process. Skin testing is used as a precautionary measure to screen for hypersensitivity; however, its predictive value for bee venom–related anaphylaxis is limited, and a negative result does not exclude subsequent allergic reactions.¹⁸

During the procedure, participants will be seated with the elbows flexed to 90°, and the affected wrist placed on a towel in dorsiflexion with the palm facing upward. The forearm will be maintained in supination. The treatment site will first be sterilized with povidone-iodine and alcohol, and a sterile cover will be placed over the US probe to improve contact between the probe and the skin. The US scan will be performed in the cross-sectional (short-axis) plane at the wrist crease level. The flexor retinaculum, median nerve, flexor tendons within the carpal tunnel, and the ulnar nerve and artery outside the carpal tunnel will be identified. If necessary, Doppler mode will be used to further confirm the location of blood vessels.¹⁹ During needle advancement and injection, the practitioner will avoid intravascular injection and continuously monitor for signs of nerve irritation or abnormal sensation.

Pharmacopuncture will be performed along the line connecting the scaphoid and pisiform. Under US guidance, the needle will be inserted using an in-plane approach.⁸ Considering the anatomical structures and the patient’s skeletal anatomy, the approach direction will be selected from either the ulnar side or radial side toward the Daling (PC7) acupuncture point. A 27 gauge, 38 mm disposable needle will be used for the procedure. The total injected volume of the prepared pharmacopuncture solution will be 2–3 mL. The needle will be inserted through a single skin entry point. The needle shaft and tip will be continuously visualized under ultrasound throughout advancement and injection. No fixed numerical safety distance from the median nerve is prespecified; instead, the needle tip will be maintained outside the median nerve under continuous ultrasound visualization. The insertion depth will be determined in real time according to the ultrasound-visualized depth and position of the median nerve and adjacent anatomical structures. Hydrodissection will be performed by injecting approximately half of the solution deep to the median nerve and the remaining half superficial to the nerve without complete withdrawal of the needle.

After the procedure, passive wrist flexion and extension will be repeated five times to facilitate distribution of the injected fluid throughout the carpal tunnel. To monitor for AEs, an ice pack will be applied to the treatment site for 15 min, during which participants will be observed for local reactions, including redness, wheals, itching, swelling, and pain, as well as systemic allergic symptoms. If an immediate systemic reaction occurs, vital signs will be measured, the participant will be placed supine with the legs slightly elevated, and the participant will be transferred to the emergency department if symptoms persist. After confirming the participant’s condition, the procedure will be considered complete. Participants who complete the pharmacopuncture procedure will receive education on infection prevention at the treatment site and pain management. Before leaving the study site, participants will also be instructed about the possibility of delayed allergic reactions and advised to contact the study team immediately using the provided emergency contact information if delayed allergic symptoms occur after discharge.

Lifestyle Management and Exercise Education

Both the intervention group and the control group will receive lifestyle management and exercise education at Visit 1. This education is intended to alleviate CTS symptoms and support functional recovery. An exercise education leaflet has been developed on the basis of relevant clinical literature and previous studies.^20,21 This leaflet will be used during the education session and provided to the participants. It includes wrist stretching and strengthening exercises, the purpose of exercise, and relevant precautions (Figure S1–S7 in the S2 File). After the education session, the leaflet will be distributed to participants.

Following the initial education session, exercise performance will be recorded in the planner included in the leaflet. For the intervention group, exercise adherence will be reviewed at Visits 2 and 3. The waiting-list control group will be contacted by telephone at the same time points to confirm exercise performance. All relevant information will be recorded in the CRF.

Participant Retention

Before randomization, participants will be informed that those allocated to the waiting-list control group will be offered the same three once-weekly sessions of US-guided pharmacopuncture as the intervention group after completing all study assessments at Visit 6. To minimize discontinuation and loss to follow-up, participants will be contacted at Visits 2 and 3 and reminded of upcoming assessment schedules and planned intervention provision in order to encourage continued participation.

