An Overview of Bee Venom Acupuncture in the Treatment of Arthritis

Bee venom acupuncture (BVA), as a kind of herbal acupuncture, exerts not only pharmacological actions from the bioactive compounds isolated from bee venom but also a mechanical function from acupuncture stimulation. BVA is growing in popularity, especially in Korea, and is used primarily for pain relief in many kinds of diseases. We aimed to summarize and evaluate the available evidence of BVA for rheumatoid arthritis and osteoarthritis. Computerized literature searches for experimental studies and clinical trials of BVA for arthritis were performed on the databases from PUBMED, EMBASE and the Cochrane Library. In addition, two leading Korean journals (The Journal of Korean Society for Acupuncture and Moxibustion and The Journal of Korean Oriental Medicine) were searched for relevant studies. The search revealed 67 studies, 15 of which met our criteria. The anti-inflammation and analgesic actions of BVA were proved in various kinds of animal arthritic models. Two randomized controlled trials and three uncontrolled clinical trials showed that BVA was effective in the treatment of arthritis. It is highly likely that the effectiveness of BVA for arthritis is a promising area of future research. However, there is limited evidence demonstrating the efficacy of BVA in arthritis. Rigorous trials with large sample size and adequate design are needed to define the role of BVA for these indications. In addition, studies on the optimal dosage and concentration of BVA are recommended for future trials.

(CAM), acupuncture is one of the most common therapies used to treat a number of human inflammatory diseases including rheumatoid arthritis and osteoarthritis (7,8). Moreover, there are a sufficient number of studies using CAM therapies, including herbal therapy, glucosamine, chondroitin sulfate and S-adenosylmethionine, in these conditions despite claims often heard about the lack of evidence for CAM (9). It is notable that BVA demonstrated anti-inflammatory and analgesic actions in animal studies (10)(11)(12)(13)(14)(15)(16)(17)(18)(19) as well as in clinical trials (20)(21)(22)(23). However, the effectiveness of BVA for this indication is still not well known and no review of this subject exists.
The purpose of the present study was, therefore, to evaluate the data from experimental and clinical studies and to explore further ways to better comprehend the effectiveness of BVA on arthritis.

Data Sources
Computerized literature searches for experimental studies and clinical trials of BVA for arthritis were performed on the databases from PUBMED, EMBASE and the Cochrane Library. In addition, two leading Korean journals (The Journal of Korean Society for Acupuncture and Moxibustion and The Journal of Korean Oriental Medicine) were searched for relevant studies. The search terms 'bee venom', 'bee venom therapy', 'acupuncture' and 'anti-inflammation', 'rheumatic arthritis' or 'osteoarthritis' were used. Further hand-searches were performed in the reference lists of all located articles.

Categorization of Studies
For experimental analysis, we focused on the animal research that have evaluated anti-inflammatory and anti-nociceptive effects. For clinical studies, we included all trials with rheumatoid arthritic and osteoarthritic patients. We included the papers in our review only when they applied bee venom treatment to acupoints. The search found 67 studies, of which 15 met our criteria.

Quality Assessment
The methodological quality of each randomized controlled trial (RCT) was rated according to the Jadad scale (24). Points were awarded as follows: the study was described as randomized, 1 point; the randomization scheme was described and appropriate, 1 point; the study was described as double blind, 1 point; the method of double blinding was appropriate, 1 point; there was a description of withdrawals and dropouts, 1 point. The maximum point-score available was 5.

