Butterbur


Article Author:
Lennox Din


Article Editor:
Forshing Lui


Editors In Chief:
Evelyn Metz
Julie Sewell
Aditya Arya


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
12/23/2018 1:21:58 PM

Indications

FDA approved indications:

  • None

Non-FDA approved indications:

  • Adult Migraine

The American Headache Society and the American Academy of Neurology: 2012 evidence-based guideline update indicated that Petasites (butterbur) demonstrates effectiveness for migraine prevention and is a valid option for patients with migraine to reduce both the severity and frequency of migraine attacks (Level A). The recommendation was questioned and then retracted in 2016.[1]

Butterbur (leaves of Petasites japonicus) has been found to be effective in the prophylaxis of adult migraines in multiple studies.[2] Based on these trials, the American Headache Society gave the herb a level A recommendation and declared it to be effective in the prevention of migraine headaches. Similarly, the Canadian Headache Society guidelines give butterbur a strong recommendation for use in migraine prophylaxis.[3] Although the American Academy of Neurology recommended butterbur, it has retracted its current guideline on it.[3] In the United Kingdom and Germany, butterbur is not authorized for official use due to concerns about safety.[3] In one randomized, parallel-group study from 2004, the group given butterbur had a response rate of 45% whereas the group who used placebo had a response rate of 15%. In another randomized controlled trial from 2004, butterbur reduced the frequency of migraines by 48% in the experimental group whereas the placebo reduced the frequency by 26% in the control group.[2]

  • Pediatric Migraine

Similar to adult migraines, there is evidence for Petasites in the prevention of pediatric migraines.[4] In one randomized controlled trial from 2005, butterbur reduced the frequency of attacks by at least 50% in 77% of the pediatric experimental group.[2] In another randomized controlled trial from 2008, butterbur reduced the frequency of attacks by 59% in the experimental group whereas the placebo reduced the frequency of attacks by 31% in the control group.[5] 

  • Allergic Rhinitis and Asthma

Butterbur has been used in countries in Asia as a herbal treatment of asthma and allergic diseases.[6]There is a limited body of evidence from randomized controlled trials that butterbur may be useful as a therapy for asthma and allergic rhinitis, but not as effective as in the prevention of migraine.[2][7]

  • Alzheimer's Disease

Studies have found that butterbur may potentially be effective in the treatment of Alzheimer's disease due to its neuroprotective effect. However, only studies involving in vitro and in vivo models have been performed.[8]

Mechanism of Action

Mechanism of action for the treatment of migraines:

  • Petasites inhibits the opening of L-type voltage-gated calcium channels which decreases vasoconstriction of vessels and excitation of neurons.[4] The herb's active components include Sesquiterpenes (Petasin and Isopetasin) which have been found to exhibit anti-inflammatory effects through the inhibition of COX-2. This leads to decreased leukotriene synthesis and prostaglandin E2 release.[9]

Mechanism of action for treatment of Asthma and Allergic Rhinitis:

  • Petatewalide B, a derivative of Petasites, has also been found to exhibit anti-allergic activities.[6] Specifically, the compound inhibits the activation of ß-hexosaminidase in RBL-2H3 mast cells. Petatewalide B also inhibits nitric oxide synthase which decreases nitric oxide production in mouse peritoneal macrophages. The compound also decreases the concentration of eosinophils, macrophages, and lymphocytes in mouse bronchoalveolar lavage fluid.[6]

Mechanism of action for treatment of Alzheimer's:

  • Derivatives of Petasites have been found to have antioxidant activity; the DPPH free radical-scavenging value and ferric ion reducing potential were both increased.[10] In one study examining the cognitive effects of butterbur, the herb significantly decreased levels of reactive oxygen species (ROS) levels and increased viability of HT22 mouse neuronal cells exposed to Aß plaques. The study found that the mechanism for the former was related to increased expression of heme oxygenase-1 (HO-1), NAD(P)H quinine dehydrogenase 1 and cyclic AMP response element-binding protein (CREB) which are all involved in antioxidant pathways.[8] Similarly, in Aß plaque-injected mice, administration of butterbur resulted in significantly decreased CREB expression in the dentate gyrus.[8]  

Administration

Butterbur is given almost exclusively via oral administration.[11]

Adverse Effects

Previous randomized controlled trials have found no serious adverse effects and good overall tolerance of the drug.[2] Minor effects include gastrointestinal symptoms (belching is most common), dyspepsia, headache, itchy eyes, drowsiness, fatigue, and asthma. Long-term use of butterbur may rarely lead to cholestatic hepatitis (estimated incidence of 1:175,000). Patients who are allergic to ragweed and daisies may also have similar allergic reactions to butterbur.[2]

One major area of concern with regards to safety is with pyrrolizidine alkaloids which are commonly found in the butterbur plant.[9] These substances can cause hepatotoxicity, lung toxicity, carcinogenesis, and thrombosis. Fortunately, the commercial preparation process of butterbur typically removes these substances. Thus, it is recommended for consumers of butterbur to only buy brands which are free of alkaloids and other plant carcinogens.

