butterbur: an alternative therapy for migraine prevention

Alternative Therapies

705Am J Health-Syst Pharm—Vol 67 May 1, 2010


Butterbur: An alternative therapy for migraine preventionP etasites hybridus, more commonly

known as butterbur, is a member of the Asteraceae family.1-4 This perennial shrub, which can grow to a height of 3 ft, has a creeping, horizontal rhizome, lilac-pink flowers, and broad leaves that can approach 3 ft in diameter (figure).1,3-5 Butterbur is found throughout Europe and in parts of Asia and North America, typically along riversides and streams and in wet, marshy ground in proximity to damp forests.1-5

The botanical genus name, Petasites, is derived from the Greek word petasos, meaning broad-brimmed hat.1,4,5 The common name, butterbur, likely came from the plant’s large leaves, which were once used to wrap butter in warm weather.1,4,5 Other common names include blatterdock, bog rhubarb, bogshorns, butter-dock, and pestwurz.1,2,5

Butterbur has been used for various medicinal purposes for more than 2000 years.1,3,4 Its medicinal use was described as early as 65 A.D. by Dioscorides, a Greek physician, pharma-cologist, and botanist.6 In the Middle Ages, butterbur was used to treat fever and bubonic plague.1,4,5 In the 17th century, it was used orally to treat cough and asthma and was applied topically to treat skin wounds.1,3,5

Other documented therapeutic uses of butterbur include treatment of lung dis-eases, urogenital tract spasms, aches and pains, dysmenorrhea, and gastrointesti-nal afflictions.1-5 In 1951, the popularity of butterbur grew when Karl Bucher was able to demonstrate the antispasmodic

Butterbur (Petasites hybridus). Photograph by Diane Earl (E2BN Gallery). Used with permission.

properties of the unrefined plant extract in guinea pigs.1,4 Currently, the most common uses of butterbur include pro-phylaxis for migraines and allergic rhini-tis and treatment of allergic skin disease and asthma.1-3,5

Chemistry and pharmacology. The bitter-tasting active constituents respon-sible for the extract’s pharmacologic activ-ity are the eremophilane sesquiterpenoid

substances, specifically petasin, isopetasin, S-petasin, and iso-S-petasin.1-7 Also found in the extracts of butterbur are volatile oils, flavonoids, tannins, and pyrrolizidine alkaloids.2,5 It is believed that petasin has the greatest antispasmodic activity of these constituents.1,4 S-petasin, however, has been extensively studied recently, and the mechanism of action of these constit-uents is becoming better established.6

Butterbur has demonstrated antiin-flammatory properties. The active com-ponents of butterbur, particularly iso-petasin, inhibit the lipoxygenase pathway and leukotriene synthesis, key processes in the activation of inflammation.1-3,5,7 Petasin and its analogues also decrease the activation of mast cells, which results in decreased release of leukotrienes and histamine into the circulation.2,3 Isopeta-sin may also contribute to the antiin-flammatory properties of butterbur by enhancing prostaglandin metabolism.5

Butterbur extracts have been shown to inhibit cyclooxygenase-2 inde-pendent of petasin content, in-dicating the presence of another potentially pharmacologically active constituent.1,7,8

The antispasmodic proper-ties of butterbur, first demon-strated in 1951, are attributed to its petasin constituents, as they cause smooth muscle and vascular wall relaxation.6,7 Petasins block calcium influx into the smooth muscle cells via voltage-dependent calcium channels.3,6,7 Interestingly, peta-sins have a high affinity for cerebral blood vessels.1,5

While limited pharmacoki-netic data are available, butter-bur has been reported to be bio-available, with petasin having a half-life of four to six hours.1 The pyrrolizidine alkaloids are

metabolized by cytochrome P-450 (CYP) isoenzyme 3A4 into toxic dehydroalka-loids and pyrroles.2,3

The Alternative Therapies column features short reviews of herbals and other “nutra-ceuticals” for which there is some scientific evidence of effectiveness. Readers are invited to send ideas for the column to AJHP at [email protected].


