Summary: One hundred thirty male and female patients (aged 18 years or older) with a history of seasonal allergic rhinitis (at least two consecutive years) were screened for a randomized, double blind trial comparing the efficacy of a butterbur extract and cetirizine (a non-sedating antihistamine). One hundred twenty-five patients were randomized to take either one butterbur (Petasites hybridus (L.) P. Gaertn. et al., Asteraceae) herb extract tablet (standardized to 8.0 mg of total petasin per tablet, ZE 339, Zeller AG, Switzerland)* four times per day or one 10 mg tablet of cetirizine in the evening. Blinding was achieved by having each patient take five tablets -- four containing either placebo or butterbur, and one containing either cetirizine or placebo -- depending on the treatment group. The main outcome measure was change of score from baseline of each item on the medical outcome health questionnaire (SF-36). The SF-36 questionnaire is a self-assessment tool with questions grouped hierarchically in eight categories with a total range of 0-100 per item. The questionnaire also includes one category with a five-point score for comparing current severity of the condition with that of the previous year. The secondary outcome measure was the physician's clinical global impression scale (CGI). The hypothesis was that butterbur was roughly equivalent to cetirizine at the end point, defined as within 10 percent of the SF-36 score or by one point in the CGI.

Improvements in both the SF-36 and CGI scores were similar in both groups. Analysis of the main outcome measures rejected the hypothesis of butterbur's being inferior to cetirizine, with none of the scores in the butterbur group more than 10 percent worse than in the cetirizine group. The overall incidence of adverse events was similar for the two treatment groups. However, two-thirds of the adverse events for the cetirizine group were drowsiness and fatigue -- symptoms not reported in the butterbur group.

Comments/Opinions: Allergic rhinitis (sometimes called hay fever) can be either seasonal or perennial and is characterized by sneezing, runny nose, nasal congestion, throat itching and irritation, and watery eyes. The allergic response is typically caused by the deposition of an allergen (e.g., pollen) on the nasal membranes. Typical treatment is the symptomatic use of over-the-counter antihistamines (e.g., clorpheniramine, diphenhydramine) or the new generation of prescription antihistamines such as loratadine (Claritin^¨, Schering Corporation, Kenilworth, NJ) or desloratadine (Clarinex^¨, Schering Corporation). While usually safe, antihistamines may cause drowsiness (please note that the last two products mentioned above are not associated with drowsiness) and may also interact with alcohol and can sometimes lead to complaints of dryness in the nasal passages and throat. The availability of an over-the-counter nasal spray containing cromolyn sodium (NASALCROMï, Pharmacia, Peapack, NJ) has offered allergic rhinitis sufferers a non-sedating alternative that helps stabilize mast cells (the cells that release histamine in the mucous membranes of the nose and sinuses) and can act as a preventive agent. Nasal steroids are another treatment option for allergic rhinitis sufferers.

Research-supported herbal alternatives for the management of allergic rhinitis are scarce. Small clinical trials have suggested that freeze-dried stinging nettle (Urtica dioica L. ssp. dioica, Urticaceae)¹ and the Japanese Kampo medicine sho-seiryu-to -- a combination of licorice root (Glycyrrhiza glabra L., Fabaceae), cassia bark (Cinnamomum aromaticum Nees, Lauraceae), schisandra (Schisandra sphenanthera Rehder & E.H. Wilson, Schisandraceae), ephedra or ma huang (Ephedra sinica Stapf, Ephedraceae), ginger root (Zingiber officinale Roscoe, Zingiberaceae), pinellia (Pinellia ternata (Thunb.) Makino ex Breit., Araceae), and asiasarum root² (Asiasarum is an outdated name for certain Asian species of Asarum. The two species used interchangeably (as Xi Xin) in Traditional Chinese Medicine for colds are Asarum heterotropoides F. Schmidt var. mandshuricum (Maxim.) Kitag. and Asarum sieboldii Miq., Aristolochiaceae.) may hold promise for the treatment of allergic rhinitis. However, there have been no follow-up studies on these products.

Petasites hybridus is an herbaceous plant of the family Asteraceae native to Europe, northern Africa, and southwestern Asia.³ Although the name butterbur is used as the common name in this study, its standardized common name is purple butterbur and it is also commonly called sweet coltsfoot.⁴ A related plant, P. frigidus (L.) Fries, is known commonly as Arctic butterbur and less commonly as Arctic sweet coltsfoot or western coltsfoot -- and should not be confused with coltsfoot (Tussilago farfara L., Asteraceae).

