Visual abstract

Introduction

Neck pain is defined as pain causing discomfort localized to the region between the superior nuchal line and the spine of the scapula, and includes the superior border of the clavicle and the suprasternal notch. This pain may radiate to the head, trunk, and upper limbs [1]. Chronic neck pain is characterized by persistent discomfort that occurs on most days, over the previous 3 months, and restricts daily activities [2].

Neck pain is a common musculoskeletal condition, with a global age-standardized prevalence of 2,450 (range: 1,960–3,040) per 100,000 individuals [3]. In the modern era, the prevalence of neck pain has increased largely due to the extensive use of computers and smartphones [4–6], as well as habitual posture imbalances. Between 14.2% and 71% of adults are estimated to have experience neck pain at least once in their lives [7]. Among those affected, nearly 47% develop chronicity [8], which is often accompanied by reduced work capacity, and emotional issues, and this carries a considerable socioeconomic burden [9]. The Global Burden of Diseases, Injuries, and Risk Factors Study 2019, reported that neck pain ranked as the 11th most common cause of years lived with disability out of the 369 diseases studied [10].

Guidelines recommend a multimodal approach for managing general nonspecific neck pain [11,12]. This includes nonopioid analgesics, exercise therapy, manual therapy, patient education, acupuncture, and pharmacopuncture [11,12]. Pharmacopuncture, a treatment modality originating in China, developed in Korea, is a Korean medicine (KM) treatment which involves the injection of herbal extracts into specific acupuncture points. Pharmacopuncture aims to enhance the therapeutic effects of traditional acupuncture by delivering a medicinal solution directly to meridians and acupoints [13].

In Korea, pharmacopuncture is widely practiced, with nearly half of Korean medicine doctors (KMDs) utilizing it to treat chronic neck pain [14]. Various formulations are employed, including bee venom, Jungsongouhyul, Carthmi-Flos, Shinbaro, and Harpagophytum procumbens [15,16]. Treatment typically targets acupoints near the affected area, particularly those along the Small intestine and Gall bladder meridians, as well as Ahshi points, trigger points, and Huatuo-HyupCheok (EX-B2) [17].

In a 2016 survey of 18,289 KMDs, approximately 99.51% of KMDs reported using traditional acupuncture therapies for patients experiencing neck pain [18]. To determine the safety and efficacy of pharmacopuncture treatment specifically, acupuncture was selected as the standard KM treatment for this study. Both acupuncture and pharmacopuncture are actively used to treat musculoskeletal disorders, including chronic neck pain [19]. However, their comparative effective-ness and safety have not been investigated.

Pharmacopuncture is considered a flexible intervention, allowing clinicians to tailor treatments based on the patient’s clinical presentation. In this context, a pragmatic, randomized controlled trial (PCT) was designed to evaluate the effectiveness of various pharmacopuncture strategies in individuals with chronic neck pain. The primary aim was to design a PCT to provide robust evidence for the implementation of pharmacopuncture in clinical practice, and inform healthcare decision-making.

Materials and Methods

1. Study setting

This pragmatic, multicenter, parallel-designed randomized, comparative clinical trial aims to recruit 128 participants from seven Korean medicine hospitals. This protocol was developed in accordance with the SPIRIT guidelines (Supplementary material).

2. Eligibility criteria

2.1. Inclusion criteria

• 1. Neck pain persisting for over 3 months.

• 2. Pain intensity which scored ≥ 5 on the numerical rating scale (NRS) for the neck region.

• 3. Aged between 19 and 70 years.

• 4. Voluntary consent to participate with signed informed consent.

2.2. Exclusion criteria

• 1. Diagnosed with a severe medical condition associated with cervical pain (including spinal metastases from tumors, acute fractures, or vertebral dislocations).

• 2. Presence of a progressive neurological deficit or severe neurological symptoms.

