Summary: The potential of fevefew, as a prophylactic treatment for reducing the incidence and severity of migraine headache attacks, has been established for a daily dose of dried encapsulated feverfew leaf contining an average of 0.54 mg of parthenolide. The conviction has been widespread that parthenolide, the dominant sesquiterpene lactone in clinically tested feverfew, is the constituent of the plant chiefly responsible for its anti-migraine activity. The recent trial of an encapsulated alcoholic extract of feverfew leaf deposited on microcrystalline cellulose found ineffective a daily dose containing 0.5 mg of parthenolide. The most reasonable explanation would indicate an insignificant role for parthenolide in migraine prophylaxis; such activity would seem to reside with some other, as yet unidentified, constituent(s) of whole dried feverfew leaf. This research also points to the need to specify preparation differences, as two previous trials on dried feverfew leaf, presum ably containing the unknown active component, tested positive for migraine relief.

The publication of a recent trial of a feverfew preparation for migraine prevention highlights a major concern regarding medicinal plant formulations. In this study,(1) the Dutch researchers, de Weerdt et al., used capsules of a dried alcoholic extract of British feverfew leaf containing 0.35 percent parthenolide, which was deposited on microcrystalline cellulose.

Of the initial number of 50 patients, 44 completed the study, satisfying the minimum requirement of 40 established by the International Headache Society Committee on Clinical Trials in Migraine? This statistical criterion was also met by the second U.K. trial of feverfew leaf, conducted in 1988,(3) in which 59 subjects completed that study; the earlier British trial conducted in 19854 involved only 17 patients, all of whom were regular feverfew users, thereby attracting the further criticism of self-selection.

In the Summary that precedes the text of the subject publication, the authors propose that the observed lack of a prophylactic effect of their feverfew preparation "...may be explained by the fact that both of the (previous) studies included patients who previously reported positive experiences with feverfew preparations for migraine prophylaxis."

However, in the Discussion segment of the paper, while noting that in the 1988 study, 17 of the 59 patients had used feverfew for a long time and that these had had a more favorable response than the remaining 42 patients who had never before used feverfew, the authors point to another possible explanation of the "nonsignificant effect" in their study. They admit that their alcoholic extract of feverfew leaf, standardized on parthenolide (the hitherto presumed chief active principle), may have lacked or been deficient in other constituents present in whole leaf. These researchers single out as a possible key active constituent of feverfew the essential oil component chrysanthenyl acetate, which is present in much lower concentration in the alcoholic extract than in dried whole leaf (0.017 percent vs. 0.25 percent).

Regarding patient differences, Prof. Start Heptinstall of the Queen's Medical Centre at the University of Nottingham, one of the authors of the 1988 publication, has stated that while the improvement in the 17 patients who had previously used feverfew was somewhat better, nonetheless, the benefit to the 42 de novo patients was unquestionably significant.(5)

As I have stated on numerous occasions, the Canadian regulatory criterion of a minimum of 0.2 percent parthenolide was meant, along with a certificate of botanical authentication, to ensure use of the proper chemotype of feverfew (Tanacetum parthenium (L.) Schultz-Bip., Asteraceae).

In face of the results of this Dutch study, I am not quite as confident about ensuring the proper nature of efficacious feverfew leaf outside of the variety grown in the U.K. used in the Nottingham trial. Unfortunately, despite cautions repeatedly expressed by Heptinstall and myself about relying too much on just parthenolide content and on the theory based on inhibition of serotonin release from blood platelets, 6, 7 most of the herbal constituencies have been propounding the view that parthenolide is the active migraine principle in feverfew and that 0.2 percent of the sesquiterpene lactone in a preparation will ensure effective migraine prevention. The scientifically competent promoters of a standardized botanical extract (SBE) must surely realize that therapeutic effectiveness of SBEs depend fundamentally either on knowledge of the active constituent(s), and dose-effect relationships (preferably from human trials) or on the ability to reproduce a sufficiently comparable chem ical profile of the clinically effective plant preparation -- whether or not any of the active constituents can be identified!

The lack of effectiveness as a migraine prophylactic of the alcoholic feverfew leaf extract employed in the Dutch research here examined may be due to the absence of essential therapeutic components of the leaf which either were not sufficiently extracted, or perhaps degraded during the protracted extraction and processing treatment (12 plus seven days). (Clearly, more careful chemical characterization and testing of feverfew constituents is indicated and clinical trials of various sesquiterpene lactone chemotypes of feverfew, including parthenolide-free varieties, as well as the efficacious, British feverfew freed of parthenolide in a process that does not significantly modify its accompanying constituents.)

An interesting initial trial might compare placebo with dried leaf of a parthenolide-rich cultivar of feverfew, morphologically distinct from the British clinically tested variety and with dried leaf of a parthenolide-free variety, such as that employed in Guatemala for treating "female" problems.

The wisdom of the Canadian regulatory authorities in not according Drug Identification Numbers, based on the migraine therapeutic claim, to anything but whole dried feverfew leaf with pronounced parthenolide content, such as was used in the successful 1988 trial, is now abundantly clear.

REFERENCES

(1.) de Weerdt, C.J., H.P.R Bootsma and H. Hendriks. 1996. Herbal medicines in migraine prevention. Randomized double-blind placebo controlled crossover trial of a feverfew preparation. Phytomedicine, Vol.3(3): 225-230.

(2.) International Headache Society Committee on Clinical Trials in Migraine. 1991. Guidelines for controlled trials of drugs in migraine. First edition. Cephalalgia 11:1-12.

(3.) Murphy, J.J., S. Heptinstall, J.R.A. Mitchell. 1988. Randomized double-blind placebo controlled trial of feverfew in migraine prevention. Lancet 8604:189-192.

(4.) Johnson, E.S., N.P. Kadam, D.M. Hylands, P. J. Hylands. 1985. Efficacy of feverfew as prophylactic treatment of migraine. Br. Med. J. 291:569-573.

(5.) Heptinstall, S. Personal communication.

(6.) Groenevegen, W.A., Knight, D.W., Heptinstall, S. 1987. Compounds extracted from feverfew that have anti-secretory activity contain an a-methylene butyrolactone unit. J. Pharm. Pharmacol 39: 709-712.

(7.) Heptinstall, S., A. White, L. Williamson, J.R.A. Mitchell. 1985. Extracts from feverfew inhibit granule secretion in blood platelets and polymorphonuclear leucocytes. Lancet 8437:1071-1074.

Article copyright American Botanical Council.

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By Dennis V.C. Awang