Bee Venom Acupuncture for Neck Pain: A Review of the Korean Literature

Bee venom is a natural toxin that is effective in treating various types of pain. The purpose of this paper was to review all the features of clinical studies conducted on bee venom acupuncture (BVA) for the treatment of neck pain in Korean publications. Six Korean databases and 16 Korean journals were searched in August 2022 for clinical studies on BVA for neck pain. We identified 24 trials that met our inclusion criteria, of which 316 patients with neck pain were treated with BVA. The most common diagnosis in the patients with neck pain was herniated intervertebral discs (HIVDs) of the cervical spine (C-spine) (29.2%), and the concentration and dosage per session were 0.05–0.5 mg/mL and 0.1–1.5 mL, respectively. The visual analog scale was most often measured for neck pain severity (62.5%), and all clinical research reported improvements in 16 outcome measures. This study shows that BVA could be recommended for the treatment of neck pain, especially HIVD of the C-spine; however, the adverse effects of BVA must be examined in future studies.


Introduction
Neck pain refers to tension or pain caused by muscle tension or muscle veins in the neck or occipital region, which may limit the range of motion (ROM) in the neck and cause local tenderness and pain radiating to the shoulder blades and upper extremities [1,2]. Compared with other vertebrae, the cervical spine has a relatively large range of motion and structurally weak joint stability owing to its anatomical characteristics [3]. It has been reported that about 67% of the world's population will experience neck pain at least once in their lifetime, and if it becomes chronic, it can cause serious reductions in quality of life [4]. Neck pain is the most common muscle pain at home and worldwide [4]. Bee venom acupuncture (BVA) involves the injection of purified and diluted bee venom (BV) into acupoints.

Medical Conditions
In total, 12 types of medical conditions were presented in the 25 studies. Seven medical conditions, including herniated intervertebral discs (HIVDs) of the C-spine (28.0%), whiplash injury (12.0%), thoracic outlet syndrome (8.0%), soft tissue damage (8.0%), and neck pain after a car accident (8.0%), were reported in more than two studies. Table 2 shows the numbers of articles and patients according to the medical conditions.

Sample Size
A total of 316 neck pain patients from 24 articles were included in the study. The sample sizes of the included studies ranged from 1 to 48.

BVA Treatment
BVA was implemented in an injection form in all of the included studies, meaning that practitioners injected BV into acupoints using a syringe. The concentration of the BVA ranged from 0.05 to 0.5 mg/mL for patients with HIVD of the C-spine, and the amount of BV used on the patients varied from 0.1 to 1.0 mL per session and from 0.11 to 27 mL for the entire treatments. The BVA concentrations and dosages for the medical conditions of patients (whiplash injury, soft tissue damage, stiffness of neck, and car accident) are presented in Table 3. Three studies did not mention the concentrations of BVA, six did not mention the dosage for one treatment, and sixteen did not mention the total dosage.

Outcome Measures
In total, 16 types of outcomes were measured in the 24 clinical studies ( Table 1). The results measured by each outcome were classified into "statistically improved," "improved," and "not improved." The visual analog scale (VAS) was most frequently used to assess neck pain severity (n = 15, 62.5%) ( Figure 3). All evaluation tools reported "improved" or "statistically improved" outcome, and none of them reported outcomes that were "not improved." The case studies and retrospective studies compared before and after treatments to derive statistical significance (statistical improvement). The CCTs and RCTs In total, 16 types of outcomes were measured in the 24 clinical studies ( Table 1). The results measured by each outcome were classified into "statistically improved," "improved," and "not improved." The visual analog scale (VAS) was most frequently used to assess neck pain severity (n = 15, 62.5%) ( Figure 3). All evaluation tools reported "improved" or "statistically improved" outcome, and none of them reported outcomes that were "not improved." The case studies and retrospective studies compared before and after treatments to derive statistical significance (statistical improvement). The CCTs and RCTs compared the BVA group and the control group to derive statistical significance (statistical improvement).