Concomitant Treatment

From the screening visit until completion of the study, invasive conventional medical treatments (eg, injections or surgery) and Korean medicine treatments other than the intervention provided in this study (eg, acupuncture, pharmacopuncture, chuna manual therapy, cupping, or herbal medicine) will not be permitted. However, during the intervention period, rescue medications may be allowed if unavoidable, based on the investigator’s judgment. Information regarding all concomitant medications (drug name, indication, dose, treatment duration, etc.) will be recorded in detail in the CRF. Medications that participants have been taking for at least 4 weeks before enrollment may be permitted if the investigator judges that they will not affect interpretation of the study results.

Outcome Measurement

Primary outcome: Hand numbness and pain Visual Analog Scale (VAS)

For participants with bilateral CTS, the more severely symptomatic hand identified at screening will be designated as the target hand, and hand-specific outcome assessments will refer to this hand throughout the study. This scale consists of a 100 mm horizontal line, with one end representing “no numbness or pain whatsoever” and the other representing “the most severe numbness or pain imaginable.” Pain and numbness are rated together on a single VAS reflecting their overall intensity during the previous week. This response will be converted into a quantitative score ranging from 0 to 100 mm for analysis.²² The combined hand numbness and pain VAS was selected as the primary outcome because pain and numbness are major symptoms of CTS and the VAS provides a simple quantitative measure of symptom intensity.^1,13,22 The primary effectiveness endpoint is the change in VAS score between baseline and Visit 4 (Week 4). Visit 4 (Week 4) was selected because it is the first post-treatment assessment after the three-week intervention at which both groups undergo the same efficacy evaluation. Assessments will be conducted at screening and at Visits 2, 3, 4, 5, and 6. At Visits 2 and 3, only the intervention group will be assessed because the control group will not attend these visits.

Secondary Outcomes

1) Boston Carpal Tunnel Questionnaire (BCTQ)

The BCTQ is a standardized self-report questionnaire designed to enable patients to assess the CTS symptom severity and functional impairment. It consists of two subscales. The Symptom Severity Scale (SSS) evaluates subjective symptoms such as pain, numbness, and sensory abnormalities. The Functional Status Scale (FSS) measures the ability to perform hand-related activities of daily living. Each item is scored on a 5-point scale, with higher scores indicating more severe symptoms or greater functional impairment.^23,24 Assessments will be conducted at Visit 1 (before treatment) and at Visits 4, 5, and 6.

2) Cross-Sectional Area (CSA) of the Median Nerve

The CSA of the median nerve is a US parameter used to diagnose and grade CTS. At the carpal tunnel inlet (the cross-sectional plane in which the scaphoid and pisiform are visualized together), the CSA is measured by tracing the epineurium of the median nerve.¹⁹ Assessments will be conducted at Visit 1 (before treatment) and at Visits 4, 5, and 6. CSA measurements will be performed by an outcome assessor who has no access to group allocation information.

Measurement Equipment and Test Position

• Equipment: Linear transducer of the V6 ultrasound system (Samsung Medison, Seoul, Korea).

• Test position: Participants will lie in the supine position with the forearm supinated, the palm facing upward, and the wrist in a neutral position.

Measurement Site

• The measurement site is the proximal inlet of the carpal tunnel, where both the scaphoid and pisiform are visualized together. This location was selected on the basis of previous studies reporting it to be the most consistent, sensitive, and specific for measurement of the median nerve CSA.²⁵

Measurement Method

• CSA will be measured using the tracing method by directly following the epineurium of the median nerve on the US screen, and the value calculated by the device will be recorded.²⁵

3) Maximum Grip Strength of the Affected Hand

Grip strength is an objective index of muscle strength recovery in the hand and also reflects the degree of functional impairment in CTS.²⁶ In this study, maximum grip strength of the affected hand will be measured using a digital dynamometer and used as a quantitative indicator of functional recovery before and after the intervention.²⁷ Assessments will be conducted at Visit 1 (before treatment) and at Visits 4, 5, and 6.

Measurement Equipment and Test Position

• Equipment: Digital dynamometer (CAMRY EH101, Camry Electronic Ltd., Guangdong, China).

• Test position: Participants will be seated with the shoulder in a neutral position, the elbow flexed to 90°, the forearm in a neutral position, and the wrist positioned at 0–30° extension and 0–15° ulnar deviation.

