HEADACHE

The Journal of Head and Face Pain

Official Publication of the American Headache Society (formerly the American Association for the Study of Headache)

Volume 43, Number 1
January 2003
Original Abstract

Ulrich Danesch, PhD, Reiner Rittinghausen, MD

Objective: To report on the safety of a patented special butterbur root extract used for migraine prevention.

Background: Two placebo-controlled clinical trials have been conducted supporting the beneficial use in humans.

Methods: Results from acute, subchronic and chronic animal toxicity studies as well as from mutagenicity studies are reported. Safety data gained from clinical trials, postmarketing surveillance studies and pharmacovigilance are evaluated and discussed.

Conclusion: The patented special butterbur root extract is safe for the treatment in humans.

Petasites hybridus (butterbur) is a native European perennial flourishing along the banks of streams and other moist areas. It has been used medically for centuries. Its spasmolytic and analgesic effects are used in conditions like migraine, asthma, urinary tract spasms, and back pain,1-5 and are thought to be mainly attributed to a group of sesquiterpene compounds, the petasins.6,7 Two recent clinical trials with the special butterbur root extract have confirmed its efficacy as a migraine prophylactic treatment.8,9

Because butterbur is known to contain pyrrolizidines alkaloids (PAs), a group of plant constituents that is burdened with hepatotoxic properties and that may also cause liver cancer,10 warnings have been issued in the United States regarding the risks of unknown PA content in herbal supplements containing butterbur preparations. Dietary supplements unlike “real drugs” are not subjected to strict registration procedures by the Food and Drug Administration (FDA). The problem of mislabeled, adulterated, contaminated, and poorly manufactured products being marketed as medications looms ever larger as some profiteers take advantage of the wide open marketplace created by the 1994 Dietary Supplement Health & Education Act.11-13 However, in Germany and Switzerland, the special butterbur root extract is a medication and under strict regulation by the respective health authorities, ie, Bundesinstitut fuer Arzneimittel und Medizinprodukte (BfArM) and Swiss Medic.

The active ingredient of the herbal product reported here is a special extract made from the underground parts (rhizome) of the plant Petasites hybridus, standardized to contain a minimum of 15% petasins. The patented manufacturing process strictly complies with Good Manufacturing Practice (GMP) requirements,14 and results in a complete removal of toxic pyrrolizidine alkaloids below 0.08 ppm in the finished extract, which represents the lower limit of detection. Therefore, no restrictions for dosage and duration of use are necessary with regard to a potential pyrrolizidine alkaloid toxicity.

Several toxicity studies were conducted in Wistar rats. Acute effects of oral and intraperitoneal application of a single dose of the special butterbur extract yielded an LD50 of less than or equal to 2.5 g/kg body weight for a single oral application and an LD50 of approximately 1 g/kg for a single intraperitoneal application, representing between 833- and 1250-fold and between 333- and 500-fold of the recommended human dose, respectively.15

A chronic toxicity study was performed in 200 Wistar rats for a period of 26 weeks. The study was conducted in accordance with ruling EEC Directives, with the ICH Guideline “Duration of Chronic Toxicity Testing in Animals” and with the OECD Guideline for Testing of Chemicals. Principles of Good Laboratory Practice (GLP) as specified by national and international legislation were strictly followed.

A no adverse effect level (NOAEL) could be established for the lower dose range tested being well above and at an adequate safety distance of the recommended dose in humans.16

In two controlled clinical trials, a total of 187 patients with migraine were exposed to doses of the special butterbur extract between 100 and 150 mg daily for at least 3 months. Compared to placebo, no significant differences were observed regarding adverse events rated to be at least possibly causally related to the product, except for “eructations.” This well-known adverse effect is of mild and transient nature, and occurred in about 20% of study patients. About 90% of study patients rated global tolerability to be “excellent” or “good.”

A total of 188 patients (145 suffering from migraine, including 50 children and adolescents from 6 to 17 years of age) were treated with the special butterbur extract at various doses for several months in the framework of 4 postmarketing surveillance studies, 2 which of have been finished and published already.17,18 Of the adverse events reported to be possibly or probably causally related to the product, 7 cases of “eructations,” 2 cases of “bad smell and taste of the product,” and 1 case of a “skin rash” need to be mentioned from these studies. Excellent tolerability at doses from 50 to 150 mg was reported for children from 6 years of age.

Assuming an individual standard treatment for 2 months with a daily dose of 100 mg of the special butterbur extract, and that 90% of capsules marketed were taken, approximately 450,000 individuals would have been exposed to the product since 1992 according to sales figures, reflecting a total of approximately 75,000 patient years of exposure.

Documentation of spontaneous reports started in 1976. A total of 75 reports of suspected adverse reactions from Germany and 18 spontaneous reports from other countries were received by the manufacturer until June 30, 2002, therefore representing an overall frequency of suspected adverse reactions of as low as 0.022%. Only 19 reports were determined to be possibly causally related to the administration of the special butterbur root extract and 8 reports to be probably causally related to the administration of the special butterbur root extract by thorough evaluation of all cases in strict accordance with EMEA pharmacovigilance guidelines and with standard operating procedures. One case of a reversible cholestatic hepatitis was diagnosed by an hepatologist at the University of Munich as a hypersensitivity reaction with a probable causal relationship to petasites.

All cases mentioned refer to the 25 mg capsule, marketed in Europe with a dosing recommendation of 2 to 3 capsules bid. Up to this date, no adverse reactions for the 50 mg formulation have been received.

The reported suspected adverse reactions with the highest frequency such as nausea, eructation, and stomach pain are considered a mild discomfort of the gastrointestinal system. However, the frequency of these suspected adverse reactions is less than 0.01% in the postmarketing surveillance, as only 29 cases with gastrointestinal problems were reported, and 11 of them were considered possibly or probably related to the product. Therefore, even the most frequently reported adverse reaction for the product can be assessed as “very rare” (according to the WHO Guidelines for Preparing Core Clinical Safety Information on Drugs; Report from CIOMS Working Group III, Geneva 1995).

In conclusion, the data presented here suggest that the special patented butterbur root extract is a safe and excellently tolerated treatment for migraine prevention.

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