The leaves, rhizome, and roots of butterbur contain a mixture of eremophilan-type sesquiterpenes consisting primarily of petasin and isopetasin.³ Renowned German phytotherapy experts Rudolf Fritz Weiss, M.D., and Volker Fintelmann, M.D., suggested that petasin has both spasmolytic and analgesic actions.⁵ They wrote that this explains the historical use of the plant for whooping cough and bronchial asthma. Interestingly, the German Commission E has separate monographs for butterbur leaf and rhizome. The leaf is given a negative rating due to the assessment that other herbal drugs were more effective in relieving cough, such as thyme (Thymus vulgaris L., Lamiaceae) or sundew (Drosera rotundifolia L., Droseraceae).⁶ Butterbur rhizome, on the other hand, receives a positive rating for the adjunctive treatment of acute spasmodic pain in the urinary tract.⁷ I was unable to find any historical references to the herb's use for allergic rhinitis.

The dark cloud hanging over butterbur leaf and rhizome is the presence of toxic pyrrolizidine alkaloids (PAs).⁸ These potentially hepatotoxic and carcinogenic constituents have led to the demise of coltsfoot and comfrey root (Symphytum officinale L., Boraginaceae) in herbal medicine as well. Drs. Weiss and Fintelmann suggest that this has been the primary explanation for the waning interest in the therapeutic use of butterbur.

The ZE 339 extract used in this trial is from the aerial parts of the herb and not the rhizome of the plant. Perhaps most important, the manufacturers remove PAs during the manufacturing process.⁹ While the butterbur product used in this trial is currently unavailable in the U.S., a product made from the rhizome and delivering 7.5 mg of total petasin per capsule is commercially available (Petadolexï, Weber and Weber, USA). Also a CO₂ extract, the Petadolex product is also free of PAs. While this product has been studied for treating migraine,^10,11 it has not been studied for treatment of allergic rhinitis.

Practice Implications: Although this trial lacks a placebo group for comparison, it suggests that butterbur extract may be as effective as the antihistamine cetirizine for the management of symptoms associated with seasonal allergic rhinitis. One advantage of the butterbur extract appears to be the absence of sedating side effects associated with many antihistamines. Placebo-controlled trials are needed as well as more safety information on the long-term use of butterbur extract.** Again, healthcare professionals should use caution to ensure that any butterbur extract recommended is free of PAs.

References

1.         Mittman P. Randomized double-blind study of freeze-dried Urtica dioica in the treatment of allergic rhinitis. Planta Med 1990;56:44-7.

2.         Baba S, Takasaka T. Double-blind clinical trial of sho-seiryu-to (TJ19) for perennial nasal allergy. Clin Otolaryngol 1995;88:389-405.

3.         Wichtl M. Bisset NG, translator. Herbal Drugs and Phytopharmaceuticals. Boca Raton (FL): CRC Press; 1994. p. 366-8.

4.         McGuffin M, Kartesz JT, Leung AY, Tucker AO, editors. Herbs of Commerce, 2nd edition. Silver Spring (MD): American Herbal Products Association; 2000. p. 109.

5.         Weiss RF, Fintelmann V. Herbal Medicine, 2nd edition. Stuttgart, Germany: Thieme; 2000. p. 200-2.

6.         Blumenthal M, Busse WR, Goldberg A, et al, editors. The Complete Commission E Monographs: Therapeutic Guide to Herbal Medicines. Integrative Medicine Communications: Boston (MA); 1998. p. 365.

7.         Blumenthal M, Busse WR, Goldberg A, et al, editors. The Complete Commission E Monographs: Therapeutic Guide to Herbal Medicines. Integrative Medicine Communications: Boston (MA); 1998. p. 183.

8.         Gruenwald J, Brendler T, Jaenicke C, editors. PDR for Herbal Medicines. Montvale (NJ): Medical Economics; 2000. p. 585-8.

9.         Boonen G (Zeller AG). Personal correspondence to Blumenthal M. 2002 April 24.

10.       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].

11.       Grossmann M, Schmidramsl H. An extract of Petasites hybridus is effective in the prophylaxis of migraine. Inter J Clin Pharmacol Ther 2000;38:430-5.

12.       Shuster S. Treating seasonal allergic rhinitis: Well designed experiments should have been used (letter). BMJ 2002;324:1277.

13.       Treating seasonal allergic rhinitis: Trial does not show that there is no difference between butterbur and cetirizine (letter). BMJ 2002;324:1277.

14.       Schapowal A. Treating seasonal allergic rhinitis: Author's reply (letter). BMJ 2002;324:1277.

 

*Note: The total milligram amount of extract per tablet is not listed in the publication.

** Note: Following the completion of this review, there have been many letters to the editor of BMJ criticizing the design of this trial.^12,13 In one response, one of the authors of the trial refers to the completion of a double-blind, placebo-controlled trial of the butterbur extract for allergic rhinitis which has been submitted for publication.¹⁴