By David Kiefer, MD
Allergy season is approaching and clinicians often find themselves in the position of helping their patients negotiate the various pharmacologic and behavioral therapies, balancing side effects and inconveniences along the road to (hopefully) a fall free of runny noses and itchy eyes. Butterbur (Petasites hybridus), a plant with an impressive amount of recent laboratory and clinical study, may be another useful treatment for patients suffering from seasonal allergic rhinitis.
History and Traditional Use
Butterbur is a perennial herb native to Europe, northern Africa, and southwest Asia,1 and was known to be an antispasmodic and analgesic, useful in acute colicky urinary pain such as might result from nephrolithiasis.2 Homeopathic forms of this plant are documented to be useful for smooth muscle cramps.3 The German Commission E approved the use of butterbur root for acute spasm pain of the urinary tract, but could not justify the traditional use of butterbur leaf for "cramp states" due to risks associated with the pyrrolizidine alkaloids contained with the all plant parts in varying amounts.4
As occurs with other medicinal plants referred to by their common name, butterbur has a confusing array of other names, including blatterdock, bog rhubarb, bogshorns, butterbur, butter-dock, butterfly dock, capdockin, flapperdock, langwort, and umbrella leaves.3 This information is provided to readers both as a reminder to always confirm a plant’s identity with its correct scientific name (in this case, Petasites hybridus), and to be aware of herbal medicine combinations that may contain this plant in its unsafe, whole form (see below).
Botany and Pharmacology
Butterbur (Petasites hybridus) is a member of the daisy family (Family Asteraceae). The plant grows to 15-40 cm high, and has reddish flowers and large basal (lower) leaves.3 Interestingly, some texts recommend only harvesting leaves as large as one’s hand because they have a higher content of active phytochemicals.3 These large basal leaves were also once used to wrap and carry pieces of butter, partly explaining one of the plant’s common names.5
All plant parts of butterbur are listed as being used medicinally. Traditionally, above-ground parts such as leaves are collected near the end of the flowering season, and the rhizome (horizontal underground stem) and roots are harvested either in the fall or the spring, a distinction being noted as important in some sources.3 Currently, most butterbur preparations are ethanolic formulations made from the rhizomes, with further processing to remove the dangerous pyrrolizidine alkaloids.
The compounds thought to be responsible for butterbur’s pharmacological activity are referred to as petasins, which fall into the category of eremophilan-type sesquiterpenes;1 sesquiterpenes are often components of essential oils. The petasins in butterbur occur in a mixture; the three main compounds are petasin, isopetasin, and neopetasin, and they each have unique actions in vitro and in vivo.
Mechanism of Action
There has been a significant amount of in vitro research demonstrating the many actions of butterbur relevant to its use in allergic rhinitis. For example, petasin has been shown to bind to the histamine-H1 receptor, and an extract of butterbur inhibits cysteinyl- leukotriene synthesis; the release of inflammatory mediators such as histamine and leukotrienes are important in the pathophysiology of allergic rhinitis.1 Another experiment found that a specific butterbur extract (Ze 339, a carbon dioxide extract standardized to 8.0 mg of total petasin per tablet,6 also called Tesalin®) blocked leukotriene synthesis in stimulated macrophages, eosinophils, and neutrophils in two in vitro models.7 The isolated compound petasin was then tested in the same models and was also found to block leukotriene synthesis.
Other studies have begun to delineate the differences between the mechanisms of action of the different phytochemicals in butterbur. For example, in vitro studies have shown that petasin, isopetasin, and neopetasin all inhibit leukotriene generation, but eosinophil cationic protein is only inhibited by petasin.8 Petasin was also the only compound to prevent an increase in cytosolic phospholipase A2. One of the conclusions that the researchers drew from these and other related experiments is that the different petasin compounds may block different intracellular signaling molecules, and affect different steps in the overall inflammatory cascade.
There have been numerous studies examining the use of butterbur in people with allergic rhinitis. One double-blind, crossover trial randomized 20 patients with seasonal allergic rhinitis to receive either 50 mg of a standardized extract of butterbur (Petaforce®, a dry extract of butterbur root) twice daily or placebo for two weeks during the grass pollen season.9 The researchers measured the nasal response to adenosine monophosphate (AMP), a known irritant and restrictor of nasal airway flow at least partly through a leukotriene mechanism, and found that butterbur attenuated the response to AMP. The researchers then added a subjective component to their research in a double-blind, crossover trial of 16 patients with mild perennial allergic rhinitis who received either 50 mg of a standardized extract of butterbur (Petaforce) twice daily, 180 mg daily of fexofenadine, or placebo for one week.10 The researchers again measured the nasal response to AMP and found that both butterbur and fexofenadine attenuated the response to AMP, while improving nasal symptoms.
Butterbur also has been compared to cetirizine in a double-blind, parallel-group trial.11 The researchers randomized 125 patients with seasonal allergic rhinitis to either one tablet of a butterbur extract (Ze 339) four times daily, or 10 mg of cetirizine in the evening, for two weeks. The results showed similar improvements in symptoms and global improvement scales between the two groups, and that both butterbur and cetirizine were well tolerated. The cetirizine patients reported sedation as the most common adverse effect; no specific adverse event, such as sedation, was associated with the use of butterbur.
Not all studies with butterbur have been favorable. One double-blind, crossover trial compared butterbur (50 mg twice daily of Petaforce) to placebo in 35 patients with intermittent allergic rhinitis.12 After two weeks, no difference was detected in objective or subjective outcomes between the two groups. One criticism is that eight of the original 43 patients withdrew and yet were not included in an intention-to-treat analysis.