• 3. Pain stemming from a non-spinal soft tissue condition, such as tumors, fibromyalgia, rheumatoid arthritis, or gout.

• 4. Other chronic illnesses (stroke, myocardial infarction, kidney disease, diabetic neuropathy, dementia, or epilepsy).

• 5. Current use of steroids, immunosuppressants, psychiatric medications, or other medications that could influence study outcomes.

• 6. Unsuitable or unsafe for the participant to receive pharmacopuncture therapy (including bleeding disorders, anticoagulant therapy, or severe diabetes with elevated infection risk).

• 7. Use of medications that may affect pain, such as nonsteroidal anti-inflammatory drugs or receiving pharmacopuncture, within the week before study entry.

• 8. Pregnant or nursing women, or those planning pregnancy.

• 9. Underwent cervical spine surgery within the last 3 months.

• 10. Participation in another clinical trial within 1 month of the trial or planning to participate in another study during this trial or follow-up period (within 6 months of enrollment).

• 11. Inability to sign the informed consent form.

• 12. Any circumstance deemed by the investigator to make study participation inappropriate.

3. Intervention

3.1. Pharmacopuncture group

Participants in the pharmacopuncture group will receive treatments twice per week for 4 weeks. Treatment frequency can be adjusted, ranging from a minimum of 1 treatment session up to a maximum of 3 treatments per week, based on individual needs. The pharmacopuncture solution will be selected, at the clinical discretion of the KMD, from among those in routine use at each institution. The specific solution used, acupoints targeted, procedural depth, and solution dosage (0.1–10.0 cc) will be determined by the KMD’s clinical judgment based on the participant’s symptoms, diagnostic imaging, and degree of improvement. All acupoints for chronic neck pain will be documented according to the World Health Organization standard acupuncture nomenclature.

3.2. Acupuncture group

Acupuncture therapy will be administered twice weekly over 4 weeks, with the possibility of adjusting the number of sessions from 1 to 3 per week depending on the participant’s condition. The KMD will select the acupoints, needle depth, and number of needles (5–30) based on symptoms, diagnostic imaging, and degree of improvement.

3.3. Modifications

Treatments could be discontinued or modified under the following circumstances: (1) violation of inclusion or exclusion criteria discovered during the study; (2) diagnosis of a condition not detected during screening that may affect study outcomes; (3) participants who request early termination or withdrawal of consent; (4) pregnancy confirmed during the study period; (5) barriers to administering medical or KM treatments for neck pain; and (6) the investigator deems continued participation inappropriate.

3.4. Adherence

Physicians will closely monitor participants for changes in symptoms and provide encouragement to maintain treatment. Individualized care will be offered to each participant within the protocol’s scope, with ongoing communication between participants and investigators throughout the study period.

3.5. Concomitant care

Participants will be allowed to use medications and other healthcare services for severe neck pain during the study. All treatment details and the number of sessions will be documented in a case report form.

4. Outcomes

4.1. Primary outcome measures

The neck pain intensity for the past week will be assessed using the NRS, where participants will rate their discomfort from 0 (no pain) to 10 (worst pain imaginable). The primary outcome will be the change in neck pain from baseline to Week 5 using the NRS score.

4.2. Secondary outcome measures

• 1. Arm pain NRS score: The NRS will also be used to assess arm pain intensity over the past week.

• 2. Neck pain visual analogue scale (VAS) score: The VAS requires participants to indicate level of pain on a 100-mm line, from no pain to the most severe pain imaginable (100-mm) over the past week.

• 3. Arm pain VAS score: The same VAS assessment will be used for arm pain intensity over the past week.

• 4. Northwick Park Questionnaire (NPQ) score: The Korean version of the NPQ, validated for reliability [20], comprises nine items on daily activities affected by neck pain (intensity, sleep, tingling, duration, lifting, reading/TV watching, working, socializing, and driving). Each item is scored 0 to 4 (higher scores indicate greater dysfunction), for a total possible score of 36. The NPQ percentage scores will be calculated.

