Clinical Studies of Bee Venom Acupuncture for Lower Back Pain in the Korean Literature

This study aimed to identify all of the characteristics of bee venom acupuncture (BVA) for the treatment of lower back pain (LBP) that are described in the Korean literature, and to provide English-speaking researchers with bibliometrics. Six Korean electronic databases and sixteen Korean journals on BVA treatment for back pain were searched up to February 2022. This report included and analyzed 64 clinical studies on BVA interventions for back pain and 1297 patients with LBP. The most common disease in patients with back pain was lumbar herniated intervertebral discs (HIVD) of the lumbar spine (L-spine). All studies used bee venom (BV) diluted with distilled water. The concentration of BVA for HIVD of L-spine patients with LBP ranged from 0.01 to 5.0 mg/mL; the dosage per treatment was 0.02–2.0 mL, and for a total session was 0.3–40.0 mL. The most used outcome measure was the visual analogue scale for back pain (n = 45, 70.3%), and most of the papers reported that each outcome measure had a positive effect. Korean clinical studies were typically omitted from the review research, resulting in potential language bias. This study provides clinical cases in Korea for future development and standardization of BVA treatment for back pain.


Introduction
Lower back pain (LBP) is a highly uncomfortable and often chronic sensation in the back below the lower rib cage and above the gluteal fold [1]. LBP is the most common musculoskeletal condition affecting the adult population, with a worldwide prevalence of 7.5% in 2017 [2][3][4]. It is a major condition leading to disability, affecting work performance and the overall wellbeing of individuals [5,6].
For the treatment of patients with acute LBP, the guidelines recommend reassurance on the favorable prognosis and advice on returning to normal activities, avoiding bedrest,

Study Description
As shown in Figure 1, our search identified 64 full-text articles that met our inclusion criteria . The first BVA-related clinical study published in Korea was published in 1999. From 1999 to 2020, such studies were published yearly, with a maximum of seven papers published in 2008 ( Figure 2). The study design is summarized in Table 1. This report includes 37 (57.8%) case studies, 5 (7.8%) case-control trials (CCTs), 6 (9.3%) RCTs, and 16 (25.0%) retrospective studies.

Medical Conditions
Of the 64 included trials, 18 types of single medical conditions were reported in 61 papers, and complex medical conditions were reported in the remaining 3 papers. Six medical conditions-HIVD of L-spine patients with back pain, back pain, failed back surgery syndrome patients with back pain, lumbar spinal stenosis patients with back pain, car accident patients with lower back pain, and back sprain patients with back pain-were mentioned in more than two papers. The numbers of papers and patients by disease are shown in Table 2.

Sample Size
In total, 1295 participants from the 64 clinical studies were included in this review. The sample size per trial ranged from 1 to 208 (20.2 ± 33.1).

BVA Intervention
The intervention used in all included studies was in injection form, using a syringe through which BV was dispensed and injected into the body. The BVA concentration range was 0.01-5.0 mg/mL, and the dosage per treatment and for the total sessions was 0.02-2.0 mL and 0.3-40.0 mL, respectively, for herniated intervertebral disc (HIVD) in lumbar-spine (L-spine) patients with back pain. The BV concentration was 0.05-0.5 mg/mL and the dosage per treatment and the total sessions were 0.03-1.0 mL and 0.51-5.1 mL, respectively, in patients with back pain. The concentration and dosage of BVA according to the participant's medical condition (e.g., failed back surgery syndrome patients with back pain, lumbar spinal stenosis patients with back pain, car accident patients with LBP, and back sprain patients with back pain) are shown in Table 3. Six papers did not report BV concentration, eight papers did not report the dosage of one session, and eighteen papers did not report the dosage of the total sessions.

Outcome Measures
A total of 22 types of outcome measures were reported in the 64 included papers. Figure 3 shows the results of classifying the main results of 11 outcome measures used in four or more papers into three categories, including "statistically improved," "improved", and "not improved". The most commonly used outcome measure was the visual analogue scale (VAS) for back pain (n = 45, 70.3%), and most of the papers reported that each evaluation tool had a positive effect.

Outcome Measures
A total of 22 types of outcome measures were reported in the 64 included papers. Figure 3 shows the results of classifying the main results of 11 outcome measures used in four or more papers into three categories, including "statistically improved," "improved", and "not improved". The most commonly used outcome measure was the visual analogue scale (VAS) for back pain (n = 45, 70.3%), and most of the papers reported that each evaluation tool had a positive effect.

Discussion
This study is an analysis of Korean clinical trials published in Korean journals, and we found several clinical studies on BVA for back pain in the Korean literature. The first study on BVA for the treatment of LBP was published in 1999. Since then, such studies have been published yearly until 2020. In Korea, the Ministry of Food and Drug Safety introduced the Good Clinical Practice Guidelines for clinical trials in the late 1990s, and these guidelines seem to have significantly impacted the progress of clinical research, including research on bee venom [19]. In addition, acupuncture for LBP patients in Korea has been reported to reduce the frequency of back surgery, and BVA has been widely used for musculoskeletal disorders (e.g., HIVD, arthritis, back pain, shoulder pain, knee pain, and sprain) [85,86]. Thus, a certain number of BVA clinical trials seem to have been conducted.

