Issue: 58 Page: 18-19
Standardized Butterbur Extract for Migraine Treatment: A Clinical Overview
by Donald J. Brown
HerbalGram. 2003; 58:18-19 American Botanical Council
by Donald J. Brown, N.D.
The development of a standardized extract of the rhizome of
purple butterbur (Petasites hybridus (L.) P. Gaertn., B. Mey. & Scherb.,
Asteraceae) has led to a new clinical approach to the management of migraine
headache. Two clinical trials with a standardized CO2 extract have
successfully demonstrated the extract’s ability to safely and effectively
reduce the frequency and intensity of migraine headaches.
Purple butterbur is a perennial shrub native to Europe, northern
Africa, and southwestern Asia that grows to about three feet tall.1 Although
butterbur is frequently used as the common name, the species is also commonly
known as purple butterbur and sweet coltsfoot.2 A related plant,
P. frigidus (L.) Fries, is known as Arctic butterbur and Arctic sweet
coltsfoot or western coltsfoot.
While both leaves and rhizomes have been used in traditional
herbal medicine,3 only medicinal preparations of the rhizome are
approved by the German Commission E for use in modern phytotherapy, for "supportive
therapy for acute spastic pain in the urinary tract, particularly if stones
Active Constituents and Mechanism of Action
The leaves, rhizomes, and roots of butterbur contain a mixture
of eremophilane-type sesquiterpenes consisting primarily of petasin (also known
as petasine) and isopetasin.5 According to phytotherapy textbooks,
petasin and isopetasin have both spasmolytic and analgesic actions.3
These active constituents also inhibit leukotriene synthesis, which may also
contribute to butterbur’s antispasmodic and anti-inflammatory actions.6,7
Butterbur leaf and rhizome contain pyrrolizidine alkaloids
(PAs), which are potentially hepatotoxic and carcinogenic constituents.8
Concern about the presence of PAs has led to the virtual demise of coltsfoot
leaf (Tussilago farfara L., Asteraceae), comfrey root (Symphytum officinale
L., Boraginaceae), and the groundsels (Senecio spp., Asteraceae) for
oral use in herbal medicine and may be the primary explanation for the waning
interest in the therapeutic use of butterbur in traditional herbal medicine.
It is imperative that healthcare professionals recommend only butterbur products
that are free of PAs or reduced to meet the limits set by the German Commission
E. It should be noted that the Commission E monographs stipulate limits for
PAs in approved herbal preparations that contain PAs, specifically 100 mcg per
day in comfrey leaf or root, 1 mcg for extracts or pressed juice from fresh
coltsfoot, and 1 mcg daily of petasites root. All limits refer to PAs with the
1,2 necine structure, including their N-oxides.4
Antispasmodic actions have led to the use of butterbur for
urinary tract spasms due to kidney stones, digestive tract spasms, as well as
lower back pain.3,9 It has also been used for whooping cough and
bronchial asthma. A clinical trial found that a PA-free extract of the leaves
(standardized to petasin content) was as effective as the antihistamine cetirizine
in the treatment of allergic rhinitis.10 (Please see my review of
this clinical trial in HerbalGram 56).
Two randomized, placebo-controlled, double-blind clinical trials
tested the efficacy of the standardized butterbur extract (Petadolex®,
Weber & Weber International GmbH & Co., Germany) in the treatment of
migraines. In the first trial, 60 migraine patients (mean age 28.7 years) were
randomized to receive either 50 mg of Petadolex or placebo two times per day
for 12 weeks.11 Starting at the fourth week of treatment, the Petadolex
group had a significant reduction in the number of migraine attacks compared
to the placebo group (P < 0.05). Compared to the placebo group, those
taking Petadolex had a 60 percent reduction in the number of migraines by week
12. The number of migraine days was also reduced significantly in the Petadolex
group (3.4 ± 1.6 at baseline to 1.7 ± 0.9 days after 12 weeks) compared to placebo
(3.0 ± 1.3 to 2.6 ± 1.2 days, P < 0.05). While the duration and intensity
of migraines was significantly reduced at 8 weeks in the Petadolex group (P
< 0.05), the difference compared to placebo was not significant at week 12.
The mean number of accompanying symptoms (e.g., nausea, vomiting) was significantly
reduced in the Petadolex group compared to placebo (P < 0.01). No
adverse events were reported at the end of the 12-week trial.
The second trial randomized 202 migraine patients (ages 19—65
years) to receive either 50 mg of Petadolex, 75 mg of Petadolex, or placebo
two times per day for 12 weeks following a four-week baseline run-in period.12
The primary endpoint, frequency of migraine attacks per four weeks, was reduced
by 38 percent, 44 percent, 58 percent, and 51 percent in patients treated with
150 mg/day of Petadolex after 1 (baseline), 2, 3, and 4 months respectively.