706 Am J Health-Syst Pharm—Vol 67 May 1, 2010

Efficacy in migraine prevention. The pathophysiology of migraine head-aches, while not completely understood, has been explained by two main theories: the vascular hypothesis and the neuronal dysfunction hypothesis.9 Ultimately, vasoconstriction and neurogenic inflam-mation are implicated in the generation of migraine headaches. Migraine head-ache prophylaxis should be considered when headaches affect a patient’s life. Specific scenarios include headaches oc-curring so frequently that acute medica-tions are overused, headaches that are un-responsive to abortive treatments, patients with contraindications to abortive agents, and headaches that significantly increase the risk of morbidity or mortality.9,10

The antispasmodic, antiinflamma-tory, and vasodilatory properties of but-terbur make it an attractive treatment option for migraine prevention. It has been studied for this indication in sev-eral clinical trials. Summarized here are the four trials published in English, two in adults and two in pediatric patients, where migraine headache diagnoses were made according to the International Headache Society’s definitions.11,12 In each of these trials, there was a run-in pe-riod where baseline migraine frequency was assessed. Patients were required to have at least two migraines during the run-in period to qualify for the study. In all four trials, patients were required to have migraines for at least one year, with two to three migraines per month for the three months before the study to ensure chronic, recurring disease. The butterbur formulation used in each of the trials was the same, the commercially avail-able product Petadolex (Weber & Weber, Ocoee, FL), which contains no less than 15% petasins.

Trials in adults. The first published clinical trial evaluating butterbur for the prevention of migraine headaches was a randomized, parallel-group, placebo-controlled, double-blind study in 58 adult patients.13 After a 4-week run-in period, patients were randomized to re-ceive either butterbur 50 mg twice daily (n = 31) or placebo (n = 27) for 12 weeks. The primary efficacy endpoint was fre-

quency of migraines at each 4-week visit. Secondary efficacy endpoints included the frequency, duration, and intensity of migraine headaches. The frequency of migraine attacks decreased from base-line at the 4-, 8-, and 12-week follow-up visits for patients receiving butterbur by 45%, 60%, and 48%, respectively. This change was significant at each time point when compared with the decrease seen in patients receiving placebo (24%, 17%, and 10%, respectively; p < 0.05). Patients receiving butterbur also experienced decreased intensity and duration of mi-graine headaches, but significance when compared with placebo was only found at the 8-week interval for these outcomes. At week 8, pain intensity with butterbur decreased by 1.5 points on a 10-point scale, compared with a decrease of 0.3 point with placebo (p < 0.05). Pain in-tensity increased again in the butterbur-treated group by week 12. The duration of migraine attack decreased by four hours at week 8 in the butterbur-treated group compared with a decrease of one hour in the placebo group (p < 0.05). Twenty-three patients receiving but-terbur reported benefit with treatment, compared with only 7 patients receiving placebo (p < 0.005).

An independent reanalysis of the data from the study described above was com-pleted in 2004 by Diener and colleagues14 to address concerns regarding statistical analysis and to ensure that the study met requirements for regulatory purposes of the International Conference of Har-monization Guideline E9. The reanalysis used an intent-to-treat (ITT) analysis instead of the per-protocol analysis conducted by the original authors. In ad-dition, the percentage of responders, de-fined as experiencing a decrease of ≥50% in migraine frequency from baseline, was assessed. The reanalysis showed that the mean monthly frequency of migraines decreased from 3.4 at baseline to 1.8 at week 12 with butterbur (p = 0.0024), compared with no significant change in patients receiving placebo (2.9 versus 2.6). In addition, 45% of patients receiv-ing butterbur were deemed responders, compared with only 15% of patients

receiving placebo. The use of medica-tions for acute migraine attacks, while only briefly discussed in the original analysis, was analyzed in more detail and revealed that the percentage of patients in the butterbur group who used medi-cations for acute attacks decreased (from 44% to 18%), while the percentage of patients in the placebo group essentially remained the same (from 27% to 26%). This reanalysis of the data confirmed that butterbur was superior to placebo for the four primary endpoints at three time points with regard to percent changes from baseline, absolute values, and abso-lute changes from baseline.

Another randomized, parallel-group, double-blind, placebo-controlled trial as-sessed the safety and efficacy of butterbur for the prevention of migraine headaches in 233 adults suffering from chronic mi-graines.15 Patients were randomized into one of three groups: butterbur extract 50 mg twice daily (n = 79), butterbur extract 75 mg twice daily (n = 77), or placebo (n = 77). After a 4-week run-in phase, eligi-ble patients entered a 16-week treatment phase. The primary outcome measured was the percent reduction from baseline in the frequency of migraines per month. Secondary outcome measures included the absolute reduction in migraines per month, number of treatment responders (as defined previously), use of acute mi-graine medications, and adverse events. In the ITT analysis, migraine frequency decreased by 45% in patients receiving butterbur 75 mg twice daily, 32% in those receiving butterbur 50 mg twice daily, and 28% in those receiving placebo. The response seen with butterbur 75 mg twice daily was significantly better than that seen with butterbur 50 mg twice daily (p = 0.04) or placebo (p = 0.005). The difference in migraine frequency did not significantly differ between patients treated with butterbur 50 mg twice daily and the placebo group. The percentage of treatment responders was significantly higher with butterbur 75 mg twice daily (68%) compared with butterbur 50 mg twice daily (56%) or placebo (49%) (p

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< 0.05). The percentage of treatment responders with butterbur 50 mg twice daily was not significantly different than that seen with placebo. The authors con-cluded that the higher dose of butterbur (75 mg twice daily) was efficacious in the prevention of migraines.