• 5. Neck Disability Index (NDI) score: The NDI [21] assesses impairment in daily activities with 10 items rated 0–5, and the total score is divided by the number of items answered.

• 6. Patient Global Impression of Change: Participants will rate their perceived improvement on a scale: 1, very improved; 2, much improved; 3, slightly improved; 4, no change; 5, slightly worse; 6, much worse; 7, significantly worse.

• 7. Health-related Quality of Life Instrument with 8 Items (HINT-8) score: HINT-8 evaluates quality of life across physical, social, mental, and positive domains (stair climbing, pain, energy, work, depression, memory, sleep, and happiness) over the past week, each with 4 response levels [22].

• 8. 5-Level EuroQol-5 Dimension (EQ-5D-5L) score: The EQ-5D-5L measures health status in 5 domains: mobility, self-care, usual activities, pain/discomfort, anxiety, and depression. Quality weights will be indirectly calculated using the pre-assigned preference score for each functional level [23].

• 9. Credibility and expectations: At the first visit, participants will answer, “How much do you think pharmacopuncture and acupuncture therapies will relieve your symptoms?” rated 1 (not at all), 5 (somewhat), or 9 (very much).

• 10. Productivity loss: A structured questionnaire will measure medical and non-medical expenses, time costs, and lost productivity. Productivity losses will be calculated using the Work Productivity and Activity Impairment Questionnaire and converted to costs for cost-effectiveness analysis.

• 11. Drug consumption: All medications and dosages used will be recorded at each visit.

• 12. Adverse events (AEs): AEs will be tracked through participant reports and investigator observations and recorded for frequency, association with intervention, and follow-up.

5. Participant timeline

Participants meeting all inclusion and exclusion criteria will be randomized in a 1:1 ratio to either the pharmacopuncture (n = 64) or acupuncture (n = 64) therapy group, each receiving a 4-week intervention. Details of the participant timeline are provided in Table 1.

6. Sample size

The sample size calculation was be based on a meta-analysis [19] that compared pharmacopuncture and acupuncture for treating neck pain. However, as no studies have directly compared these therapies using the numeric rating scale (NRS) score in chronic neck pain, the endpoint visual analog scale (VAS) score difference of −1.79 [95% confidence interval (CI): −2.39, −1.19] between therapy groups will be used, where this yields a Cohen’s d of 0.65. With a significance level of α = 0.05 (two-tailed) and a Type 2 error (β) of 0.1, the power study will be set at 90%, which results in 51 participants per group. Assuming a 20% dropout rate and recruiting across seven institutions, a total of 128 participants will be recruited.

7. Recruitment

Recruitment will be conducted through advertisement on posters placed inside and outside the clinical trial centers, as well as online through the clinical trial recruitment website.

8. Assignment of interventions

8.1. Sequence generation

A statistician will create the randomization table using R 4.1.1 (© the R Foundation for Statistical Computing, Vienna, Austria). Block randomization will be applied, with block sizes of 2, 4, or 6 selected at random.

8.2. Concealment mechanism

The generated randomization results will be sealed in opaque envelopes and securely stored in a double-lock cabinet by an independent third party.

8.3. Implementation

After participant screening, a screening investigator at each site will open the sealed randomization envelope for each participant to assign a randomization number.

8.4. Blinding

Due to the nature of the intervention, participant blinding will not be possible. However, outcome assessors will not participate in the intervention and they will conduct their assessments in a separate room before the procedures.

9. Data collection, management, and analysis

9.1. Data collection plan

Clinical data will be extracted from electronic medical records, and outcome data will be collected through paper-based, participant-reported surveys. For telephone surveys, the assessor will complete the survey form on behalf of participants. All data will subsequently be entered into an electronic case report form.

