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Bee Venom

Scientific Name(s): Apis mellifera
Common Name(s): Bee venom, Honeybee venom

Medically reviewed by Drugs.com. Last updated on Jun 17, 2019.

Clinical Overview

Use

Bee venom is used to hyposensitize individuals highly sensitive to bee stings. There is some evidence that it might also help inhibit or suppress arthritis and multiple sclerosis.

Dosing

There is no recent clinical evidence to guide dosage of bee venom.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Documented adverse reactions. Avoid use.

Interactions

None well documented.

Adverse Reactions

Various adverse reactions may occur to bee venom, the severity of which depends on the number of stings sustained.

Toxicology

A single bee sting can produce anaphylaxis in sensitive individuals. Regardless of history, monitor any patient with multiple stings.

Source

Honeybee venom is obtained from A. mellifera, the common honeybee. Other venoms are derived from related members of the hymenoptera.

History

Anaphylaxis to insect stings is a relatively uncommon problem, affecting approximately 0.4% of the general United States population. It is the cause of an estimated 40 deaths per year in the United States.Reisman 1992

The allergic reactions are mediated by immunoglobulin E (IgE) antibodies directed at constituents of honeybee, yellow jacket, hornet, and wasp venoms. In order to minimize allergic reactions, hyposensitization immunotherapy techniques have been developed in which small doses of the venom are administered under controlled conditions over a period of months to years. Patients allergic to honeybee venom may be particularly sensitive to hymenoptera venoms in general and have been found to be at a higher risk of developing systemic adverse reactions to venom immunotherapy than patients who are sensitive to yellow jacket venom.Muller 1992

More recently, it has been suggested that honeybee venom may alleviate the symptoms and slow the progression of immune-modulated diseases such as arthritis and multiple sclerosis.

Chemistry

Bee venoms are complex mixtures of enzymes and polysaccharides. They are collected from the insects and diluted to standardized concentrations. Melittin, a phospholipase activating protein in bee venom, has been shown to induce neutrophil degranulationBomalaski 1989 and to increaseBomalaski 1989 or inhibitSomerfield 1986 the formation of superoxide. This variation in activity appears to depend upon the test method employed. Melittin induces neutrophil degranulation with subsequent superoxide formation in vitroBomalaski 1989; however, melittin binds to calmodulin, an effect associated with inhibition of superoxide production.Somerfield 1986

The polypeptide adolapin isolated from bee venom inhibits inflammation (carrageenan, prostaglandin, and adjuvant rat paw edema models) and appears to inhibit the prostaglandin synthase systems.Shkenderov 1982

Uses and Pharmacology

Acne

Clinical data

A Cochrane review of complementary therapies for acne identified 1 randomized trial (n=12) of low quality that showed a statistically significant benefit of purified bee venom for reducing the numbers of skin lesions in acne vulgaris compared to control (P=0.01). Cosmetics were applied with or without the intervention (0.06 mg/mL purified bee venom) for 2 weeks.Cao 2015

Anti-inflammatory effects

Animal data

In a study using the mouse air pouch model, dilute bee venom (dBV) treatment produced a potent anti-inflammatory effect, as indicated by a marked reduction in leukocyte migration compared with that of saline pre-treatment.

Dilute bee venom's anti-inflammatory effect (dBVAI) is reversed by intrathecal pretreatment with atropine but not with hexamtehonium, indicating that dBV stimulated an increase in spinal acetylcholine, specifically activating spinal muscarinic receptors.

Intrathecal administration of a muscarinic type 2 (M2) receptor antagonist (methoctramine), but not M1or M3 receptor antagonists, abolished dBVAI, indicating that spinal M2 receptors are specifically involved in dBVAI.Yoon 2005

Systemic pretreatment with the beta-adrenergic receptor antagonist propranolol, but not the corticosteroid antagonist RU-486, inhibited dBVAI. This suggests that dBVAI is meditated by adrenal medullary catecholamines acting through beta-adrenoreceptors expressed by immune cells and that it is not dependent on corticosteroid release from the adrenal cortex.Kwon 2003 A study in mice demonstrated that bee venom-induced anti-inflammatory effect is dependent on activation of capsaicin-insensitive primary afferent fibers and the central noradrenergic system, including the locus coeruleus.

These findings demonstrate the complex nature of the neuroimmune interactions that underlie the anti-inflammatory effect produced by subcutaneous bee venom administration.

