The Elusive Source of Feverfew's Anti-migraine Activity

Introduction

The development, as well as the relief, of the symptoms of migraine headache is an extremely complex process that has eluded understanding for over a century despite more than 60 years of intensive research. Attention has been mainly focused on three theoretical causes: chemical (prominently concerned with serotonin), vascular, and neural. Blau has pointedly observed, "Migraine, like gravity, becomes evident only by its effects,"( n1) and research has therefore depended largely upon observations made about or by migraineurs. No satisfactory animal model of migraine is currently available, for as Blau further noted: "Animals may get headaches, but they cannot tell us about it."( n1)

Feverfew (Tanacetum parthenium, Asteraceae) has been used since antiquity for a variety of medicinal purposes but prominently to alleviate fever, headache, and women's genito-urinary ailments.( n2) Claims of efficacy for these traditional uses are almost invariably anecdotal. However, over the past 2 decades, randomized controlled trials have been conducted in the prophylaxis of migraine. While the quality of these trials vary, there is good evidence of feverfew's potential in migraine: statistically significant reduction in frequency and severity of attacks as well as decrease of nausea and vomiting has been observed following the administration of feverfew leaf. Neither the constituent(s) of feverfew responsible for the migraine-preventing activity nor the mechanism(s) of action are yet known. Parthenolide, the dominant sesquiterpene lactone (STL) constituent of the clinically tested sesquiterpene chemotype and long considered the active antimigraine principle, is no longer considered by many to be a significant contributor in that respect. Also, the latest trial, using a supercritical carbon dioxide extract of feverfew leaf, lends promise to the development of a reliably consistent and effective standardized preparation. No serious adverse reactions have been recorded, although the development of mouth ulcers has caused a small percentage of consumers to discontinue treatment. No interactions with conventional medications have been observed so far.
Parthenolide

The decades-long flush of adherents to the theory of inhibition of the release of serotonin ( 5-hydroxytryptamine) from blood platelets by parthenolide--as the basis for feverfew's antimigraine activity( n3)--has apparently only slightly paled as a belief, despite the shock of a 1996 Dutch study,( n4) in which an extract of feverfew leaf, with ample (more than 4%) charged parthenolide content, was found ineffective in mitigating the symptoms of migraine. I find it frankly baffling that, despite the lack of any evidence of a contribution by parthenolide to feverfew's anti-migraine activity, a number of scientists still believe that the cytotoxic allergenic STL could somehow contribute to the plant's prophylactic potential. Also, generally, manufacturers, unfazed by or unaware of the negative Dutch trial, continue to strive for ever-increasing parthenolide content in their feverfew leaf products.

Subsequently, studies conducted by researchers of the reputable German company Schaper & Bruemmer Gmbh Co. KG of Salzgitter, Germany, demonstrated the effectiveness in migraine prophylaxis of a supercritical carbon dioxide extract of feverfew leaf, but only in a small subset of patients with a minimum of 4 migraine headache attacks per month.( n5, n6) From 45 samples of feverfew leaf, these researchers selected the 6 highest in parthenolide content and touted their proprietary extract for its stable parthenolide content, exceeding 1%. The 0.2% content criterion established in 1992 by the Canadian regulatory authority was an identity criterion, seeking to ensure approval of the same STL chemotype that had been used in the two positive British trials upon which recognition of the therapeutic claim was based.( n7, n8) This criterion was established upon a recommendation by this author and Heptinstall( n2) based on a measured average of 0.42% parthenolide content found in feverfew leaf material used in the two British clinical trials.( n7, n8*)

These two trials were of very different qualities: the earlier( n6) was widely criticized because of its small subject population (n=17) as well as the basis of self-selection, and did not persuade the UK health authorities to recognize a therapeutic claim, while in the United States feverfew is regarded as simply a "dietary supplement" for which no therapeutic claims can be made. The German Commission E did not provide a product monograph (since fever-few was not widely used in German pharmacies during the time that the Commission was reviewing herbs for its widely-touted monographs), but the European Scientific Cooperative for Phytotherapy (ESCOP) produced, in 2003, a therapeutic monograph for dried aerial parts, with a limit for parthenolide (0.1%) acknowledging value of feverfew in the prophylaxis of migraine.( n9)

On the feverfew front, the first few years of the 21st century have witnessed a curious and interesting development, namely, the registration of patents for the preparation and application of "substantially parthenolide-free feverfew extracts" for both oral and topical treatment of migraine, arthritis, bronchial complaints, inflammatory disorders, and related conditions. This last application is particularly interesting in view of the loudly trumpeted anti-inflammatory potential of parthenolide: the authors of US Patent 7,229,650,B2, June 12, 2007, from the Netherlands, France, and the US, claim that their innovation provides "a method for treating and preventing inflammatory disorders and related conditions by applying a topical composition containing an effective amount of an extract of feverfew to a patient where said extract is substantially free of ?-unsaturated y-lactone." The other patent (US 7,192,614,B2, March 20, 2007) proclaimed: "Methods of treating migrainous headaches and their associated symptoms are provided by administering a composition comprising parthenolide or feverfew sublingually to a patient in need thereof. Treatments are surprisingly effective with low total administered amounts of parthenolide or feverfew." (It should be noted that a use for an herb can be patented even without ample proof of the herb's and/or an herbal preparation's actual activity for the patented claim.) An earlier patent (US 6,224,875,B1) acquired in 2001 by Bombardelli and Morazzoni of the botanical extractor Indena S.P.A., Milan, Italy, claimed to generate "Extracts of Tanacetum parthenium with a reduced content of ?-unsaturated y-lactones, particularly of parthenolide, obtainable by elution on basic resins… The extracts of the invention have favourable pharmacological properties together with reduced risks of allergic reactions." However, while STLs have long been associated with allergic reactions and cross-reactivity with other plants of the Asteraceae / Compositae family, such as ragweed (Ambrosia spp.), chamomile (Matricaria recutita), echinacea (Echinacea spp.), and yarrow (Achillea millefolium), no allergic reactions from oral ingestion have been documented.
The Active Principle(s)