Anti-inflammatory and Anti-nociceptive Effects of BVA in Animals
The anti-inflammation and analgesic effects of BVA have been proven in various kinds of animal arthritic models, such as adjuvant, carrageenan or lipopolysaccharide (LPS)-induced arthritis.
Kwon et al. (10) and Seo et al. (12) conducted a comparative study of acupoint versus non-acupoint stimulation on an adjuvant induced RA animal model with BVA. Direct injection of bee venom into acupoint ST36 produced a potent anti-nociceptive effect, suggesting that this alternative form of acupoint stimulation using bee venom can be applied for relieving pain.
Kim et al. (14) and Choi et al. (13) conducted an experiment to show effectiveness of BVA at acupoint ST36 by inducing arthritis in rats by a mixture of type II collagen. It compared levels of proteolytic enzyme activities and free-radicalinduced protein damage in synovial fluid from this animal model. BVA at acupoint BL23 significantly reduced proteolytic enzyme activities and level of reactive oxygen species (ROS)-induced oxidative damage to synovial fluid proteins in this model (14).
Doh et al. (17) observed anti-inflammatory effects on knee arthritis induced by carrageenan in rats. Numbers of white blood cells and red blood cells increased, and values of hemoglobin hematocrit also showed significant therapeutic effects. Lee et al. (18) administered bee venom at acupoint ST36 prior to carrageenan, and evaluated acute edema and heat on the paw and analyzed the Fos expression of the spinal cord quantitatively. Pretreatment with BVA prior to carrageenan administration inhibited both carrageenan-induced edema and heat on the paw, showing clear correlation between change rates of edema on the foot and the expression of Fos positive neutron on the spinal cord.
The effects of BVA at acupoint GB34 on LPS-induced arthritis were conducted to examine the therapeutic effects of BVA in mice (15,19). Bee venom decreased numbers of white blood cells, infiltration of leukocytes and fibroblasts into synovial joints, CD56, IL-1 ␤, IL-2R, CD54 and CD106 in synovial membrane when compared with controls.
Kim et al. (16) and Yim et al. (11) administered adult Sprague-Dawley rats with bee venom directly into acupoint ST36 or into an arbitrary non-acupoint located on the back. Pretreatment with bee venom into the ST36 acupoint significantly decreased paw-licking time in the late phase of the formalin test and also markedly inhibited spinal cord Fos expression induced by formalin injection.
Several studies suggest that the effects of BVA depend on the locations injected; acupuncture points exert much stronger effects than non-acupoints (10)(11)(12)16). The effects of bee venom might be intensified by acupuncture stimulations, which may help in reaching therapeutic goals.

Favorable Effects of BVA on RA and OA Patients in Clinical Trials
One RCT and two uncontrolled clinical trials were found for RA (Table 1). Kwon (20) performed BVA on 10 patients diagnosed with RA. The results showed 90% validity with remarkable improvement in two cases, good improvement in five cases, and effective improvement in two cases. In Lee et al.'s study (21), patients with RA who met ACR (American College of Rheumatology) 1987 revised criteria for diagnosis of RA were treated with BVA therapy twice a week for 3 months. Tender joint counts, swollen joint counts and duration of morning stiffness in patients after BVA therapy was significantly lower than those before BVA therapy. Lee et al. (22) also performed the RCT for evaluating effects of BVA in RA patients. RA patients were recruited and randomly divided into a BVA group and a control group by random selection. Each group was treated with BVA or normal saline injection on acupoints twice a week for 8 weeks. Tender joint count, swollen joint count, morning stiffness, pain, health assessment questionnaire, ESR (erythrocyte sedimentation rate) and CRP (C-reactive protein) were estimated and analyzed at baseline, at 1 month and 2 months after BVA therapy. Compared to the control group, the BVA group showed a significant decrease in tender joint count, swollen joint count, morning stiffness and health assessment questionnaire after 2 months. Pain, ESR and CRP also showed a significant decrease in the BVA group after 1 and 2 months.
One RCT and one uncontrolled trial were searched for OA (  (25) conducted an experiment to investigate whether direct administration of bee venom into an acupoint is a clinically effective and safe method for relieving pain of patients with knee OA as compared to traditional needle acupuncture. Four weeks of BVA treatment were followed by pain relief scores and computerized infrared thermography (IRT) for evaluation of efficacy of BVA. The group of subjects receiving BVA showed substantial relief of pain as compared to the group receiving traditional needle acupuncture, and the IRT score was significantly improved to parallel the level of pain relief. They demonstrated that a majority (82.5%) of subjects receiving BVA (33 out of 40 subjects) reported substantial pain relief as compared with traditional acupuncture therapy (55%). The therapeutic efficacy was favorable irrespective of disease duration (acute, subacute or chronic stage), arthritic type (unilateral or bilateral knee OA) and radiological severity.

