Knee OA has been recognized as a 'Bi' syndrome or 'Haksulpoong' in Oriental medicine .
BVP is prepared with bee venom from live honey bees and is artificially extracted and refined . It has varying actions on the immune system, anti-inflammatory and analgesic actions, cell lysis, neurotoxic and antibacterial actions, antipyretics, and invigoration of blood circulation. Therefore, it can be used for a wide range of diseases, including acute chronic arthritis, muscle pain, neuralgia, gout, etc. [22, 23].
BVP should be used carefully in treatment because allergic reactions are stronger than they are for other pharmacopunctures due to a combination of the antigens of the heterologous proteins and antibody. Therefore, because a stabilization of the body's immune system to bee venom is needed, in this triala small dose of BVP was used at first and was then increased gradually . Existing treatment methods for using BVP to treat knee OA are intradermal, subcutaneous, intra-acupoint, and intraarticular injections, etc.
With intradermal injection, the response of the body after treatment can be identified precisely, and hyper stimulation and side effects can be controlled quickly. However, it has the disadvantage of severe skin pain and itching. With subcutaneous injection, treatment is quick, and pain and itching are reduced. However, identifying the response of the body after bee venom injection is difficult, and a risk of injecting bee venom into a blood vessel exists . With intra-acupoint injection, absorption of bee venom is faster than it is intradermal or subcutaneous injection and injection painis reduced . With intraarticular injection, treatment takes less time, and systemic hypersensitivity is relatively reduced. However, identifying the body's response after bee venom injection is difficult and incorrect injection can cause severe pain .
In reviewing previous studies on the treatment method for using BVP to treat knee OA, Lee and by An et al. [9, 12] reported that intradermal BVP injection was significantly more effective than filiform acupuncture. A study by Kim et al. reported that intramuscular injection had no significant difference compared with intradermal injection, but did have more effect. A study by Rye et al.  reported that intra-articular BVP injection was significantly more effective than filiform acupuncture.
In this study we tried to compare intra-acupoint injection, intra-articular injection, intra-acupoint combined with intra-articular injection with BVP and to analyze the efficacy of these treatments for knee OA. We excepted intra-dermal injection which is widely used because the progress of clinical trials might be difficult due to the increased number of control groups. The acupoints used were ST35, GB34, EX32, ST36, and SP9 because Kim et al. concluded that these acupoints were effective for treating Knee OA through an analysis of 21 RCT papers .
Approximately 12 (22%) of all participants had allergic reactions to the procedure. These hypersensitivity reactions caused discomfort to the patient or the practitioner. Despite the excellent effects of BVP, the reactions cause practitioners to tend to avoid using BVP in clinics . Control groupⅠhad the highest numbers of dropouts due to hypersensitivity reactions and the lowest average number of treatment times at dropout. On the contrary, control groupⅡhad the lowest numbers of dropouts and the average number of treatment times at drop out was the highest. However, there were no significant differences.
The reason for these results seemed to be that the risk of hypersensitivity reactions was relatively infrequent for intra-articular injection which injects BVP on points isolated from systemic circulation . However, in the case of intra-articular injection, some patients complained of severe stiffness due to edema. During this trial, if participants showed a certain degree of hypersensitivity reactions or participants wanted to continue treatment in spite of hypersensitivity reactions, the amount of the scheduled injection was reduced by half, but the concentration was increased to 1:5000. Therefore, the amount of bee venom was maintained because the effects of bee venom treatment are not related to the volume of the injected BVP, but to the amounts of the bee venom ingredients . The intent was to decrease the discomfort of the patient by reducing the volume of BVP injected while maintaining the amounts of bee venom ingredients. Especially in the case of edema, reducing the volume of the BVP injected may relatively decrease the discomfort of the patient.
The results showed that all three groups experienced significant changes in the VAS and the KWOMAC at the 1 - week assessment and according to the progress of the treatment. Moreover, the four-week follow-up after the final treatment showed a persistence of BVP effects. However, when the groups were compared, no statistically significant difference in the VAS and the KWOMAC were noted.
In comparing the effects among groups after the final treatment and at the four-week follow-up after the final trea-tment, the VAS was not consistent with the KWOMAC pattern due to the subjective assessment of the participants own pain with the VAS, and the KWOMAC being composed of sub-items of pain, stiffness, and function. In addition, the pain KWOMAC score was not consistent with the VAS pattern because the results were estimated from a KWOMAC questionnaire which might have been difficult for most elderly participants to complete.
In this study, the results showed that intra-articular injection was more effective than intra-acupoint injection. Especially intra-acupoint combined with intra-articular injection was the most effective among the three treatments. A study by Ryu et al.  reported that intraarticular injections for treating knee OA was more effective in reducing pain and improving joint function; consequently, a rapid analgesic effect can be achieved with this treatment method. Intra-articular injection inserted bee venom closer to the affected lesion compared with subcutaneous injection. By pharmacokinetics, the drug injected subcutaneously acts through the circulatory system of the body via the blood vessels in the subcutaneous layers, but the drug injected intra-articularly acts locally and can increase a localized treatment effect, minimizing systemic hypersensitivity reactions or risks of side effects due to bee venom .
In summary, accurate intra-articular injection of BVP may be a proper treatment method for the treatment of knee OA as long as the practitioner is cautious in maintaining sterile conditions in preparing for injection to avoid infection and in managing edema properly. Moreover, combining intra-acupoint with intra-articular injection properly, depending on the patient's symptoms, may produce better results when conservatively treating knee OA. The limitations of this study were as follows: the completion of the questionnaire was difficult for elderly participants; limited concentration and capacity were used without considering the severity of the symptoms; there were relatively few participants; no detailed investigation regarding hypersensitivity reactions was done.
Thus, further studies are required to investigate the treatment methods of BVP on various body parts affected by arthritis, so that three methods can be used more aggressively in clinics.