Transection of the sciatic nerve completely eliminated BVAI on zymosan-induced inflammation, indicating that BVAI is dependent on peripheral nerve integrity and is not a locally mediated anti-inflammatory effect.Kwon 2006

A study in Sprague-Dawley rats showed that sciatic nerve transaction, L4-L6 dorsal rhizotomy, and local treatment of the sciatic nerve with capsaicin produced a depression of subcutaneous injection of bee venom-induced inflammation, indicating that neurogenic components are involved in the bee venom-induced inflammatory response. Dorsal root reflex together with axon reflex conducted by capsaicin-sensitive primary afferents are the potential mechanisms underlying the generation of neurogenic inflammation.

It is further suggested that capsaicin-sensitive primary afferents may play differential roles in the development of dynamic and static mechanical allodynia in the bee venom test.Chen 2006

Arthritis therapy

It has been speculated that honeybee venom may prevent the development of or improve the status of patients with rheumatoid arthritis. This conclusion is based largely on anecdotal observations of a general lack of arthritis among beekeepers stung routinely during their lifetimes. In one survey of a random sampling of the general population, 83% of respondents believed that bee venom could be an effective treatment for arthritis based on information they had read in the lay press.Price 1983

Animal data

Honeybee venom administered to rats with adjuvant arthritis resulted in a suppression of the disease.Yiangou 1993 Melittin has blocked the production of superoxide and hydrogen peroxide in human neutrophils. Melittin and other agents that bind calmodulin have decreased superoxide production. An elevated superoxide level has been suggested as a possible cause of oxidative damage to synovial fluid and other joint membranes. Therefore, agents that decrease the production of the superoxide may prevent or halt the progression of inflammatory diseases such as arthritis. Also, honeybee venom has decreased the production of the inflammatory mediator interleukin-1 in rat splenocytes. Honeybee venom treatment of rats with adjuvant arthritis inhibits certain macrophage activities and, thus, indirectly inhibits the activation of T and B cells.Hadjipetrou-Kourounakis 1988

Treatment with bee venom resulted in a reduction of tissue swelling and osteophyte formation in a model of chronic arthritis, as well as reduction of edema formation in a model of acute arthritis.Reisman 1992

Bee venom inhibited lipopolysaccharide-induced prostaglandin E 2 and nitric oxide production in Raw 264.7 cells. The inhibitory actions of bee venom on the generation of inflammation mediators were also effective in synoviocytes from rheumatoid arthritis patients. The inhibitory effect of bee venom was consistent with that of indomethacin.Park 2004

Atopic dermatitis

The Eczema Area and Severity Index (EASI) score was significantly improved in patients with atopic dermatitis who were randomized to receive bee venom emollient in a 4-week, double-blind, controlled trial (n=114). The improvement in EASI scores was also significantly larger than those in the control group at both 2 and 4 weeks (P=0.023 and P=0.022, respectively). At week 3, the visual analog score of itching was also significantly reduced in the experimental group (P=0.03). Adverse drug reactions (ie, irritation, pruritus, erythema, urticaria, disease exacerbation) were experienced by 35.2% of participants in the bee venom group compared to 23.1% of controls.You 2016

Immunotherapy

Hypersensitivity to honeybee venom is mediated by a number of antibodies and immunomodulators, the most important of which appears to be IgE. Venom immunotherapy (VIT) reduces the likelihood of systemic response in patients with systemic allergic reactions to insect venom. Criteria to precisely identify the point in time when protection becomes persistent are unknown. In addition, despite the remote possibility of severe reaction, the supervised sting challenge test is the only current method for evaluating the efficacy of VIT. The identification of markers that can be used to predict protection is needed.Konno 2005

Clinical data

The infusion of beekeepers' plasma has been shown to protect patients against systemic reactions that can occur during active immunotherapy.Boutin 1994 Following infusion of this plasma, a decrease in the sensitivity to honeybee venom has been noted; in one study, this was accompanied by increases in the levels of anti-idiotypic antibodies and decreases in specific antibodies to honeybee venom (immunoglobulin G and E). The study was conducted over a 76-week period of immunotherapy with the venom. These findings suggest that several mechanisms play an interrelated role in the development of immunity to honeybee venom. An upregulation of osteopontin expression associated with successful VIT has been reported, suggesting a potential role of osteopontin as a biomarker in VIT. In addition to its known regulatory role in bone metabolism, osteopontin has been postulated to be a TH1 cytokine and is involved in TH1-associated immune responses.Konno 2005

Multiple sclerosis (MS)

Uses for bee venom, although poorly substantiated, include the treatment of diseases of the locomotor systemMund-Hoym 1982 particularly MS. Despite widespread anecdotal reports, there is no scientific consensus as to the safety and effectiveness of bee venom in the management of this disorder.Wesselius 2005

Clinical data

In a study of 26 patients with relapsing-remitting or relapsing secondary progressive MS, bee sting therapy had no effect on disease activity as measured using gadolinium-enhanced magnetic resonance imaging of the brain.Wesselius 2005

Dosing

There is no recent clinical evidence to guide dosage of bee venom.