9.2. Retention

To support retention, telephone surveys will replace in-person assessments for participants who are unable to attend the site. Transportation costs will be reimbursed to participants during the follow-up periods.

9.3. Data management and access

Prior to database setup, a data dictionary will be created according to the study protocol. Data will be recorded using the MyTrials web-based electronic database (Bethesda software, Seoul, Republic of Korea). Authorized clinical research coordinators will record the data, and the data safety monitoring committee will have access to the database for monitoring, auditing, and managing the data. Automatic queries will be generated based on predefined algorithms.

10. Statistics

10.1. Outcomes

The primary analysis for this trial will employ the intention-to-treat approach, whereas the per-protocol analysis will include only participants who have completed at least 6 treatments within the 4-week treatment period.

Sociodemographic characteristics and treatment expectations of the participants in each group will be compared. Continuous variables will be expressed as mean (± standard deviation) or median (quartiles), and differences between the 2 groups will be compared using the student t-test or the Wilcoxon rank sum test. Categorical variables will be expressed as frequencies (%) and compared using chi-square or Fisher’s exact tests.

To analyze changes in continuous outcomes (NRS, VAS, NDI, NPQ, EQ-5D-5L, and HINT-8 scores) from baseline to each assessment point, a linear mixed model will be employed as the primary analysis method. This model will include random intercepts for participants and fixed effects for baseline measurements, and any clinically significant covariates differing at baseline between groups. Time, group allocation, and their interactions will be included to assess differences in outcome changes over time. For sensitivity, analysis of covariance will be conducted on multiple imputation and last observation carried forward datasets, using the same covariates as in the primary analysis, with the group as a fixed effect. The proportions of participants experiencing AEs in each group will be compared using chi-square or Fisher’s exact tests. A two-sided p < 0.05 will be considered statistically significant.

10.2. Additional analyses

The area under the curve will be calculated for each post-randomization time point to compare the total difference in outcomes between groups during the treatment and the entire study period.

The proportion of participants achieving NRS and VAS neck pain scores at or below half the baseline values will be analyzed by time point. Kaplan-Meier survival analysis will be performed, with comparisons between groups made using the log-rank test. Hazard ratios will be estimated using the Cox proportional hazards model.

Subgroup analyses will be conducted for exploratory purposes, and pain improvement scores between the pharmacopuncture and acupuncture therapy groups will be compared.

10.3. Analysis population and missing data

Missing values will be addressed with mixed model for repeated measures, while multiple imputation and last observation carried forward strategies will be used for sensitivity analyses. For Kaplan-Meier and log-rank tests, right censoring will be applied to participants who withdraw. For intermittent censoring, it will be assumed that no events occurred during the censored period.

11. Monitoring

11.1. Formal committee

This multicenter trial will involve seven hospitals. The coordinating center, comprising the principal investigator, study coordinator, physician, and an assessor from each institution, will oversee the entire trial process. The trial steering committee, consisting of the chief investigator, project manager, and monitoring agent, will provide support, with investigators meeting online, monthly. The data monitoring committee will comprise a data manager and independent statisticians. The data manager, with clinical medicine and statistics expertise, is responsible for developing data management plans and supervising data recording. Under their supervision, the committee will ensure data security and participant safety.

11.2. Interim analyses

An interim analysis will be conducted after the primary endpoint to assess the validity of the results.

11.3. Harm

Any undesirable and unintended signs, symptoms, or disease occurring after the intervention will be documented as AEs.

11.3.1. Serious adverse event

A serious AE is defined as any event resulting in death, posing a life-threatening risk, requiring hospitalization or extended hospitalization, or resulting in persistent or significant disability. In cases of serious impact on a participant’s health, a determination will be made by the attending KMD and relevant medical experts. All serious AE must be reported to the institutional review board (IRB) and the supervising institution, with necessary follow-up actions being taken.