Trials in pediatric patients. A four-month, open-label trial was conducted with 108 pediatric patients who were di-vided into two groups: children (age 6–9 years, n = 29) and adolescents (age 10–17 years, n = 79).16 Children received but-terbur 25 mg twice daily for two months, with the option of a dosage increase to 25 mg three times daily if needed to at-tain response. Adolescents received 50 mg twice daily for two months, with the option to increase to 50 mg three times daily if needed. Outcome measures were assessed two and four months after the start of therapy and included the num-ber, duration, and severity of migraines; severity of associated symptoms; and physical and general impairment. Chil-dren and adolescents experienced a reduction in migraine frequency from baseline (67% and 62%, respectively). Responder rates were 85.7% for chil-dren and 74.1% for adolescents. Twelve adolescents had no migraines during treatment, and more than half of all patients had fewer than two migraines during the four-month treatment pe-riod. The mean duration of migraines also decreased from 10 to 6.5 hours. Substantial improvement was reported by 81.6% (71 of 87) of patients overall. While the open-label study design limits the conclusions that can be drawn, the results support the use of butterbur in children and adolescents for the preven-tion of migraines.

The efficacy of butterbur was com-pared with music therapy and placebo in the prevention of migraines in pediatric patients (age 8–12 years) in a prospec-tive, randomized, placebo-controlled, three-arm, parallel-group study.17 After an 8-week run-in phase, there was a 12-week treatment phase, an 8-week posttreatment phase, and an 8-week

follow-up phase six months after treat-ment. Patients were evaluated during the 8-week posttreatment phase and during the 8-week follow-up phase. In this study, patients were randomized to receive butterbur (n = 19), placebo (n = 19), or music therapy (n = 20). Similar to the previous study,16 younger patients (age 8–9 years) received butterbur 25 mg twice daily, and older patients (age 10–12 years) received butterbur 50 mg twice daily. If deemed nonresponders with the initial dosage, the dosage was increased to three times daily. The pri-mary outcome measure was the percent reduction in migraine frequency from baseline. Secondary outcome measures included responder rates and the clini-cal level of improvement in migraine intensity. Eight of 19 patients in both the placebo and butterbur groups required dosage increases. In the posttreatment per-protocol analysis, the reduction in headache frequency was greater with music therapy (65.7%) than with but-terbur (36.1%) or placebo (28.8%), but the difference was significant only between music therapy and placebo (p = 0.005). In the six-month follow-up per-protocol analysis, music therapy (63.2%, p = 0.018) and butterbur (58.7%, p = 0.044) significantly decreased migraine frequency from baseline compared with placebo (31.4%), with no significant dif-ference between the two active treatment groups. The responder rate in the post-treatment period did not differ between placebo and butterbur groups but was significantly higher with music therapy (p = 0.01). By the six-month follow-up point, there was no significant difference in responder rates among any of the three treatments. This study’s results regarding the efficacy of butterbur for migraine prevention have limited applicability, given that the efficacy assessments were made at times when patients were not taking butterbur.

Summary of clinical trials. Evidence from clinical trials suggests that butter-bur is an effective therapy for migraine prevention in adults, with 75 mg twice daily potentially being superior to 50 mg twice daily. Evidence from clinical trials

in children is limited largely by study design; however, butterbur may be effica-cious for migraine prevention in pediat-rics. The maximum treatment duration studied in both adults and pediatric patients was 16 weeks. Butterbur, when used for migraine prevention, is recog-nized as possibly effective, with good scientific evidence to support its use.1,2

Safety and toxicology. Raw and unprocessed butterbur extracts contain pyrrolizidine alkaloids, such as senecio-nine and integerimine.1-5,18-20 In humans, pyrrolizidine alkaloids have been shown to cause hepatotoxicity, specifically veno-occlusive disease. Animal studies have revealed pyrrolizidine alkaloids to be carcinogenic.19,20 In the commercially available product Petadolex, the pyrroliz-idine alkaloids are removed to levels less than 0.08 ppm, the lowest limit of detec-tion.19 Warnings have been issued in the United States regarding the consumption of unprocessed or raw butterbur extracts that may contain pyrrolizidine alkaloids because of their potential to cause he-patotoxicity.19 This is partly due to the concern that butterbur is regulated as a dietary supplement in the United States and, as such, is not subject to the strict good manufacturing practices to which pharmaceuticals must comply.