Measurement Method

• Grip strength will be measured three times, with participants instructed to grip as forcefully as possible during each measurement. The highest of the three values will be recorded as the maximum grip strength.

4) Patient Global Impression of Change (PGIC)

The PGIC is a measure of subjective improvement following treatment. Participants will be asked to rate, on a 7-point scale, how much their hand pain and numbness have improved compared with before participation in the clinical trial.²⁸ Assessments will be conducted at Visits 4 and 6. A PGIC response will be defined as a rating of “very much improved” or “much improved.” Participants selecting any other response category will be classified as nonresponders.

Safety Assessment

Safety assessment will focus on AEs and SAEs. AEs refer to all undesirable and unintended signs, symptoms, or diseases occurring during the study period and will be recorded regardless of their causal relationship with the intervention.²⁹ For all AEs, investigators will record the event name, date of onset, date of resolution, outcome, treatment (if applicable), and severity in the electronic case report form (eCRF). Expected procedure-related AEs include bruising, pain, redness, wheals, and itching at the treatment site, as well as dizziness and nausea. SAEs are defined as death, life-threatening events, events requiring hospitalization or prolonged hospitalization, events causing severe or permanent disability or dysfunction, events causing congenital deformity or fetal abnormality, or other medically important events.²⁹ The severity of all AEs will be assessed according to the three-level classification system of Spilker,³⁰ and causal relationships with the intervention will be assessed using the UMC causality assessment system.³¹ SAEs will be reported by sub-investigators to the principal investigator within 24 h, and the principal investigator will immediately report them to the IRB for review of whether the study should continue.

Criteria for Early Termination and Study Completion

The study will be completed once the planned number of participants have been enrolled, all follow-up observations and data collection have been completed according to the clinical trial protocol, and data completeness has been verified. The time at which the last participant completes all planned follow-up visits will be defined as the time of study completion. Study completion for individual participants will be defined as completion of all planned visits, assessments, and procedures specified in the study protocol without dropout or discontinuation.

Data Management and Monitoring

Data will be collected using unified CRFs. Monitoring will be conducted to verify that participants’ rights and welfare are protected, to confirm the accuracy, completeness, and verifiability of reported data, and to assess adherence to the study protocol and relevant regulations. A clinical trial monitor from the Korea Institute of Oriental Medicine will review trial conduct and CRFs with the investigators and, if necessary, verify supporting documents by telephone, email, on-site visits, or access to the data management system. Following initial monitoring, the first regular monitoring visit will be conducted within 3 weeks after enrollment of the first participant, with subsequent monitoring performed regularly throughout the trial. Final monitoring will be conducted after trial completion. The scope of monitoring will include adherence to the study protocol, appropriateness and accuracy of data collection, confirmation of consent forms, collection and reporting of AEs, and management of study-related data.

Statistical Analysis

The primary analysis set for effectiveness assessment will be the Full Analysis Set (FAS), which represents a modified intention-to-treat (ITT) population. Participants included in the FAS will be analyzed according to their randomized group. Per-protocol (PP) analyses will also be performed to verify the consistency of the results. The FAS will include randomized participants who have at least one post-randomization measurement of an effectiveness outcome variable. All data obtained from these participants will be included in the analysis. Participants meeting any of the following criteria will be excluded from the FAS: violation of the inclusion or exclusion criteria; for participants allocated to the intervention group, no receipt of ultrasound-guided pharmacopuncture; or no data provided after screening. The PP analysis will include participants in the FAS who complete all study procedures as specified in the clinical trial protocol and have no major protocol violations that could affect the trial results, including violations of the inclusion or exclusion criteria. Safety variables will be analyzed in both the Safety Set and per-protocol (PP) populations. The Safety Set will serve as the primary analysis set for safety and will include participants from either randomized group who receive at least one study intervention and from whom safety-related data are collected at least once.³² Study interventions include lifestyle management and exercise education; waiting-list participants who receive this intervention and have at least one safety assessment will therefore be included in the Safety Set. Pharmacopuncture administered to waiting-list participants after Visit 6 will not be included in the trial safety analysis.