Discussion
Collective evidence from in vivo experiments shows that BVA has a potent analgesic and anti-inflammatory effect. Two clinical studies on degenerative arthritis and three clinical studies on RA suggest that BVA may become a promising treatment for both RA and OA. The number of controlled studies of BVA in arthritis is quite small, and their quality is limited. However, it would be worth considering BVA as an applicable treatment for arthritis in CAM.
Many animal investigations cited in this review have shown that BVA is capable of producing anti-nociception and antiinflammatory actions in several animal models (10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Several studies suggested that the effects of bee venom were intensified by acupuncture stimulations, which may help in reaching therapeutic goals. The anti-nociceptive property of BVA may be explained by the process of counter irritation; that is, when noxious stimuli are applied to body regions, these stimuli increase the pain thresholds and reduce pain rating scores through the body. For centuries, pain has been relieved by counter-irritation methods such as moxibustion (a method of burning herbs to stimulate acupuncture points) on arthritic limbs (25). The two uncontrolled investigations (20,21) and one RCT study (22) from the above search results showed that bee venom therapy was very effective in the treatment of RA. The treatment goal for RA can be summarized as follows: first, pain and inflammation should be prevented, since it can lead to pain in the joints, disformity of the joints, or loss of functions; second, chronic inflammation is inhibited so that loss of function in the joints is prevented or minimized to help patients back to normal life. The RCT study of Lee et al. (22) observed that BVA treatment improved the number of painful joints, swollen joints, morning stiffness and hematological indices. Utilizing the Korean health-related questionnaire, it also showed that BVA treatment could contribute to improvement of patients' quality of life.
One RCT investigations (25) and one uncontrolled trial study (23) demonstrated that herbal acupuncture using bee venom for knee arthritis was effective. Previous studies have established the effectiveness of acupuncture treatment both in relieving pain and recovering dysfunction of knees in elderly patients with OA in comparison to non-acupuncture treated control groups (26). Kwon et al. (25) compared therapeutic effects of acupuncture by hand manipulation with herbal acupuncture using bee venom. BVA is more effective than acupuncture. Computerized IRT objectively displayed changes in skin temperature in the painful region. Computerized IRT is a method of examination whereby infrared rays naturally emitted from the body are detected, displaying minute changes in body temperature on painful or other diseased parts on the computer monitor. It is a widely employed method of examination, now used for evaluation of pain and prognosis. Kwon et al. (25) showed that the temperature on the knee region significantly decreased after treatment with bee venom. However, significant change was examined in all groups with severe, moderate or mild degrees of degenerative arthritis.
RA is a typical autoimmune disease, of which exact causative factor have not yet been verified various aspects. The pathogenesis and pathophysiology of RA are being investigated. Until now, there are no methods recommended from perfect prevention or perpetual extermination after onset of RA. Existing methods of treatment for RA can be categorized as medication, surgery, rehabilitation and physical therapy. Medication therapy used in most cases utilizes various kinds of medicine such as NSAIDs, adrenal cortical hormone,