Patients who have hypersensitivity reactions or allergies to other plants in the Asteraceae family (e.g., ragweed, marigolds, daisies, chrysanthemums) should use caution when taking but-terbur, as there is the potential for cross-reactivity.1-3 No allergic reactions, however, have been reported.3 Pregnant and lactating women should not take butterbur, as its safety has not been estab-lished in these populations.1-3,5

Adverse events reported in clinical tri-als for migraine prevention were limited. The most commonly reported adverse events related to butterbur were gastro-intestinal upset, with belching being the most frequently reported (approximately 20% of patients), dermal symptoms, and dizziness.3,15,17 Other adverse events reported included headache, drowsiness,

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fatigue, nausea, vomiting, diarrhea, stomach pain, flatu-lence, allergic conjunctivitis, eye and skin discoloration, and sneezing.1-3,19 These adverse events are generally considered mild and self-limiting. Mild elevations in liver enzymes were reported in some patients in clinical trials, but these increases were transient and not considered clinically relevant.14,17 In pediatric patients, the primary adverse events seen with but-terbur were also gastrointestinal in nature (belching, abdomi-nal pain, nausea, bitter taste).16,17

In 2003, based on marketed capsules of Petadolex sold, it was estimated that 450,000 people had taken butterbur since 1992. Butterbur demonstrated excellent tolerability, evidenced by the low overall frequency of reported adverse events (0.022%).19 There have been no reports of butterbur overdose.1 Commercially available butterbur is thought to be likely or possibly safe when taken in recommended doses; however, butterbur has not been well studied for treatment periods of greater than 12–16 weeks.1,2

Drug interactions. Few potential drug–drug and drug–herbal product interactions exist with butterbur. The use of butterbur should not be combined with that of other herbal products containing pyrrolizidine alkaloids to avoid any potential additive toxicity.1,2 Since pyrrolizidine alkaloids are metabolized to toxic metabolites by CYP3A4, concomitant administration of butterbur and 3A4 inducers (e.g., St. John’s wort, carbamazepine, phenytoin, rifampin, phenobarbital) should be avoided, as this may enhance toxicity.2,3 Butterbur should not be used in combination with medications or herbs (e.g., bittersweet) that have anticholinergic properties because of the potential for additive therapeutic or adverse effects.1,3 The drug interactions listed above are theoretical, as no clini-cally significant specific drug interactions with butterbur in adults or children have been reported.3

Products and dosage. Extracts of butterbur are prepared from the shrub’s rhizomes, roots, and leaves.1,4,5,21 Petadolex, the butterbur product used in clinical trials for migraine pre-vention, was developed in Germany in the 1970s and has been patented in the United States since 2003.21 The Food and Drug Administration does not subject dietary supplements to strict registration procedures. However, Petadolex is manufactured in Germany, where the special butterbur root extract is con-sidered a medication and thereby subject to strict regulation by health authorities. Petadolex is manufactured to be free of pyrrolizidine alkaloids, defined as levels below detectable lim-its. Other commercially available butterbur products used in clinical trials for the prevention of allergic rhinitis and treat-ment of asthma include Petaforce (Bioforce Ltd., Irvine, Unit-ed Kingdom) and Tesalin (Zeller Medical AG, Romanshorn, Switzerland).1 Both Petadolex and Petaforce are standardized to contain 7.5 mg of petasins in each 50-mg tablet or gel cap, and Tesalin contains 8 mg of petasins. While various other products containing butterbur are available in the United

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711Am J Health-Syst Pharm—Vol 67 May 1, 2010

States, care should be taken to ensure that they are free of pyrrolizidine alkaloids. Unprocessed butterbur products should be avoided due to safety concerns.

Based on clinical trials and avail-able dosage forms, butterbur dosing for migraine prevention in adults is 50–75 mg twice daily.1,13,15,21 Pediatric dosage recommendations are 50–150 mg daily, using the lower end of the dosing range for younger patients.1,16,17 Therapeutic benefit may be seen as early as two to four weeks after initiation of therapy, but patients should allow for a couple of months to see a benefit. It is also suggest-ed that therapy be tapered after four to six months and reinstituted if migraine frequency increases.5

Summary and conclusion. Butter-bur has been used for centuries for the treatment of many diseases. In recent years, butterbur has been studied in clini-cal trials for the prevention of migraine headaches. While limited data are avail-able, clinical studies tend to support the use of butterbur in adults for migraine prophylaxis. The results from clinical trials in pediatrics are limited by study design, but preliminary evidence sug-gests that butterbur may be of some ben-efit for migraine prevention in children. Butterbur has a good safety profile and has demonstrated excellent tolerability in both adult and pediatric patients when the purified product is used. Butterbur has not been incorporated into the most recent practice guidelines for the prevention of migraine headaches, likely because data supporting its use emerged after the last guideline update.10 Based on the available evidence and favorable tolerability profile, butterbur can be considered a treatment option in pa-

tients who meet the criteria for migraine prophylaxis.