Discussion
This study was conducted to analyze the research pattern and usage of BV in Korean clinical studies. A total of 24 articles based on BVA treatments for neck pain were identified. Among them, four were RCTs and the rest were CCTs (2), case studies (15) [45].
The pain induced by musculoskeletal disorders is generally evaluated subjectively by patients with self-reported outcome measures (e.g., numerical rating scale and VAS). These outcomes of pain severity are regarded as the primary outcomes of neck pain and are appropriate to provide patient satisfaction results to TKM doctors and clinical evidence. The Neck Disability Index (NDI), created in 1991, is a representative questionnaire for evaluating cervical pain that consists of 10 items [46,47]. The Korean version of the NDI was reported in 2009, and the correlation coefficient of its test-retest reliability was 0.927 [48]. There are other questionnaires for evaluating cervical pain: the Neck Pain and Disability Scale, the Cervical Spine Outcome Questionnaire, Patient-Specific Functional Scale self-reports with Neck Dysfunction, and the Copenhagen Neck Functional Disability Scale [48]. Biomarkers for inflammation (e.g., C-reactive protein and interleukin-6 (IL-6))

Discussion
This study was conducted to analyze the research pattern and usage of BV in Korean clinical studies. A total of 24 articles based on BVA treatments for neck pain were identified. Among them, four were RCTs and the rest were CCTs (2), case studies (15) [45].
The pain induced by musculoskeletal disorders is generally evaluated subjectively by patients with self-reported outcome measures (e.g., numerical rating scale and VAS). These outcomes of pain severity are regarded as the primary outcomes of neck pain and are appropriate to provide patient satisfaction results to TKM doctors and clinical evidence. The Neck Disability Index (NDI), created in 1991, is a representative questionnaire for evaluating cervical pain that consists of 10 items [46,47]. The Korean version of the NDI was reported in 2009, and the correlation coefficient of its test-retest reliability was 0.927 [48]. There are other questionnaires for evaluating cervical pain: the Neck Pain and Disability Scale, the Cervical Spine Outcome Questionnaire, Patient-Specific Functional Scale selfreports with Neck Dysfunction, and the Copenhagen Neck Functional Disability Scale [48]. Biomarkers for inflammation (e.g., C-reactive protein and interleukin-6 (IL-6)) are also utilized to measure pain. In addition to physical function, psychological function, quality of life, and painkiller dosage can be used as indicators [49].

Current Status of BVA Production in Korea
In Korea, pharmacopunctures containing BVA are prepared at external herbal dispensaries (EHDs) with a good manufacturing practice (GMP) level [50]. We presented a figure of the preparation process of animal venom acupuncture in a previous study [51]. An EHD is a pharmacy that provides TKM clinics with various types of herbal medicines and pharmacopunctures in Korea [52,53]. These EHDs were institutionalized in 2008 and are licensed and managed by the Ministry of Health and Welfare (MoHW) [54]. As a result of a survey in 2019 by the MoHW, BV ampules (vials) were found to be the second most (13.3%) produced pharmacopuncture [55]. As such, the BVA used in Korea is not a drug manufactured by the MFDS. It is prepared in a facility (EHD) that was approved by the MoHW and is used in TKM clinics [56]. In the future, it is expected that research on the use of natural toxin medicines, including the BVA used in Korea, will be activated. In addition, we hope that our results will be used as basic data for the development of natural toxins.

BVA Treatment in TKM Clinics
Pharmacopunctures prepared from EHD are distributed to TKM clinics and hospitals and are utilized for the treatment of various diseases [50]. Based on a national survey of TKM, BVA has mostly been used to treat musculoskeletal disorders (62.3%) [10]. BVA has been reported to be effective for neck pain with all evaluation tools because acupuncture is commonly used to treat musculoskeletal disorders [8,[57][58][59][60][61][62][63], including neck pain. BVA plus NASIDs showed significant effects in the outcomes of bothersomeness, pain intensity, and functional status compared with a sham BVA plus NASIDs group [64,65]. Thus, it can be considered that clinical studies on neck pain have been published steadily. In addition, the fact that pharmacopuncture was recognized as a Korean medical practice through the authentic interpretation of the Ministry of Health and Welfare in 1998 may have contributed to the increase in its use [8].

BVA Treatment Standardization Based on TKM CPG
Few studies have examined the optimal dose of BVA for treating neck pain. BVA has become one of the most commonly utilized pharmacopuncture treatments in TKM institutions. BVA is an acupuncture treatment that injects BV into the bodies of patients using a syringe [66,67]. A survey of 393 Korean medicine doctors in 2018 showed that approximately 30% of the respondents used BVA in their clinical practice, which was ranked first among all types of pharmacopuncture [67]. In addition, 38.9% (14 out of 36) of clinical practice guidelines (CPG) of TKM officially accredited and released in Korea include recommendations for BVA, most of which is used for pain alleviation in musculoskeletal disorders [68][69][70][71][72][73][74][75][76][77][78][79][80][81]. However, data on permitted dose information in certifications are limited. Even in the CPG of TKM, only four guidelines recommend BV therapies with specific dose regimens (Table 4). Therefore, we need more evidence of the optimal dose to develop, obtain an authority's approval, and clinically apply the medical products of BVA. Future follow-up studies such as dose-considered surveys, clinical trials, and a practice-based research network are needed.