The 100 mg/day group had a reduction of 24 percent, 37 percent, 42 percent,
and 40 percent, while the placebo group was 19 percent, 26 percent, 26 percent,
and 32 percent, respectively. Treatment differences between those taking 100
mg/day of Petadolex were not significant compared to placebo. However, those
taking 150 mg/day had a significant reduction in migraine count over 3 months
of treatment compared to placebo (P < 0.001). The number of patients
who had a 50 percent reduction in mean migraine attack frequency per month relative
to baseline were considered therapy responders. The mean percent of responders
in the 150 mg/day group (68 percent) was significantly greater than those taking
placebo (49 percent) (P < 0.05). The mean three-month assessment
of headache intensity also favored the Petadolex 150 mg/day group compared to
placebo (P = 0.01). Eighty participants reported 131 adverse events –
23 patients in the placebo group and 29 patients and 28 patients in the 100
mg and 150 mg groups, respectively. The most frequently reported adverse events
in patients taking Petadolex were gastrointestinal complaints with burping being
the most common complaint (reported by approximately 20 percent of patients
Petadolex is a CO2 extract of the butterbur rhizome
(concentrated at a ratio of 28—44:1) standardized to 15 percent petasin
and isopetasin with PAs reduced to < 0.08 ppm in the finished product (which
represents the lower limit of detection). Adults and children over the age of
12 years may take 50 mg of the extract two to three times per day. Although
clinical trials have only studied continuous use for up to 12 weeks, current
product recommendation is for 4 to 6 months of continuous use of the product.
Side effects are rare with the use of the PA-free extract and
have consisted primarily of mild gastrointestinal complaints (nausea, burping,
and stomach pain) with rare reports of vomiting, diarrhea, and skin rash. In
a recent safety report on standardized butterbur root extract, documentation
of adverse events from 1976 to June 30, 2002 found a total of 75 reports of
suspected adverse reactions from Germany and 18 spontaneous reports from other
countries received by the manufacturer (Weber and Weber).13 Only
19 reports were determined to be possibly causally related to the administration
of the medication and 8 reports to be probably causally related to the medication
by thorough evaluation by German pharmacovigilance guidelines and standard operating
procedures. One case of cholestatic hepatitis was diagnosed as a hypersensitivity
reaction with a probable causal reaction to butterbur. Butterbur should not
be used during pregnancy or lactation due to lack of safety studies, nor should
it be used by those who have suffered from hepatitis or other liver ailments.
There are no known drug interactions for butterbur rhizome extract.
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Review of Natural Products. St. Louis, MO: Facts and Comparisons Publishing
2. McGuffin M, Kartesz JT, Leung AY, Tucker AO, eds. Herbs
of Commerce, 2nd edition. Silver Spring, MD: American Herbal Products Association;
3. Weiss RF, Fintelmann V. Herbal Medicine. Stuttgart,
Germany: Thieme; 2000:200-2.
4. Blumenthal M, Busse WR, Goldberg A, Gruenwald J, Hall
T, Riggins CW, Rister RS, eds. Klein S, Rister RS, trans. The Complete German
Commission E Monographs: Therapeutic Guide to Herbal Medicines. Austin,
TX: American Botanical Council; 1998.
5. Bisset NG, Wichtl M. Herbal Drugs and Phytopharmaceuticals.
Boca Raton, FL: CRC Press; 1994:366-8.
6. Bickel D, Röder T, Bestmann HJ, Brune K. Identification
and characterization of inhibitors of peptido-leukotriene synthesis from Petasites
hybridus. Planta Med 1994;60:318-22.
7. Thomet OAR, Wiesman UN, Schapowal A, et al. Role of petasine
in the potential anti-inflammatory activity of a plant extract of Petasites
hybridus. Biochem Pharmacol 2001;61:1041-7.
8. Gruenwald J, Brendler T, Jaenicke C, eds. PDR for
Herbal Medicines. Montvale, NJ: Medical Economics; 2000:585-8.
9. Eaton J. Butterbur: herbal help for migraine. Natural
10. Schapowal A. Randomised controlled trial of butterbur
and cetirizine for treating seasonal allergic rhinitis. BMJ 2002;321:1-4.
11. Grossmann M, Schmidramsl H. An extract of Petasites
hybridus is effective in the prophylaxis of migraine. Inter J Clin Pharmacol
12. Lipton RB, Gobel H, Wilkes K, Mauskop A. Efficacy of
Petasites (an extract from Petasites rhizome) 50 and 75 mg for
prophylaxis of migraine: Results of a randomized, double-blind, placebo-controlled
study. Neurology 2002;58(suppl 3):A472 [Presented at the 44th Annual
American Headache Society Meeting, June 22, 2002, Seattle, WA].
13. Danesch U, Rittinghausen R. Safety of a patented special
butterbur root extract for migraine prevention. Headache 2003;43:76-8.