1. Giles M, Park C, Khalsa K et al. But-terbur (Petasites hybridus). www.natural standard.com (accessed 2008 Aug 30).

2. Natural Medicines Comprehensive Da-tabase. Butterbur. www.naturaldatabase.com (accessed 2008 Aug 30).

3. Sadler C, Vanderjagt L, Vohra S. Com-plementary, holistic, and integrative medicine: butterbur. Pediatr Rev. 2007; 28:235-8.

4. Debrunner B, Meier B. Petasites hybridus: a tool for interdisciplinary research in phytotherapy. Pharm Acta Helv. 1998; 72:359-62.

5. Monograph. Petasites hybridus. Altern Med Rev. 2001; 6:207-9.

6. Sheykhzade M, Smajilovic S, Issa A et al. S-petasin and butterbur lactones dilate vessels through blockage of voltage gated calcium channels and block DNA synthe-sis. Eur J Pharmacol. 2008; 593:79-86.

7. Agosti R, Duke RK, Chrubasik JE et al. Effectiveness of Petasites hybridus prepa-rations in the prophylaxis of migraine: a systematic review. Phytomedicine. 2006; 13:743-6.

8. Fiebich BL, Grozdeva M, Hess S et al. Petasites hybridus extracts in vitro inhibit COX-2 and PGE2 release by direct inter-action with the enzyme and by prevent-ing p42/44 MAP kinase activation in rat primary microglial cells. Planta Med. 2005; 71:12-9.

9. Ropper AH, Brown RH. Headache and other craniofacial pains. In: Ropper AH, Brown RH. Adams and Victor’s principles of neurology. 8th ed. New York: McGraw Hill Professional; 2005:144-67.

10. Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the quality standards subcom-mittee of the American Academy of Neu-rology. Neurology. 2000; 55:754-62.

11. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neural-gias and facial pain. Cephalalgia. 1988; 8(suppl 7):1-96.

12. Headache Classification Subcommittee of the International Headache Society. The international classification of head-

ache disorders: 2nd edition. Cephalalgia. 2004; 24(suppl 1):9-160.

13. Grossmann M, Schmidramsl H. An ex-tract of Petasites hybridus is effective in the prophylaxis of migraine. Int J Clin Pharmacol Ther. 2000; 38:430-5.

14. Diener HC, Rahlfs VW, Danesch U. The first placebo-controlled trial of a special butterbur root extract for the prevention of migraine: reanalysis of efficacy criteria. Eur Neurol. 2004; 51:89-97.

15. Lipton RB, Göbel H, Einhäupl KM et al. Petasites hybridus root (butterbur) is an effective preventive treatment for mi-graine. Neurology. 2004; 63:2240-4.

16. Pothmann R, Danesch U. Migraine prevention in children and adolescents: results of an open study with a special butterbur root extract. Headache. 2005; 45:196-203.

17. Oelkers-Ax R, Leins A, Parzer P et al. But-terbur root extract and music therapy in the prevention of childhood migraine: an explorative study. Eur J Pain. 2008; 12:301-13.

18. Evans RW, Taylor FR. “Natural” or alter-native medications for migraine preven-tion. Headache. 2006; 46:1012-8.

19. Danesch U, Rittinghausen R. Safety of a patented special butterbur root extract for migraine prevention. Headache. 2003; 43:76-8.

20. Wildi E, Langer T, Schaffner W et al. Quantitative analysis of petasin and pyrrolizidine alkaloids in leaves and rhi-zomes of in situ grown Petasites hybridus plants. Planta Med. 1998; 64:264-7.

21. Weber & Weber USA. Petadolex homep-age. www.petadolex.com (accessed 2009 Jan 6).

Anna Sutherland, Pharm.D., Oncology Pharmacy Practice Resident

Burgunda V. Sweet, Pharm.D., FASHP, Director, Drug Information Service

[email protected]

Department of Pharmacy ServicesUniversity of Michigan Health SystemAnn Arbor, MI 48109-5008

The authors have declared no potential conflicts of interest.

DOI 10.2146/ajhp090136

butterbur: an alternative therapy for migraine prevention

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