Adverse Events of BVA
Only two studies [31,32] reported mild side effects of BVA treatment. In a study by Kim et al. [82], 16.7% of the patients in the BVA group experienced mild to severe symptoms. BV is an animal venom, and side effects may occur when it is applied to the human body.
In Korea, when a patient first receives BVA at a TKM clinic, a skin test is mandatory in most cases [67]. According to a pharmacopuncture textbook, patients must be tested for allergies before treatment [8]. This is because the prevention of unexpected immune reactions, such as anaphylaxis, is possible through a skin test prior to treatment [83][84][85][86][87][88]. After subcutaneously injecting 0.1 mL of BV into the skin on the inside of the arm, the injection site was marked and observed for approximately 10 to 15 min [89,90]. The severity and frequency of side effects of BVA for neck pain are currently unclear; therefore, a systematic investigation into the safety of BVA is required.
BV has been used as a drug for a long time, and it is a drug that is widely and legally used in clinics by TKM doctors [51]. There is also a drug approved by the Ministry of Food and Drug Safety with the same ingredients that doctors can use [91]. In particular, melittin, one of the main components of BV, is a controversial ingredient [92]. It is specialized in non-specific cytolytic activity, so recent studies reported its possible adverse effects and how to overcome them [93,94]. The cytotoxic effect can be useful in antitumor methods, but it can interrupt the other purpose, therapeutic application [95]. The natural form of melittin induces non-specific cell lysis and toxicity, so studies on mutation and fusion proteins to decrease the toxicity have been conducted [96].

Study Limitations
This review had several limitations. First, the included studies were mostly case studies with relatively small numbers of the samples. Moreover, it is well-known that case studies are located in a low-quality position in the hierarchy of the evidence pyramid. Therefore, high-quality clinical evidence, such as from randomized controlled trials, is required. Second, the statistical significance of VAS and NDI before and after treatment was reported; however, the measured values were not reported, and a meta-analysis was not conducted. Third, only clinical studies conducted and retrieved in Korea were included in the systematic review; however, those published in international journals (e.g., PubMed, Embase, and the Cochrane Central Register of Controlled Trials) might have been omitted in this review. Fourth, it would be better to report the injection site for the BVA. Nonetheless, this review provides comprehensive information about BV toxins in clinical fields. Additionally, the BVA details provided in this review will help in planning clinical trials for the development of new drugs for neck pain.

Future Suggestion
During BVA treatment, a patient's typical constitution and condition are diagnosed, and a specific amount of BV is injected into acupoints. BVA provides an immediate effect after treatment because BV is directly absorbed without passing through the gastrointestinal tract [97]. Based on clinical experience, the Korean Pharmacopuncture Institute suggested that BVA can be used for various diseases such as guanwasa, pain, inflammatory joint disease, mental disease, gynecological disease, and brain and cardiovascular disease ( Table 5) [8]. In the future, referring to the diseases presented in Table 5, it is expected that evidence-based treatments using BVA will be achieved by verifying its clinical effectiveness and safety based on high-quality multicenter clinical studies.

Conclusions
This study reports that BVA is being used in TKM clinics and has therapeutic effects in the treatment of neck pain in various diseases. In South Korea, BVA is manufactured in an EHD equipped with GMP-level facilities, and it is diluted and used in the form of injections in the clinical field. In addition, most patients receive treatment after confirming an allergic reaction to bee venom through a skin test before treatment. However, for the potential drug development and clinical application of BVA, identifying its concentration, dosage, treatment sessions, and side effects is necessary.

Study Selection
We selected all types of clinical research, including RCTs, retrospective studies such as CCTs, and case studies, that explored the effectiveness of BVA for neck pain. There were no restrictions on the age or gender of patients with neck pain. All types of outcomes (e.g., pain score, Neck Disability Index, ROM, computed tomography, symptom severity change, quality of life, and adverse events) were considered, but they had to be related to the neck pain condition. We did not include in vitro or in vivo experimental studies and reviews.

Data Extraction
Two independent researchers (H.-J.L. and J.-E.H.) sorted the data with a predefined form. The characteristics of the included clinical studies were analyzed, and data were collected on references, study design, sample size, medical conditions, BVA interventions, side effects, outcomes, and major results. When a published paper did not provide sufficient outcome data, we requested raw data via e-mail. Disagreements were settled by discussion with the corresponding author (G.L.).  Data Availability Statement: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Conflicts of Interest:
The authors declare no conflict of interest.