Feverfew for Migraine Prevention
Feverfew for Migraine Prevention
August 2000; Volume 2; 62-63
By Dennis V.C. Awang, PhD, FCIC
Feverfew (tanacetum parthenium) is a relative of the chrysanthemum, with small, daisy-like flowers. Chewing one or two fresh leaves daily has been popular among migraineurs for the prevention or treatment of migraine, and various preparations of feverfew (FF) are now marketed. The increased popularity of herbal remedies has been paralleled by greater attention to the evidence supporting their efficacy and safety. Systematic reviews have become popular; although these do not pool data as is done in meta-analyses, systematic reviews attempt to minimize publication and review-author bias by using multiple reviewers, considering "all existing information of a predefined quality," and including non-English publications.1
Review of Clinical Trials
Several systematic reviews of herbs have been performed by the Department of Complementary Medicine at University of Exeter, UK. In a systematic review of five FF clinical trials for migraine prevention, Edzard Ernst, MD, PhD, FRCP, concentrates on the methodological merits of the examined trials.2 However, two of the trials (one positive and one negative) do not merit consideration on more serious grounds. First, the 1985 trial by Johnson et al, involved only 17 patients (nine in the FF group and eight in the placebo group) and has been roundly criticized on the basis of its small sample size as well as self-selection: Trial subjects had been using FF leaf for 2-4 years, so were obviously satisfied with its beneficial effect; thus, the trial tested the effect of FF deprivation.3 Second, the 1994 study by Kuritzky et al is reported only as an abstract of a poster presentation, with no information as to the nature of the FF preparation or details about outcome measures.4 The entire results section reads, "100 mg of FF a day was found to be ineffective in the prophylaxis of migraine. No effect was found on platelet serotonin uptake and activity measured by beta TG levels."
Of the remaining three trials, two are positive. Conducted in the UK5 and Israel,6 the two positive trials used encapsulated dried whole FF leaf, containing 0.62% and 0.2% parthenolide, respectively, and assessed severity and incidence of migraine attacks as well as the occurrence of nausea and vomiting. The third trial,7 which scored higher than the two positive trials on the Jadad system for rating methodological quality8 observed no significant difference between the treatment (a 90% ethanol extract) and placebo.
Active Constituents
It is unclear what the active constituent of FF is, and by what mechanism it prevents migraine. Previously, the sesquiterpene lactone parthenolide was thought to be the active compound, and many FF preparations are standardized to 0.2% parthenolide (an arbitrary level equivalent to about half the amount of parthenolide in UK-grown FF). In fact, this level was set as an identity rather than an efficacy criterion. There is no evidence that parthenolide is the active compound; it may well be only a marker compound that contributes nothing to FF’s efficacy. The De Weerdt trial, which used a preparation amply charged with parthenolide (0.35%), found no effect on migraines.7 This trial has convinced many that parthenolide does not contribute significantly to the migraine prophylactic effect of FF leaf. The negative outcome indicates that either the active principle was retained in the marc (residue after extraction)—or was lost during the protracted (19 days) extraction process.9 Support for the latter rationale emerges from the reported effectiveness of a super-critical CO2 extract of FF leaf in a randomized, placebo-controlled German trial.10 This study has not yet been published, so details, including the composition of the FF extract, are not available, but the extract can be expected to contain a substantial amount of parthenolide.
Adverse Effects
Although relatively safe, FF has been associated with minor adverse effects. In a survey of 300 FF users, aph-thous ulcers from chewing fresh leaves were reported by 11.3% of users, while 6.5% reported digestive disturbances.3 About 10% of regular FF users who were switched to placebo in the Johnson study experienced a "post-feverfew syndrome" including rebound of migraine symptoms, anxiety, sleep difficulties, and muscle and joint stiffness. It is possible that sleep disturbances in some of those who stopped FF were caused by withdrawal of melatonin, present in significant quantities in FF (2.45 µg/g in fresh green leaf; 2.19 µg/g in freeze-dried green leaf).11
Summary and Recommendations for Future Research
Clinical trials of FF have varied in methodological quality. Almost all positive trials to date have used dried whole-leaf preparations; the one exception, so far published only in abstract form, used a super-critical CO2 FF leaf extract. More and better clinical trials of FF are clearly needed, as is closer examination of the plant’s constituents regarding their relevance to therapeutic effect.
The absence of effect of a parthenolide-rich preparation in the Dutch study raises the question of whether a non-parthenolide-containing preparation could be effective. Whether or not parthenolide is relevant, it appears that the active constituent in whole FF leaf is extractable, raising the prospect of its isolability—if the latest German study is reliable. However, the absence of any bioassay that can predict effectiveness of any drug in the prophylaxis of migraine makes it mandatory that any new FF preparation be clinically tested in order to establish efficacy. It would be edifying to conduct a trial comparing placebo to several FF preparations: perhaps a fresh 90% ethanol extract, the purportedly efficacious super-critical CO2 extract, and whole FF leaf. After the optimal preparation is identified, future study can focus on identifying the active principle in FF and on determining its stability.
References
1. Ernst E. The clinical efficacy of herbal treatments: An overview of recent systematic reviews. Pharm J 1999;262:85-87.
2. Vogler BK, et al. Feverfew as a preventive treatment for migraine: A systematic review. Cephalalgia 1998;18:704-708.
3. Johnson ES, et al. Efficacy of feverfew as prophylactic treatment of migraine. Br Med J 1985;291:569-573.
4. Kuritzky A, et al. Feverfew in the treatment of migraine: Its effect on serotonin uptake and platelet activity (293P). Neurology 1994;44(Suppl 2):A201.
5. Jadad AR, et al. Assessing the quality of reports, of randomized clinical trials: Is blinding necessary? Controlled Clin Trials 1996;17:1-12.
6. De Weerdt CJ, et al. Herbal medicines in migraine prevention: Randomized double-blind placebo-controlled crossover trial of a feverfew preparation. Phytomedicine 1996;3:225-230.
7. Awang DVC. Feverfew trials: The promise of and the problem with standardized botanical extracts. HerbalGram 1997;41:16-17.
8. Pfaffenrath V, et al. Clinical dose-response study for the investigation of efficacy and tolerability of Tanacetum parthenium in migraine prophylaxis. Der Schmerz 1999;13(Suppl 1):1-13.
9. Murphy JJ, et al. Randomised double-blind placebo-controlled trial of feverfew in migraine prevention. Lancet 1988;ii:189-192.
10. Palevitch D, et al. Feverfew (Tanacetum parthenium) as a prophylactic treatment for migraine: A double-blind placebo-controlled study. Phytother Res 1997;11:508-511.
11. Murch SJ, et al. Melatonin in feverfew and other medicinal plants. Lancet 1997;350:1598-1599.
August 2000; Volume 2; 62-63
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