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An overview of bee venom acupuncture in the treatment of arthritis *Jadad score (randomization 1 point ϩ appropriate randomization method 1 point ϩ blinding 1 point ϩ appropriate blinding method 1 point ϩ describing withdrawals and dropouts 1 point ϭ maximum 5 points). Acu, acupuncture; NA, not applicable; NS, not significant. Treatments: • BVA: twice a week for 4 weeks at Ex-LE2, and Ex-LE5 and LR8.
• Lysholm and Karsson's knee joint evaluation scale: Most systematic reviews of therapeutic interventions include only RCTs, which are generally considered as the gold standard for evaluation. However, the medical literature is full of non-randomized and uncontrolled studies. It is certainly highly problematic to draw conclusions on causal effects from non-randomized or uncontrolled studies. However, RCTs also have flaws in other aspects. First, they often recruit only a small and non-representative sample of patients who are then treated and monitored under man-made conditions (31,32). As a result, the degree to which the results can be generalized and are externally valid is unclear. Second, RCTs in chronic conditions have limited observation periods because of ethical reasons, feasibility or resources (33,34). If the number or quality of available randomized trials is not sufficient to draw conclusions, non-randomized studies might be useful to give a better overview of what is known so far and to inform future research. It is obvious that the number of subjects and the quality of the studies in this review have limitations. However, BVA is considered to be highly promising in the treatment of arthritis.

Conclusion
A sufficient number of animal studies have shown that BVA has significant anti-inflammatory and analgesic effects. Due to paucity and methodological flaws in the existing clinical studies, it is premature to draw any firm conclusions at this time. However, the effectiveness of BVA for arthritis is likely to be a promising area of future research. Rigorous trials with large sample sizes and adequate design are required to define the role of BVA for these indications. anti-rheumatic drugs and immunosuppressive agents, which can cause severe adverse effects such as depression, peptic ulcers, enterohemorrhage, liver malfunction and renal disorders. OA is the most commonly examined arthritis, also known as 'degenerative arthritis' or 'degenerative arthritic disease'. Mostly occurring in middle-aged or elderly people, it attacks the weight-bearing joints-mostly the knee joint-and causes local degenerative changes in cartilage, hypertrophy of subchondral bones, excessive bone formation around osteochondral regions and disformity of joints. Clinically, it shows repetitive pain, ankylosis and gradual dysfunction of movement with inflammatory changes occurring only in a few patients. Western medical treatment of knee arthritis utilizes conservative methods such as medication therapy, rest and exercise, and physical therapy, and surgical methods like arthroscopic debridement, osteomy, arthroscopic surgery and total knee arthroplasty. Patients with mild symptoms should be provided with teaching, physical therapy, and non-narcotic medication and when these do not improve symptoms, prescription of non-steroidal drugs can be considered only when patients have no contraindications for the drug. Steroids are administered to patients with exudative knee arthritis. These treatments have certain adverse effects in RA, calling for safer and more effective methods of treatment (27,28). In general, in order to determine the appropriateness of using CAM therapy in various conditions, it is necessary to consider the relevant problems such as: the severity and acuteness of illness; curability of the illness by conventional forms of treatment; degree of invasiveness, associated toxicities and side effects of conventional treatment; availability and quality of evidence of utility and safety of desired CAM treatments; level of understanding of risks and benefits of CAM treatments combined with the patient's understanding and voluntary acceptance of those risks; and the patient's persistence of intention to use CAM therapies (29). A number of complications or adverse effects of conventional treatment call for safer and more effective methods of treatment (7). There have been investigations on the effects of acupuncture treatment on RA and OA (7,26). Recently, bee venom therapy has been proposed as another approach. Several clinical trials have demonstrated that BVA could improve arthritis-related symptoms. However, evidence for BVA is still scarce. In order to enlarge the clinical therapeutic field of BVA throughout the world, rigorous trials of well-organized design are urgently required to determine the role of BVA in treatming of arthritis. A greater understanding of the risks and benefits of BVA is also needed.
Safety intervention is important for estimating its riskbenefit framework. Serious adverse events such as anaphylaxis and non-serious adverse effects such as local swelling or itching are reported with BVA treatment but are infrequent provided that it is practiced according to established safety rules in appropriate anatomic regions (30). Similarly, there is concerned about the extra cost of BVA. At present no conclusive cost-effectiveness of BVA for arthritis is available, but it requires consideration from an economic point of view. In addition, the determination of acupoints, amount and