All statistical analyses will be performed using two-tailed tests with a significance level of 5%. SAS software (Version 9.4 or higher; SAS Institute Inc., Cary, NC, USA) will be used for all analyses. Continuous variables will be presented as mean with 95% confidence interval or median and interquartile range, according to data distribution. Categorical variables will be presented as frequency and percentage. Baseline clinical characteristics, including baseline VAS, symptom duration, and treatment history, will be summarized by randomized group. Between-group comparisons of baseline characteristics will be performed using the independent t-test or Wilcoxon rank-sum test for continuous variables, and the chi-square test or Fisher’s exact test for categorical variables.

The primary effectiveness endpoint is the change in hand numbness and pain VAS score between baseline and Visit 4, which will be analyzed using a mixed model for repeated measures (MMRM).³³ The primary between-group analysis will include measurements at baseline and Visit 4. Treatment group, visit, and treatment-by-visit interaction will be included as fixed effects, and participant will be included as a random effect. Baseline VAS and other relevant baseline characteristics, such as symptom duration, treatment history, repetitive wrist use and daily wrist-use duration, will be included as covariates if statistically significant between-group differences are identified at baseline. Study center will not be included in the model. An unstructured covariance structure and the Satterthwaite approximation for degrees of freedom will be used. The primary contrast will be the between-group difference in mean change in VAS from baseline to Visit 4. Measurements at Visits 2 and 3 will be used to examine trends within the intervention group and will not be included in the primary between-group analysis. Secondary endpoints, including BCTQ-FSS, BCTQ-SSS, median nerve CSA, and maximum grip strength of the affected hand, will be analyzed using the same methods as the primary endpoint. PGIC responder proportions will be compared between groups at Visits 4 and 6 using cross-tabulation analysis. All secondary outcome analyses will be exploratory, and no multiplicity adjustment will be applied.

Because maximum likelihood estimation in the MMRM will be used under the missing-at-random assumption, missing data for effectiveness endpoints will not be imputed separately.³⁴ Results from the PP analysis will be compared with those from the FAS analysis to assess consistency across analysis populations.

Patient and Public Involvement

Patients and the public were not involved in the design, conduct, reporting, or dissemination plans of this study. However, information on the study results will be made available to participants upon request after study completion.

Ethics and Dissemination

This study was approved by the Institutional Review Board of Pusan National University Korean Medicine Hospital on 14 November 2025 (approval no. PNUKH IRB 2025–08-003-002) and the Institutional Review Board of Woosuk University Korean Medicine Hospital on 17 November 2025 (approval no. WSOH IRB H2508-01-01). The study will be conducted in accordance with the Declaration of Helsinki. Written informed consent will be obtained from all participants before enrollment. Any important protocol modifications will be updated in the Clinical Research Information Service registry (KCT0011180). The findings of this study will be disseminated through peer-reviewed publications and academic presentations.

Consent

All participants will receive the written participant information sheet and consent form before enrollment in the study (S3 File). The forms for the collection and use of personal information and the handling of sensitive information are provided as Tables S1 and S2, respectively, and the Participant Consent Form is provided as Box S1. Written informed consent will be obtained from all participants prior to participation in the study.

Study Status

This clinical trial is currently enrolling participants. The first participant was enrolled on January 20, 2026. Participant enrollment is expected to be completed in September 2026, and the entire trial is expected to be completed in December 2026.

Discussion

Carpal tunnel syndrome (CTS) imposes a substantial clinical burden, often affecting daily activities and work performance.⁴ Pharmacopuncture, particularly US-guided pharmacopuncture, may have clinical utility because the intervention can be performed while visualizing the lesion site in real time. However, few randomized controlled trials have investigated pharmacopuncture for CTS, and the available evidence is still inadequate to support clear conclusions regarding its comparative effectiveness and safety. This study is a multicenter, randomized, assessor-blinded, waiting-list control group clinical trial designed to evaluate the effectiveness and safety of US-guided pharmacopuncture in patients with CTS. This study is expected to expand the clinical evidence supporting Korean medicine interventions for CTS by evaluating a clinically used intervention within a randomized controlled design.