Another study contributes some information to our understanding of the action of butterbur, but is less clinically useful due to methodological problems.13 This trial was non-randomized and found that a specific extract of butterbur (Ze 339) in a dose of 16 mg three times daily in patients with allergic rhinitis improved symptoms and quality of life and decreased leukotrienes and histamine in nasal fluids, without affecting generalized leukotriene production. An interesting result, but one that requires controlled study before definitive clinical conclusions can be drawn.
Other Clinical Conditions
Butterbur also has been studied in the context of asthma and allergic skin conditions. In 16 asthmatic patients stable on inhaled corticosteroids, a randomized, double-blind, crossover trial comparing one week of a standardized butterbur extract (Petaforce) 25 mg twice daily to placebo showed that butterbur improved AMP bronchial hyper-responsiveness and several inflammatory markers, apparently acting as a complementary anti-inflammatory for asthmatic patients already on inhaled corticosteroids.14 In other asthma research, a non-randomized, open trial used a butterbur extract in 80 people (64 adults, 16 children) with asthma.15 The extract was Petadolex®, softgel capsules with 50 mg of a standardized lipophilic extract of butterbur rhizome with a minimum of 15% petasins and with pyrrolizidine alkaloids removed. Adults were treated with 50 mg three times daily and the children with 50-150 mg daily for two months, with a second month of treatment being optional. The patients’ regular asthma medication was continued. The researchers documented improvements in number, duration, and severity of asthma attacks, and some patients were able to lessen the use of their regular asthma medication; an interesting result, but one that needs to be verified by further research.
Testing the hypothesis that the effect of butterbur on inflammatory mediators such as cysteinyl leukotriene and histamine in allergic rhinitis and asthma could also benefit people suffering from atopic skin conditions, researchers conducted a randomized, double-blind, crossover study on 20 atopic patients sensitized to at least one common allergen on skin-prick testing.15 The patients received either 50 mg twice daily of a standardized butterbur extract (Petaforce), 180 mg daily of fexofenadine plus placebo, 10 mg daily of montelukast plus placebo, or just placebo for one week. Only fexofenadine successfully attenuated the skin wheal response to skin-prick provocation, showing that butterbur had no effect on the immediate histamine and allergen cutaneous response, and suggesting that butterbur’s main in vivo effects in this system are via inhibition of leukotriene synthesis rather than through effects on histamine.
Dosage and Formulation
There is little if any dosing information about butterbur in many of the commonly used clinical herbal medicine books. What is clear is that any form of the raw, unprocessed butterbur plant should not be ingested due to the toxicity of pyrrolizidine alkaloids; this includes any teas (decoctions or infusions), capsules of raw herb, or unprocessed tinctures or extracts.
Due to these concerns a number of standardized, patented formulas have been developed which have undetectable levels of pyrrolizidine alkaloids and therefore are presumed free of the related mutagenicity, carcinogenicity, and hepatotoxicity. These formulas (and dosing) include Petaforce (25-50 mg two or three times daily), Petadolex (25-75 mg two or three times daily, maximum 150 mg/d), and Tesalin (or Ze 339, 1-2 tablets two or three times daily). The manufacturers of Petadolex provide a dosing for children 10-12 years of age: 50 mg daily with meals.
Adverse Effects, Contraindications and Drug Interactions
Warnings about the use of butterbur usually are based on preparations from the plant that still contain pyrrolizidine alkaloids, known to be carcinogenic (probably from a genotoxic mechanism) and hepatotoxic; these preparations are dangerous to everyone, but are specifically contraindicated for pregnant and nursing women.5
One review article about the safety of butterbur was published by Weber and Weber, the German company that makes one of the standardized butterbur extracts (Petadolex) often used in clinical trials.16 The authors mention that butterbur products are under strict regulation in Europe and the standardized extracts have the dangerous pyrrolizidine alkaloids removed. They review the favorable results in animal toxicity testing, and the side effects in humans for using the 25 mg capsule dosed 2-3 capsules twice daily, which include nausea, eructations, and mild stomach pain, though these reactions appear to be very rare as determined by post-marketing surveillance.
As with other plants from the daisy family (Family Asteraceae), some caution is prudent for individuals who wish to try a course of butterbur and who are also particularly sensitive to other plants in the daisy plant family, such as ragweed, marigolds, or echinacea.
Butterbur and, more specifically, its phytochemical complex of petasins (petasin, isopetasin, and neopetasin) have been shown to be effective inhibitors of various stages of the inflammatory cascade relevant to allergic rhinitis. Butterbur extracts inhibit cysteinyl-leukotriene synthesis and the compound petasin has been shown to bind to the histamine-H1 receptor. These in vitro studies have translated into clinical effects: Double-blind, placebo-controlled trials have demonstrated a benefit with butterbur in allergic rhinitis both in objective signs (through attenuation of the nasal response to the irritant adenosine monophosphate) and subjective symptoms. The effect of butterbur seems to be comparable to cetirizine, or perhaps even better given a lack of side effects (i.e., sedation) as demonstrated by many of the current research trials. Only standardized extracts that are free of pyrrolizidine alkaloids should be used in the treatment of the above conditions.
At this point, based on a significant amount of in vitro research, as well as several small, but high-quality clinical trials, the use of butterbur warrants consideration as a treatment for allergic rhinitis, especially given its excellent tolerability. It is extremely important to recommend only standardized extracts free of pyrrolizidine alkaloids (the three products used in most of the research trials are listed in the Dosage and Formulation Section).
More research is needed to further clarify the use of butterbur in other clinical conditions such as asthma, following up on promising initial research results.
Dr. Kiefer recently completed a fellowship at the Program in Integrative Medicine, College of Medicine, University of Arizona, Tucson.
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