Discussion
This study is an analysis of Korean clinical trials published in Korean journals, and we found several clinical studies on BVA for back pain in the Korean literature. The first study on BVA for the treatment of LBP was published in 1999. Since then, such studies have been published yearly until 2020. In Korea, the Ministry of Food and Drug Safety introduced the Good Clinical Practice Guidelines for clinical trials in the late 1990s, and these guidelines seem to have significantly impacted the progress of clinical research, including research on bee venom [19]. In addition, acupuncture for LBP patients in Korea has been reported to reduce the frequency of back surgery, and BVA has been widely used for musculoskeletal disorders (e.g., HIVD, arthritis, back pain, shoulder pain, knee pain, and sprain) [85,86]. Thus, a certain number of BVA clinical trials seem to have been conducted.
Although most studies have reported that BVA is effective for LBP, six studies reported side effects including fever [36], itching [51,52,59,82], local redness [59], edema [59], skin hypersensitivity [73], mild chilling [82], and local rash [82]. BV contains active substances such as peptides, enzymes, and amines, which can exert anti-inflammatory, anti-nociceptive, and anticancer effects, but can also induce neurotoxic symptoms (e.g., redness, swelling, dizziness, nausea, and vomiting) or severe symptoms, such as anaphylaxis [87,88]. Kim et al. [89] suggest that the following are necessary for the safe use of BVA: (1) a qualified or licensed practitioner to treat the patient, and (2) a skin test and post-injection observation in the clinic to manage potential adverse events. Additionally, to develop a treatment using BV for patients with back pain, information on the dosage and concentration is essential to maximize the therapeutic effect while minimizing side effects. Future clinical studies with information on the side effects are necessary.
All 64 Korean clinical trials reported that BV was diluted with saline at a certain ratio and injected into the patients. The BV concentration used for each study was found to cover a wide range, from 0.01 mg/mL to 5.0 mg/mL. In particular, in the case of HIVD in L-spine patients with back pain, the concentration deviation was the largest. When a survey was conducted with 468 TKM doctors, it was reported that the BV concentration used without considering the disease was 0.1-0.3 mg/mL [89]. As such, it can be seen that the deviation of the BV concentration is very large even when compared with the previous study [89]. Based on these basic data, a clinical trial should be established to find the optimal BVA treatment concentration, dose, and frequency for lower back pain.
Pain is mainly evaluated subjectively in patients. Inflammation-related biomarkers, such as interleukin-6, C-reactive protein, and tumor necrosis factor α, along with range of motion (ROM), are also used to measure pain. However, self-reported outcomes, including the VAS, numerical rating scale (NRS), and Oswestry disability index (ODI), are more appropriate to show the clinical effectiveness and patient satisfaction with therapies. Quality of life is also used as an indicator, because LBP lowers the overall physical and psychological health. Although symptom changes in patients confirmed whether the subjectively felt pain of the patient improved, it was not quantified in the same way as when using the VAS. To develop a therapeutic agent, clinical trials that evaluate the effectiveness of the commonly used evaluation tools are necessary.
This study has several limitations. First, this review mostly included case or retrospective studies with low levels of clinical evidence and a relatively small sample size. A higher level of evidence from large-scale clinical studies is needed. Second, the VAS, ODI, and EQ-5D are validated questionnaires, although a meta-analysis was not performed considering the heterogeneity of the included RCTs and the individual variation of the study participants. Third, since this review searched only domestic Korean databases, clinical studies conducted in Korea but published in international journals might have been missing. Finally, the 64 included studies were conducted at university hospitals, and may differ from real-world data obtained at TKM clinics. Therefore, whether this study is representative of the use of BVA for LBP treatment in Korea is difficult to confirm. Nonetheless, many cases of BVA application for the treatment of back pain in Korea exist; the details of BVA summarized in this review could provide information to help in planning clinical trials for new drug development.

Conclusions
This study showed the clinical research trend for BVA's use in LBP treatment as published in Korean journals. BV was diluted to an appropriate concentration for clinical purposes, and was confirmed to be an effective treatment for patients with LBP. However, no side effects were reported in most studies, and large variations in the concentration, dose, and number of BVA treatments were noted. This study provides clinical evidence for the future drug development and standardization of LBP treatment using BVA.

Data Sources and Searches
We searched six Korean bibliographic databases (the Korea Institute of Science and Technology Information, the Korean Traditional Knowledge Portal, KoreaMed, OASIS, RISS, and the National Library of Korea) up to February 2022. The Korean trials indexed in non-Korean databases such as PubMed and Embase were not considered.
The search terms were as follows: "bee venom OR bee toxin OR apitherapy OR bee venom therapy OR bee venom acupuncture" AND "back pain" AND "clinical studies OR clinical trial".

Study Selection
We included all clinical studies (e.g., case studies, case series, CCTs, and RCTs) that evaluated the effects of BVA on back pain. All patients with back pain and without age-or sex-based restrictions were included. We included all types of BVA and all outcome measures (e.g., pain score, symptom change, quality of life, ROM, and adverse events) used for treating back pain. Non-clinical trials-including animal studies, experimental studies, surveys, and reviews-were excluded.

Data Extraction
Three authors (J.-E.H, H.-J.L., and J.-Y.L.) independently extracted data using a predefined data extraction form. Two independent reviewers (S.-H.S. and M.P.) collected data regarding author information, study design, sample size, medical conditions, interventions (i.e., form, concentration, treatment sessions, and dosage), adverse events, outcome measures, and main results. In cases of insufficient outcome data, the corresponding authors were contacted whenever possible. Any disagreements were resolved through discussions with G.L.  Data Availability Statement: The datasets (Korean clinical studies) used and/or analyzed during this study are available from the corresponding author upon reasonable request.

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