11.3.2. Assessment of AEs

The AE, onset date, duration, causality of the intervention, severity, follow-up outcome, interventions, and actions taken will be recorded using MedDRA terminology. The World Health Organization-Uppsala Monitoring Center causality scale will be used to assess intervention-related causality at 6 levels: certain, probable/likely, possible, unlikely, conditional/unclassified, and unassessable/unclassifiable. Severity will be graded as mild, moderate, or severe, following the three-level taxonomy proposed by Spilker et al [24].

11.4. Auditing

A monitor will regularly visit the hospital to ensure the study is being conducted according to the protocol, standard operating procedures, good clinical practice guidelines, and applicable regulations. The monitor will closely track study progress and discuss any issues with the investigators. The principal investigator will be required to submit annual summaries of study progress to the IRB in accordance with the requirements, policies, and procedures

12. Ethics and dissemination

12.1. Research ethics approval

This study was approved by the IRBs of seven institutions (no.: JASENG 2024-01-002, JASENG 2024-01-005, JASENG 2024-01-003, JASENG 2024-01-004, KOMCIRB 2024-02-002, KHNMCOH 2024-02-010, and DOBUH 2024-001).

12.2. Protocol amendments

All protocol amendments must receive IRB approval before implementation, excluding those required to address immediate risks to participants or administrative updates.

12.3. Consent

Investigators at each institution will provide a thorough explanation of the study objectives and procedures to all participants and obtain informed consent before enrollment.

12.3.1. Consent for ancillary studies

Research data may be anonymized for use in secondary studies, but only with explicit participant consent. Each IRB will evaluate and approve the use of research data for secondary purposes. External transportation and secondary use of specimens are not permitted, and specimens will be disposed of following the guidelines of each institution.

12.4. Confidentiality

The participants’ personal information will be managed in accordance with rigorous standards under the supervision of the IRB to ensure confidentiality and data protection. All data will be anonymized.

12.5. Declaration of interests

The principal investigators declare that they have no competing interests.

12.6. Ancillary and post-trial care

If the participants experience recurrent pain after the intervention, they will be permitted to seek care from any healthcare provider during the follow-up period. In the event of delayed AEs, participants will be encouraged to promptly seek medical care as directed by the investigator.

13. Dissemination policy

The principal investigator may share trial information with healthcare professionals and the public at conferences, and in publications whereby all publication requirements will be followed. Approval from the supervising organization is required to publish or use, in whole or in part, the data from the trial.

Discussion

Chronic nonspecific neck pain, defined as pain lasting more than 3 months, is accompanied by various symptoms, including persistent pain and disturbances in daily activities. A 1-year follow-up study showed that most cases of neck pain persisted as episodic (37%), followed by fluctuating (36%), mildly ongoing (9%), and severely ongoing cases (2%), while only 14% experienced a single recurrent episode [25]. Ongoing pain often necessitates frequent hospital visits over several years [26], and contributes to significant healthcare costs. When neck pain becomes chronic, opioid use tends to increase [27]. This highlights the need to explore more effective nonpharmacological treatment options.

In the clinical setting, various conservative treatments are used for chronic nonspecific neck pain, including education, manual therapy, therapeutic exercises, electrotherapy, acupuncture, medications such as nonsteroidal anti-inflammatory drugs, or combinations of these approaches. A network meta-analysis study showed that acupuncture and dry needling were the most effective treatments, among seven conservative treatments, for long-term improvement in both pain and disability [28].

Pharmacopuncture, an evolved form of acupuncture, with enhanced effectiveness, has been practiced in Korea since the 20th century [13]. It has been applied in multiple areas of conditions/diseases, including musculoskeletal and nervous system disorders, metabolic diseases, genitourinary conditions, and neoplasms [13]. Clinical applications of pharmacopuncture have diversified with the use of various herbal extracts. Physicians tailor treatments by selecting the type, target meridian or acupoint, volume of herbal extract, and treatment plan based on the severity of each patient’s symptoms [14,29,30]. This results in considerable variability in treatment strategies.

