Feverfew for the Prevention of Migraine Headache

By Felise Milan, MD

Migraine headache is a very common, chronic, recurrent, and, in some patients, incapacitating disorder. In studies that use the International Headache Society diagnostic criteria, the one-year prevalence of migraine is 15%-18% among women and 6%-9% among men in the United States and Western Europe.1-3 A more recent population survey found a peak prevalence of 27% in women between the ages of 30-49.4 Migraine occurs in up to 10% of children ages 5-15 and equally among boys and girls until menarche.5 In adulthood (ages 25-64), a female-to-male ratio among migraine sufferers of 3:1 is consistent among epidemiological studies.1 Migraine prevalence decreases after the age of 65, but women continue to be more commonly affected (7.5% of women and 2.5% of men).4 Almost exclusively, those who suffer from migraine without aura account for the gender difference in migraine prevalence. Migraine with aura occurs equally among men and women.1

Migraine Headache in Women

The relationship between migraine and estrogen is well-accepted but has never been explained definitively. Several clinical findings have indicated an influence of female sex hormones on migraine.6 In young women, onset of migraine is frequently at menarche.1 Migraines are reported to occur almost twice as often during the two days before menstruation begins ("menstrual migraine").7 There is 50%-80% improvement of migraine during pregnancy, and altered prevalence in women on oral contraceptives.6 In addition, the relationship between female hormones and migraine without aura clearly was stronger than in migraine with aura.1 The physiological mechanism by which estrogen or other female hormones affect migraine is not well understood. Some have suggested that platelet aggregation, fluid and salt retention, or alteration in serotonin and prostaglandin levels could be responsible.8 Several studies have shown the effectiveness of triptans for prophylaxis of difficult-to-treat menstrual migraine.9,10

Preventive Treatment of Migraine

Approach to migraine patients should include a comprehensive treatment plan including education, identification, and avoidance of triggers and good sleep hygiene, exercise, and utilization of non-pharmacological treatments (i.e., biofeedback, relaxation techniques). Published guidelines recommend that prophylactic pharmacological therapy may be warranted in several circumstances.11 (See Table 1.)

One herb that has been investigated as a prophylactic therapy for migraine headaches is feverfew. Feverfew (Tanacetum parthenium) is a perennial in the daisy family. Traditionally, feverfew leaves are used for fever, menstrual irregularities, arthritis, and, most commonly, for prevention of migraine headache. The traditional method of administration is to chew on the leaves.

Mechanism of Action

Feverfew extract has been shown to have biological activity including inhibitory effects on platelet aggregation and on the release of serotonin from platelets and leukocytes.12 It may interfere with prostaglandin biosynthesis by inhibiting phospholipase A.13

Although several active constituents have been identified in feverfew, there is controversy surrounding which of the constituents present in the leaves are responsible for its medicinal effect. Previously, it had been assumed that parthenolide (a sesquiterpene lactone) represented the active component responsible for its effect on migraine headache.

Chrysanthenyl acetate, an essential oil and component in feverfew leaf, is another active ingredient that inhibits prostaglandin synthesis and has analgesic properties.13 In addition, melatonin has been found in large quantities in feverfew leaves.14 There is evidence that melatonin may play a role in women who suffer from menstrual migraine.15

Clinical Studies

Several randomized controlled trials and two systematic reviews have evaluated the efficacy of feverfew as a prophylactic treatment for migraine headaches. The first review described five double-blind, randomized controlled trials on feverfew monopreparations.16 The reviewers concluded that, "The majority of studies favor feverfew over placebo. Yet important caveats exist. The clinical effectiveness of feverfew in the prevention of migraine has not been established beyond a reasonable doubt."

One of the six studies included in the second review evaluated the in vivo effect of feverfew on serotonin uptake and platelet activity in 20 migraine sufferers.17 It did not measure effect on migraine prevention. Four studies18-21 also are reviewed in the latest systematic review by the Cochrane Collaboration22 in addition to a newer study by Pfaffenrath.23

A double-blind, randomized controlled pilot study identified 17 patients with eight or fewer migraines per month who had been using raw feverfew leaves for at least two years.19 These patients were randomized to receive either placebo or two 25 mg capsules per day of powdered freeze-dried feverfew leaves for 24 weeks. All patients recorded the frequency of migraine and nausea and vomiting. The placebo group recorded a significant increase (P < 0.02) in the number of migraines while the feverfew group remained constant. The number of attacks associated with nausea and vomiting was significantly fewer in the feverfew group (42% vs. 79%) (P < 0.05). The bouts of nausea and vomiting also were reduced significantly in the feverfew group (39 vs. 116) (P < 0.05).