Pregnancy / Lactation

Documented adverse reactions. Avoid use.

Interactions

None well documented.

Adverse Reactions

Immediate effects after multiple stings include localized pain, swelling, and erythema at individual sting sites. Stings to the eyes can result in corneal edema and ulceration. When bees are swallowed, life-threatening pharyngeal edema and respiratory obstruction may occur. Early systemic symptoms after large-volume envenomation include fatigue, dizziness, nausea, vomiting, and diarrhea. Within 24 hours, hemolysis, hemoglobinuria, rhabdomyolysis, and hepatic transaminase enzyme elevations may develop. Subendocardial damage and cardiac enzyme elevations seen in human case reports and animal studies may result from direct venom effects in the absence of anaphylaxis and hypotension. Renal insufficiency and electrolyte abnormalities such as hyperkalemia may occur secondary to rhabdomyolysis, hemolysis, and acute tubular necrosis. Nonanaphylactic responses to multiple stings often will be apparent within the first several hours; however, severe systemic signs and symptoms have been delayed for up to 24 hours or more.Betten 2006

Toxicology

Bee stings cause human reactions in 2 distinct patterns. One or a few stings may induce allergic responses that are sometimes severe or fatal. On the other hand, massive attacks with hundreds to thousands of stings can cause severe systemic injury affecting many different organs, resulting in high mortality. Melittin has been shown to be the main lethal component in bee venom.

Signs and symptoms of multiple stings include urticaria (hives), nausea, vomiting, diarrhea, hypotension, confusion, seizures, and renal failure. Treatment is supportive, with attention to blood pressure, renal function, and maintenance of an open airway. Stingers should be removed with gentle scraping to prevent further venom injection.Tunget 1993 Mass inoculation of bee venom may induce acute renal failure (ARF), adult respiratory distress syndrome, liver injury, cardiac damage, pancreatitis, skin necrosis, shock hypertension, bleeding, thrombocytopenia, hemolysis, and rhabdomyolysis. Bee venom-induced ARF after multiple stinging has been sporadically reported in Europe, Africa, and Asia.Grisotto 2006

Animal studies have shown a decrease in glomerular filtration rate and urinary volume after bee venom infusion. In the same way, venom caused a sharp and immediate decrease in renal blood flow. Experimental injection of bee venom caused a reaction similar to that observed in patients with bee venom-induced ARF.Grisotto 2006

Because cardiac levels of noradrenaline have increased dramatically in animals following bee venom injection, it is suggested that all patients, regardless of sensitivity history, have cardiac monitoring if they are victims of multiple bee stings.Ferreira 1994 Rare cases of anuria and rhabdomyolysis/rhabdomyonecrosis have been reported.Azevedo-Marques 1992, Beccari 1992