PCTs differ from explanatory clinical trials by focusing on overall treatment effectiveness to maximize real-world applicability [31]. Interventions in PCTs reflect routine clinical care, allowing for individualized treatment approaches. Given the widespread use of KM treatment modalities, there is a need for evidence regarding their real-world effectiveness and comparative performance against other standard care options. PCTs are more suitable than explanatory trials in this context. Notably, many clinical studies assessing acupuncture and pharmacopuncture effectiveness have adopted pragmatic designs, allowing clinicians to determine intervention methods at their discretion [32–36]. This study adopted a PCT design to closely reproduce real-world scenarios when investigating the effectiveness and safety of pharmacopuncture strategies for chronic neck pain. By allowing for variation in treatment, the PCT allows physicians to individualize interventions for each participant [37]. In this study, physicians at seven hospitals performed pharmacopuncture and acupuncture, selecting the optimal practice for each participant according to the protocol. Treatment details will be reviewed and described alongside the results.

A recent PCT compared the effectiveness of pharmacopuncture therapy with physical therapy for chronic neck pain, and reported superior results for pharmacopuncture in pain relief and functional recovery [16]. Similar to the protocol for the intended study, clinicians showed flexibility in selecting the specific pharmacopuncture modalities. However, this study protocol describes a trial designed to directly compare the effectiveness of pharmacopuncture with acupuncture, providing practical evidence for physicians in KM to guide their selection of treatment modalities.

As part of the pragmatic design, participants in both groups may receive additional treatments from other medical institutions or take medications. All supplementary treatments and drug use will be documented and analyzed. Cost assessments will identify differences in participants’ behaviors and medical usage. In addition, pain outcomes will be evaluated at each visit and tracked to reveal time-varying symptoms of chronic neck pain to reveal external study validity.

This study may have limitations because of differences in treatment methods, and physicians and participants would not be blinded, however, the outcome assessor will be blinded. In addition, due to its pragmatic design, this study may involve variability in treatment procedures and potential confounding from concomitant care. While such factors increase external validity, they may also limit internal consistency. To address this, detailed information on treatment procedures and concomitant care will be collected, and explanatory subgroup analyses will be considered.

Conclusion

This protocol aimed to design a clinical trial with internal validity which is highly applicable to the real-world setting to provide practical evidence for clinicians and policymakers regarding the use of pharmacopuncture strategies to treat chronic neck pain. By planning a direct comparison of pharmacopuncture with standard acupuncture to determine its effectiveness in pain relief, disability reduction, quality of life improvement, safety profile, and cost-effectiveness, the results of this trial may offer valuable insights for healthcare decision-making.

The trial began in September 2024 and is expected to conclude in December 2025. The trial was registered at ClinicalTrials. gov (no.: NCT06520462) on July 25, 2024 and is being periodically updated.

Supplementary Materials

Article information

Author Contributions

Conceptualization: DN, YP, EJK, SHL, YJL, and IHH. Methodology: SK, YL, HWC, YH Resources: SK, YL, HWC, and YH. Writing (original draft preparation): JYK. Writing (review and editing): DN, YP, EJK, and IHH. Supervision: YJL. Project administration: SHL and JYK. Funding acquisition: IHH. All authors read and approved the final manuscript.

Conflicts of Interest

The authors declare that they have no competing interests.

Author Use of AI Tools Statement

The authors declare that no generative AI tools were used for the writing of this manuscript.

Funding

This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (grant no.: RS-2021-KH111842).

Ethical Statement

This study was approved by the institutional review board of each site (no.: JASENG 2024-01-002, JASENG 2024-01-005, JASENG 2024-01-003, JASENG 2024-01-004, KOMCIRB 2024-02-002, KHNMCOH 2024-02-010, and DOBUH 2024-001) before enrollment. Informed consent was obtained from all participants.

Data Availability

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