Murphy also studied the effect of dried feverfew leaves.20 After a one-month placebo run-in period, 72 patients with common or classic migraine were randomized to receive either 82 mg/d of dried feverfew leaves in a capsule or placebo for four months. Patients then were crossed over to the other group for another four months. There was no washout period. Patients recorded migraine symptoms in a diary. There was a significant decrease in migraine frequency (P < 0.05) in the group receiving feverfew. The number of migraines accompanied by nausea and vomiting was greater in the placebo group (P < 0.02). Patients used a visual analogue scale to report a global assessment of efficacy and indicated a significant difference in favor of feverfew (P < 0.0001). The benefit of feverfew over placebo for migraine frequency, as well as global assessment of efficacy, was greater in patients with classical migraine than common migraine.

In another crossover RCT evaluating dried feverfew, 57 patients with migraine received 100 mg/d of feverfew for two months during the open phase of the trial.21 One group continued taking feverfew while the other was given placebo (double-blind) for 30 days; the groups then were crossed over to the other arm for another 30 days. At the end of the open phase of the trial, there was a significant decrease in migraine severity (reported by patients on a scale of 1 to 10) as compared to baseline (P < 0.001). The group randomized to feverfew continued to report a reduction in migraine severity and nausea and vomiting, with the placebo group reporting an increase in severity (P < 0.01). The results were the same for the second phase of the crossover.

Two other studies have used a different kind of feverfew preparation. de Weerdt randomized 50 patients with migraine to receive either placebo or a capsule with 143 mg of an alcoholic feverfew extract standardized to parthenolide content in a crossover design.18 Prior to the two 2-month crossover treatment periods was a one-month placebo run-in period. This study found no difference between groups in the number or severity of migraines or the number of work days lost.

Most recently, Pfaffenrath evaluated a CO2 feverfew extract in a multicenter, double-blind, randomized controlled trial.23 After a four-week baseline period, 147 patients with migraine were randomly assigned to one of three doses (2.08 mg/d, 6.25 mg/d, 18.75 mg/d) of the extract or placebo for 12 weeks. Analysis of primary (frequency of migraine) and secondary (missed days of work, maximum intensity of migraines, and migraines with confinement to bed) outcomes were performed using an intention-to-treat analysis on the whole group as well as on a preselected subset of patients (n = 49) experiencing four or more migraines in the baseline four weeks. After a 24% dropout rate, there was no treatment benefit seen for any of the three doses in the overall sample. However, in the preselected subset, the group receiving 6.25 mg/d feverfew extract had a statistically significant average decrease of 1.8 ± 1.5 attacks during the course of the study. In addition, the secondary efficacy parameters improved in a significant dose-response relationship in this subset.

Dosage and Formulation

Many feverfew medicinal preparations are standardized to 0.2%-0.7% parthenolide. However, a study using an alcoholic extract of feverfew standardized to 0.35% parthenolide found it ineffective for preventing mi- graine.18 As the above studies illustrate, the most effective preparations use encapsulated dried feverfew leaves. However, there is some controversy over how the leaves should be dried. Some authors and manufacturers insist on the superiority of freeze-dried leaves and claim that using high temperatures to dry the leaves denatures some of the active ingredients. There also is concern that the parthenolide content of the preparations may decrease over time. This loss may accelerate when the herb is stored in heat or light.24

Safety

There are no consistently reported adverse effects after using feverfew for up to four months. There are some reports of mouth ulcerations when the raw feverfew leaves are chewed.25 A post-feverfew syndrome, which includes migraine symptoms, anxiety, insomnia, and muscle and joint stiffness, was reported in one study by the patients who had been using feverfew for a number of years and then stopped.19 Unlike some of the pharmaceuticals used for migraine prophylaxis, feverfew does not affect blood pressure, heart rate, body weight, or blood chemistry. Anyone who is allergic to the Asteraceae/Compositae family (ragweed, chrysanthemums, marigolds, or daisy) could have an allergic reaction to feverfew. Feverfew inhibits platelet-activating factor so patients should be instructed to stop taking feverfew prior to surgical or invasive procedures.12