A major strength of this study is that intervention effects will be evaluated from multiple perspectives, including symptom assessment, functional assessment, and US-based objective assessment. Changes in median nerve cross-sectional area and grip strength will be interpreted as complementary structural and functional secondary outcomes alongside the patient-reported VAS, thereby providing supportive context for the overall treatment effect. In addition, the effectiveness assessor will remain blinded to group allocation, and different practitioners will provide pharmacopuncture and lifestyle management/exercise education to minimize potential bias during assessment and intervention delivery. The waiting-list control design also supports ethical acceptability while allowing comparisons that reflect routine clinical practice.

This study has several limitations. First, participant and practitioner blinding is not feasible because pharmacopuncture will be administered only to the intervention group, and the use of a self-reported VAS as the primary outcome may therefore increase susceptibility to expectation or reporting bias. Second, although the waiting-list control design may enhance clinical applicability, it does not provide the same level of control as a placebo-controlled or sham-controlled design. Therefore, the findings of this trial should be interpreted primarily as evidence on the pragmatic clinical effectiveness of US-guided pharmacopuncture rather than as an isolated estimate of its specific physiological effect. Third, the individualized use of multiple pharmacopuncture preparations and the bundled nature of the intervention introduce heterogeneity, and the findings should therefore be interpreted as reflecting the overall US-guided pharmacopuncture treatment approach rather than the efficacy of any specific preparation or the isolated contribution of ultrasound guidance. The two-center, single-country setting may limit generalizability, while standardized procedures are intended to minimize variation between centers and practitioners. Fourth, because pain and numbness are assessed using a single combined VAS, symptom-specific treatment effects cannot be distinguished. Fifth, excluding participants who use medications that may affect pain or sensory symptoms may limit the generalizability of the findings to patients receiving such medications in routine clinical practice. Sixth, the follow-up period extends only to Week 11, approximately 8 weeks after the final pharmacopuncture treatment, thereby limiting the assessment of long-term durability and recurrence. Although clinical features related to CTS severity are assessed at screening, electrodiagnostic severity grading is not performed, which limits the characterization of severity heterogeneity within the study population. These design characteristics should be considered when interpreting the study findings.

Additional considerations relate to the statistical analysis. The sample size was informed by an effect estimate from a previous study of perineural dextrose injection in CTS. Statistical power may be lower if the actual treatment effect is smaller than assumed, and a post hoc power analysis is planned after trial completion. Findings for secondary outcomes should be interpreted cautiously in view of multiple comparisons.

Nevertheless, this trial is expected to provide comparative evidence on the effectiveness and safety of US-guided pharmacopuncture added to lifestyle management and exercise education for CTS.

Funding Statement

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (RS-2025-02220993). The funder had no role in the study design, trial conduct, data collection, data management, analysis, interpretation, manuscript writing, decision to publish, or authority over these activities.

Declaration of Generative AI Use

The teaching illustrations included in the S2 File were generated using ChatGPT with GPT-4o image generation (OpenAI; May 2025). The authors reviewed and confirmed the originality, accuracy, and appropriateness of the illustrations, checked the applicable terms of use and suitability for publication, confirm the right to publish the generated images, and take full responsibility for the integrity of the content.

Data Sharing Statement

No datasets have yet been generated since this manuscript reports a study protocol.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

Mrs Jung-Gyung Lee reports Support for the manuscript from Korea Health Industry Development Institute (KHIDI), during the conduct of the study.

Dr Sun-Young Park reports Support for the manuscript from Korea Health Industry Development Institute (KHIDI), during the conduct of the study.

Mr Bong-Jin Shin reports Support for the manuscript from Korea Health Industry Development Institute (KHIDI), during the conduct of the study.

Professor Yoomin Choi reports Support for the manuscript from Korea Health Industry Development Institute (KHIDI), during the conduct of the study.

Dr Ojin Kwon reports Support for the manuscript from Korea Health Industry Development Institute (KHIDI), during the conduct of the study.

Prof. Dr. Eui-Hyoung Hwang reports Support for the manuscript from Korea Health Industry Development Institute (KHIDI), during the conduct of the study. The authors report no conflicts of interest in this work. This study protocol (version 1.3, 31/Oct/2025) has been registered on November 19, 2025 at Clinical Research Information Service (KCT0011180).