It appears eminently reasonable to infer from the Dutch and German clinical trials that protracted (19 days) 90% ethanol extraction used for the product employed in the former, resulted in loss / degradation of the actual anti-migraine principle(s). Prominent candidates considered for the active principle mantle include the volatile trans-chrysanthenyl acetate and the isomeric cis/trans-spiroketal enolether diynes. Clearly, talented organic chemists, allied with competent pharmacologists, are needed to advance the current understanding of the agent(s) and mechanism(s) involved in feverfew migraine prophylaxis.

Of possible interest is that UK's Medicines and Healthcare products Regulatory Agency (MHRA) granted a Traditional Herbal Registration Certificate for the traditional herbal remedy "Migra-Herb hard capsules" to MH Pharma Ltd on April 3, 2007. This product has been granted a general sales license (GSL), presumably with no therapeutic claim allowed. This application was submitted as a complex process according to Article 16.c of Directive 2001/83 EC, as amended, as part of the Traditional Herbal Medicines Registration Scheme. The data supplied by the applicant demonstrated 30 or more years of traditional use of feverfew in the European Community. A satisfactory review of the available safety data on feverfew has also been provided, together with an Expert Safety Report supporting the proposed product. Of interest is that the approved product is a capsule containing 100mg of dried feverfew leaf with no reference to parthenolide content--and is not an extract.

PHOTO (COLOR): Feverfew Tanacetum parthenium ©2008 Steven Foster
References

(n1.) Blau JN. Migraine: theories of pathogenesis. Lancet 339, May 16, 1992:1202-1206.

(n2.) Blumenthal M, Hall T, Goldberg A, Kunz T, Dinda K, Brinckmann J, et al, eds. The ABC Clinical Guide to Herbs. Austin, TX: American Botanical Council; 2003.

(n3.) Heptinstall S, Awang DVC. Feverfew: A review of its history, its biological and medicinal properties, and the status of commercial preparations of the herb. In: Lawson LD, Bauer R (eds). Phytomedicines of Europe: Chemistry, and Biological Activity. Washington, DC: American Chemical Society; 1998:158-175.

(n4.) de Weerdt CJ, Bootsma HPR, Hendriks H. Herbal medicines in migraine prevention. Phytomed. 1996;3:225-230.

(n5.) Pfaffenrath V, Diener HC, Fischer M, Friede M, Heinnecke-von Zepelin HH. The efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis--a double-blind, multicentred, randomized, placebo-controlled, dose-response study. Cephalalgia.2002; 22:523-532.

(n6.) Diener HC, Pfaffenrath V, Schnitker J, Friede M, Heimecke von, Zepelin H-H. Efficacy and safety of a 6.25 mg tid feverfew-CO2-extract (MIG-99) in migraine prevention--A randomized double-blind, multicentre, placebo-controlled study. Cephalalgia. 2005;25(11):1031-1041.

(n7.) Johnson ES, Kadam NP, Hylands DM, Hylands PJ. Efficacy of feverfew as prophylactic treatment of migraine. BMJ. 1985;291:2569-2573.

(n8.) Murphy JJ, Heptinstall S, Mitchell JRA. Randomised double-blind placebo-controlled trial of feverfew in migraine prevention. Lancet. July 23,1988:189-192.

(n9.) European Scientific Cooperation on Phytomedicine. ESCOP Monographs: The Scientific Foundation for Herbal Medicinal Products, 2nd edition. New York, NY: Thieme Medical Publishers; 2003.

* As far as the 0.42% v. 0.2% calculation, the former was the average level of the parthenolide found in feverfew leaf grown in the Chelsea Physic Garden which provided the material used in the two successful UK clinical trials. After consultation with Prof. Stan Heptinstall of the University of Nottingham who was involved with the vastly superior 1988 study, we thought it reasonable to propose a level of 0.2% parthenolide simply to ensure that the sesquiterpene lactone chemotype approved was the same as that used in the two positive trials. (Recall that the positive Israeli trials used whole leaf containing 0.2% parthenolide while the extract that did not produce any clinically positive results in the trial conducted at a Dutch university contained more than 0.4%. Note also that no one has yet demonstrated any role whatsoever for parthenolide in feverfew for anti-migraine activity. I believe that the deWeerdt study, though singular, is definitive--and rather than the onus being on the anti-parthenolide group to demonstate the lack of parthenolide participation one more time, it ought to be up to the pro-parthenolide group to demonstrate its relevance.

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By Dennis V. C. Awang, PhD

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