Index Terms

  • Hymenoptera

References

Azevedo-Marques MM, Ferreira DB, Costa RS. Rhabdomyonecrosis experimentally induced in Wistar rats by Africanized bee venom. Toxicon. 1992;30(3):344-348.1529465
Beccari M, Castiglione A, Cavaliere G, et al. Unusual case of anuria due to African bee stings. Int J Artif Organs. 1992;15(5):281-283.1601512
Betten DP, Richardson WH, Tong TC, Clark RF. Massive honey bee envenomation-induced rhabdomyolysis in an adolescent. Pediatrics. 2006;117(1):231-235.16396886
Bomalaski JS, Baker D, Resurreccion NV, Clark MA. Rheumatoid arthritis synovial fluid phospholipase A2 activating protein (PLAP) stimulates human neutrophil degranulation and superoxide ion production. Agents Actions. 1989;27(3-4):425-427.2552770
Boutin Y, Jobin M, Bedard PM, Hebert M, Hebert J. Possible dual role of anti-idiotypic antibodies in combined passive and active immunotherapy in honeybee sting allergy. J Allergy Clin Immunol. 1994;93(6):1039-1046.7516355
Cao H, Yang G, Wang Y, et al. Complementary therapies for acne vulgaris. Cochrane Database Syst Rev. 2015;1:CD009436.25597924
Chen HS, Lei J, He X, et al. Pivotal involvement of neurogenic mechanism in subcutaneous bee venom-induced inflammation and allodynia in unanesthetized conscious rats. Exp Neurol. 2006;200(2):386-391.16624301
Ferreira DB, Costa RS, Oliveira JS, Muccillo G. Cardiac noradrenaline in experimental rat envenomation with Africanized bee venom. Exp Toxicol Pathol. 1994;45(8):507-511.8054829
Grisotto LS, Mendes GE, Castro I, et al. Mechanisms of bee venom-induced acute renal failure. Toxicon. 2006;48(1):44-54.16774771
Hadjipetrou-Kourounakis L, Yiangou M. Bee venom, adjuvant induced disease and interleukin production. J Rheumatol. 1988;15(7):1126-1128.3262759
Konno S, Golden DB, Schroeder J, Hamilton RG, Lichtenstein LM, Huang SK. Increased expression of osteopontin is associated with long-term bee venom immunotherapy. J Allergy Clin Immunol. 2005;115(5):1063-1067.15867867
Kwon YB, Kim HW, Ham TW, et al. The anti-inflammatory effect of bee venom stimulation in a mouse air pouch model is mediated by adrenal medullary activity. J Neuroendocrinol. 2003;15(1):93-96.12535175
Kwon YB, Yoon SY, Kim HW, et al. Substantial role of locus coeruleus-noradrenergic activation and capsaicin-insensitive primary afferent fibers in bee venom's anti-inflammatory effect. Neurosci Res. 2006;55(2):197-203.16621078
Moon DO, Park SY, Heo MS, et al. Key regulators in bee venom-induced apoptosis are Bcl-2 and caspase-3 in human leukemic U937 cells through downregulation of ERK and Akt. Int Immunopharmacol. 2006;6(12):1796-1807.17052670
Muller U, Helbling A, Berchtold E. Immunotherapy with honeybee venom and yellow jacket venom is different regarding efficacy and safety. J Allergy Clin Immunol. 1992;89(2):529-535.1740583
Mund-Hoym WD. Bee venom containing Forapin in the treatment of mesenchymal diseases of the locomotor system. Report on treatment results in 211 patients [in German]. Med Welt. 1982;33(34):1174-1177.7132669
Park HJ, Lee SH, Son DJ, et al. Antiarthritic effect of bee venom: inhibition of inflammation mediator generation by suppression of NF-kappaB through interaction with the p50 subunit. Arthritis Rheum.2004;50(11):3504-3515.15529353
Price JH, Hillman KS, Toral ME, Newell S. The public's perceptions and misperceptions of arthritis. Arthritis Rheum. 1983;26(8):1023-1028.6882478
Reisman RE. Stinging insect allergy. Med Clin North Am. 1992;76(4):883-894.1614238
Roh DH, Kim HW, Yoon SY, et al. Bee venom injection significantly reduces nociceptive behavior in the mouse formalin test via capsaicin-insensitive afferents. J Pain. 2006;7(7):500-512.16814689
Shkenderov S, Koburova K. Adolapin--a newly isolated analgetic and anti-inflammatory polypeptide from bee venom. Toxicon. 1982;20(1):317-321.7080045
Somerfield SD, Stach JL, Mraz C, Gervais F, Skamene E. Bee venom melittin blocks neutrophil O2- production. Inflammation. 1986;10(2):175-182.3011670
Tunget CL, Clark RF. Invasion of the 'killer' bees. Separating fact from fiction. Postgrad Med. 1993;94(2):92-94, 97-98, 101-102.8341628
Wesselius T, Heersema DJ, Mostert JP, et al. A randomized crossover study of bee sting therapy for multiple sclerosis. Neurology. 2005;65(11):1764-1768.16221950
Yiangou M, Konidaris C, Victoratos P, Hadjipetrou-Kourounakis L. Modulation of alpha 1-acid glycoprotein (AGP) gene induction following honey bee venom administration to adjuvant arthritic (AA) rats; possible role of AGP on AA development. Clin Exp Immunol. 1993;94(1):156-162.8403499
Yoon SY, Kim HW, Roh DH, et al. The anti-inflammatory effect of peripheral bee venom stimulation is mediated by central muscarinic type 2 receptors and activation of sympathetic preganglionic neurons. Brain Res. 2005;1049(2):210-216.15953592
You CE, Moon SH, Lee KH, et al. Effects of emollient containing bee venom on atopic dermatitis: a double-blinded, randomized, base-controlled, multicenter study of 136 patients. Ann Derm. 2016;28(5):593-599.27746639

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