Severe hepatotoxicity may be associated with butterbur use, but the evidence is unclear. From the World Health Organization's Vigibase, one study reported 40 cases of hepatotoxicity including two liver transplants associated with the use of Petasites formulations.[3] However, these cases may be the result of the use of butterbur contaminated with alkaloids. Another article reported detecting levels of toxic alkaloids in seven out of 21 commercially available compounds.[3] Therefore, at least some brands are inadequately removing alkaloids from their butterbur formulations. In summary, it is unclear if hepatotoxicity is due to alkaloids in the formulation or the butterbur itself. To evaluate the hepatotoxic effects of butterbur more clearly a future study can collect data on brands which claims to be alkaloid-free, by thoroughly reviewing the literature and the Periodic Update Safety Report. The data can then be analyzed with the Roussel Uclaf Causality Assessment Method test to determine if butterbur carries an association with hepatotoxicity.[12]

Contraindications

Butterbur use is contraindicated in patients using anticholinergic medications. Also, there have not been studies establishing safety criteria in children under six years of age, pregnant or lactating women. Therefore, butterbur use is not recommended in these groups.[9]

Monitoring

Multiple studies recommend a daily dose of 50-150 mg.[11] Monitoring of liver function (AST, ALT,  ALP, GCT, bilirubin) is recommended due to potential hepatotoxicity from butterbur or drug contamination with pyrrolizidine alkaloids.[2] 

Toxicity

The list of side effects of butterbur is in the adverse effects section. Long-term use of butterbur may rarely lead to reversible cholestatic hepatitis (estimated incidence of 1:175,000).[9] Butterbur may also interact with anticholinergic medications. There is no known antidote for butterbur overdose. The recommendation in such cases is to cease using the drug.

Enhancing Healthcare Team Outcomes

There have been no formal studies examining interprofessional care and its relationship to butterbur. Nevertheless, close coordination amongst physicians, nurses, pharmacists, and other healthcare providers is recommended to monitor for side effects and interactions with other medications especially anticholinergics. As a herbal remedy, butterbur may often not appear on a patient's official prescribed medication list. Therefore, it is essential for every healthcare provider to inquire about alternative or natural remedies when interviewing patients and record it in the patient's chart.


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Butterbur - Questions

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A patient comes into the clinic and inquires about the use of butterbur. Select the incorrect statement about this herb.



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A 28-year-old female comes into the emergency department complaining of a right-sided throbbing headache for the past 10 hours. She reports that her pain is 8/10. She also reports seeing bright lights about 4 hours after her headache began. She denies any similar headaches in the past or any recent trauma. Her only past medical history is significant for a 3-day cold last week. Her vitals are within normal limits. A physical examination reveals no abnormal findings. She is eventually diagnosed and discharged without hospitalization. As a connoisseur of herbal remedies, she elects to take butterbur, hoping it will prevent future symptoms. What is the most likely mechanism of action for this herb in possibly preventing her symptoms?



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A 25-year-old male has been diagnosed with migraines. He elects to take butterbur for preventive treatment. After one week of taking it, he develops frequent belching and comes into the clinic. What should be recommended?



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A 26-year-old patient comes in for an annual check-up. He has no medical problems, and the physical examination is normal, including normal vital signs. He tells the provider he has been taking 50 mg of butterbur daily since his last visit because he believes it to be healthy. The brand he is taking does not come from the United States. What is the best next step?



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A 75-year-old male presents to the clinic with progressive memory difficulty over the past 2 years. Initially, his symptoms mainly consisted of misplacing everyday items. Over time, his symptoms worsened and include forgetting to turn off the stove, forgetting names of friends and family, and being unable to handle his finances. The provider who examines him diagnosis him with dementia and orders some lab tests. A family member inquires if butterbur can improve his symptoms. Assuming this herb is effective in humans, which of the patients below would benefit the most?



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Butterbur - References

References

Kim N,Choi JG,Park S,Lee JK,Oh MS, Butterbur Leaves Attenuate Memory Impairment and Neuronal Cell Damage in Amyloid Beta-Induced Alzheimer's Disease Models. International journal of molecular sciences. 2018 Jun 1     [PubMed]
Ezzatzadeh E,Hossaini Z, Green synthesis and antioxidant activity of novel series of benzofurans from euparin extracted of Petasites hybridus. Natural product research. 2018 Jan 28     [PubMed]
Malone M,Tsai G, The evidence for herbal and botanical remedies, Part 1. The Journal of family practice. 2018 Jan     [PubMed]
D'Onofrio F,Raimo S,Spitaleri D,Casucci G,Bussone G, Usefulness of nutraceuticals in migraine prophylaxis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2017 May     [PubMed]
D'Andrea G,Cevoli S,Cologno D, Herbal therapy in migraine. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2014 May     [PubMed]
Oelkers-Ax R,Leins A,Parzer P,Hillecke T,Bolay HV,Fischer J,Bender S,Hermanns U,Resch F, Butterbur root extract and music therapy in the prevention of childhood migraine: an explorative study. European journal of pain (London, England). 2008 Apr     [PubMed]
Orr SL, The Evidence for the Role of Nutraceuticals in the Management of Pediatric Migraine: a Review. Current pain and headache reports. 2018 Apr 4     [PubMed]
Rajapakse T,Pringsheim T, Nutraceuticals in Migraine: A Summary of Existing Guidelines for Use. Headache. 2016 Apr     [PubMed]
Chen CW, [Carefully reviewing the history of diagnostic scales and paying more attention to the diagnostic value of Roussel - Uclaf causality assessment method scale for drug - induced liver injury]. Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology. 2016 Nov 20     [PubMed]
Lee DK,Haggart K,Robb FM,Lipworth BJ, Butterbur, a herbal remedy, confers complementary anti-inflammatory activity in asthmatic patients receiving inhaled corticosteroids. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2004 Jan     [PubMed]
Choi YW,Lee KP,Kim JM,Kang S,Park SJ,Lee JM,Moon HR,Jung JH,Lee YG,Im DS, Petatewalide B, a novel compound from Petasites japonicus with anti-allergic activity. Journal of ethnopharmacology. 2016 Feb 3     [PubMed]
Holland S,Silberstein SD,Freitag F,Dodick DW,Argoff C,Ashman E, Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012 Apr 24     [PubMed]

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