Conclusion

In summary (see Table 2), the three studies that have evaluated powdered or dried whole feverfew leaves have shown significant benefits, including reduced frequency and severity of headaches, for patients with migraines.19-21 The two studies that have used feverfew extracts largely have been unable to show such an effect.18,23 Of note, the latest Cochrane review on feverfew includes these same five studies18-21,23 and reaches a very different conclusion: "There is insufficient evidence from randomized, double-blind trials to suggest an effect of feverfew over and above placebo for preventing migraine."22 Curiously, the two reviews on feverfew were done by the same authors and included the same studies except for the most recent one by Pfaffenrath.23

Recommendation

Many patients suffer from chronic and recurrent migraines. Many are ambivalent about taking a daily medication to prevent these headaches and others cannot tolerate the side effects of the pharmaceutical agents used for prophylaxis. Feverfew should be strongly considered as an effective alternative prophylactic therapy for migraine headaches. Preparations of dried whole feverfew leaves should be used. Although there are many active ingredients in feverfew extracts, it is not clear which if any are responsible for feverfew’s effect on migraine headache. There are no data showing the extracts of feverfew are effective in preventing migraines.

References

1. Rasmussen BK. Epidemiology of headache. Cephalalgia 1995;15:45-68.

2. Goadsby PJ, et al. Migraine—Current understanding and treatment. N Engl J Med 2002:346:257-270.

3. Stewart WF, et al. Prevalence of migraine headache in the United States: Relation to age, income, race and other sociodemographic factors. JAMA 1992;267:64-69.

4. Lipton RB, et al. Prevalence and burden of migraine in the United States: Data from the American Migraine Study II. Headache 2001;41:646-657.

5. Abu-Arefeh I, Russell G. Prevalence of headache and migraine in schoolchildren. Br Med J 1994;309:765-769.

6. Gladstone JP, et al. Migraine in special populations. Postgrad Med 2004;115:39-50.

7. MacGregor EA, Hackshaw A. Prevalence of migraine on each day of the natural menstrual cycle. Neurology 2004;63: 351-353.

8. Welch KMA, et al. The role of estrogen in migraine: A review and hypothesis. Cephalalgia 1984;4:227-236.

9. Loder E. Prophylaxis of menstrual migraine with triptans. Neurology 2002;59:1677-1681.

10. Silberstein S, et al. A randomized trial of frovatriptan for the intermittent prevention of menstrual migraine. Neurology 2004;63:261-269.

11. Silberstein SD, et al. for the U.S. Headache Consortium. Practice parameter: Evidence-based guidelines for migraine headache. Neurology 2000;55:754-762.

12. Heptinstall S, et al. Extracts of feverfew inhibit granule secretion in blood platelets and polymorphonuclear leucocytes. Lancet 1985;1:1071-1074.

13. Pugh WJ, Sambo K. Prostaglandin synthetase inhibitors in feverfew. J Pharmacy Pharmacol 1988;40:743-745.

14. Murch SJ, et al. Melatonin in feverfew and other medicinal plants. Lancet 1997;350:1598-1599.

15. Brun J, et al. Nocturnal melatonin excretion is decreased in patients with migraine without aura associated with menses. Cephalalgia 1995;15:136-139.

16. Vogler BK, et al. Feverfew as a preventive treatment for migraine: A systematic review. Cephalalgia 1998;18:704-708.

17. Kuritzky A, et al. Feverfew in the treatment of migraine: Its effect on serotonin uptake and platelet activity. Neurology 1994;44(Suppl 2):A201.

18. 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.

19. Johnson ES, et al. Efficacy of feverfew as prophylactic treatment of migraine. BMJ 1985;291:569-573.

20. Murphy JJ, et al. Randomized double-blind placebo- controlled trial of feverfew in migraine prevention. Lancet 1988;2:189-192.

21. 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.

22. Pittler MH, Ernst E. Feverfew for preventing migraine. The Cochrane Database of Systematic Reviews. 2004:2.

23. Pfaffenrath V, et al. The efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis—A double-blind, multicentre, randomized placebo-controlled dose-response study. Cephalalgia 2002;22:523-532.

24. Awang DVC. Feverfew fever: A headache for the consumer. HerbalGram 1993;29:34.

25. Jellin J. Natural Medicines Comprehensive Database. 4th Ed. Stockton, CA: Therapeutic Research Faculty; 2002:528.