Feverfew

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Tanacetum parthenium (L.) Sch. Bip.

[Fam. Asteraceae]

Overview

Traditionally, feverfew was used for a wide range of disorders including psoriasis, toothache, insect bites, rheumatism, vertigo, colic, cleansing the kidneys and bladder, stomach pain, menstrual problems, inflammation, and fever (Hobbs, 1989; Groenewegen et al., 1992). The ancient Greeks called feverfew “parthenium” because, according to legend, it was used to save the life of someone who had fallen from the Parthenon, the Doric temple of the virgin goddess Athena on the Acropolis in Athens (Hobbs, 1989). However, its name may be more likely based on feverfew’s traditional use for alleviating menstrual cramps in young girls (parthenos = virgin in Greek). Currently, feverfew is used primarily for migraine prophylactic effects, and for concomitant nausea and vomiting (Brown, 1995; ESCOP, 1996; Johnson et al., 1985; Murphy et al., 1988). Feverfew is ranked 19th among herbal supplements sold in mainstream retail outlets in the U.S. (Blumenthal, 2001).

Description

Feverfew preparations consist of the aerial parts or leaves of Tanacetum parthenium (L.) Sch. Bip. (syn. Chrysanthemum parthenium (L.) Bernh.) [Fam. Asteraceae], collected when the plant is in flower (Bradley, 1992; Reynolds, 1993; Newall et al., 1996). The fresh leaves can also be chewed to obtain the purported therapeutic benefits (Newall et al., 1996). Many commercial feverfew preparations are standardized based on parthenolide content (0.1% [French regulatory authorities] to 0.2% [Canadian authorities] are suggested as minimum contents for quality control purposes) (Bruneton, 1999; Evans, 1998). However, different commercial preparations can vary widely in parthenolide content depending upon the geographical location from which the seeds were derived, the vegetative cycle of the plant at the time of harvest, the parts of the plant used, and the duration and conditions of storage (Bruneton, 1999; Evans, 1998; Heptinstall, 1992). No parthenolide was detected in feverfew grown in Mexico or Yugoslavia, and the feverfew in both countries contained eudesmolides and guaianolides as the primary constituents (Heptinstall et al., 1992). Recent evidence indicates that the pharmacological activity of feverfew in the treatment and prophylaxis of migraines is not attributed to parthenolide content as was previously thought, but to other unidentified constituents (Awang, 1998a; de Weerdt et al., 1996). In addition, parthenolide is not a unique constituent of feverfew (Heptinstall et al., 1992); parthenolide is detected in 34 plant species (25 from Asteraceae, nine from Magnoliaceae) (Heptinstall et al., 1992; Heptinstall and Awang, 1998). Therefore, parthenolide is used to ensure that the correct chemotype of T. parthenium is used, but it is not an assurance of the botanical identity or efficacy of feverfew products (Awang, 1998b). Since the active constituents are unknown, it is recommended that preparations containing the whole leaf (dried or fresh) should be used (Awang, 1998b; Heptinstall and Awang, 1998). Since parthenolide stability can vary with storage conditions, feverfew should be stored in a cool, dry, dark environment (Heptinstall et al., 1992; Heptinstall and Awang, 1998).

Primary Uses

Migraine prophylaxis (de Weerdt et al., 1996; Palevitch et al., 1997; Anderson et al., 1988; Murphy et al., 1988; Johnson et al., 1985)

Nausea and vomiting associated with migraine (Palevitch et al., 1997; Murphy et al., 1988; Johnson et al., 1985)

Dosage

Optimal doses of feverfew for therapeutic benefits have not been established; however, an adult dose equivalent to 0.2–0.6 mg of parthenolide is recommended for migraine prophylaxis (ESCOP, 1996; Johnson et al., 1985; Murphy et al., 1988).

Internal

Crude Preparations

Dried leaf: 50–150 mg daily (Palevitch et al., 1997; Murphy et al., 1988; Johnson et al., 1985).

Fresh leaf: 2.5 leaves daily, with or after food (Newall et al., 1996).

Tincture: 1:5, 25% ethanol, 5–20 drops daily (Bradley, 1992).

Duration of Administration

Internal

Crude Preparations

Prophylaxis benefit for migraine can usually be seen within four to six weeks of the initiation of treatment (Brown, 1995; Palevitch et al., 1997). However, the duration of treatment will vary for individual migraine sufferers (Brown, 1995). Successful clinical studies involving feverfew for migraine prophylaxis have been conducted for durations of up to 46 months; longer-term safety data are not presently available (Johnson et al., 1985; Murphy et al., 1988; Palevitch et al., 1997). It is recommended that patients continuing long-term use should discontinue therapy for at least one month per year to evaluate efficacy and determine whether continuation is necessary (ESCOP, 1996; Baldwin et al., 1987). The feverfew dose should be tapered gradually over the preceding month to prevent potential withdrawal symptoms (ESCOP, 1996; Baldwin et al., 1987).

Chemistry

The constituents of feverfew can vary depending upon the chemotype and the geographical location from which the seeds were derived (Heptinstall et al., 1992). Constituents include sesquiterpene lactones including germacranolides—parthenolide (Bohlmann and Zdero, 1982; ESCOP, 1996; Hausen, 1992), eudesmolides—reynosin, and santamarin (Awang, 1989; Bohlmann and Zdero, 1982; Leung and Foster, 1996), guaianolides—canin and articanin (Bohlmann and Zdero, 1982; Bradley, 1992; Hausen, 1992; Leung and Foster, 1996). Parthenolide is usually the primary sesquiterpene lactone, but it is lacking in samples from Mexico and Yugoslavia (Heptinstall et al., 1992). Additional sesquiterpenes and monoterpenes include camphor, b-farnesene, germacrene, chrysanthenyl acetate, a-pinene derivatives, bornyl acetate, bornyl angelate (Bohlmann and Zdero, 1982; Bradley, 1992; Newall et al., 1996), pyrethrin (Newall et al., 1996), flavonoids (Bruneton, 1999; Newall et al., 1996; Williams et al., 1995), tannins (Newall et al., 1996), and melatonin (Murch et al., 1997).

Pharmacological Actions

Human

Antimigraine (Johnson et al., 1985; Murphy et al., 1988; Palevitch et al., 1997); however, more information is needed. Although past studies have focused upon parthenolide as the active component responsible for antimigraine activity, a recent Dutch study determined an alcoholic feverfew leaf extract (containing an appropriate level of parthenolide) to be ineffective in migraine prophylaxis, challenging previous hypotheses (Awang, 1998b; de Weerdt et al., 1996). The Dutch researchers suggest that another compound such as chrysanthenyl acetate, detected in significantly reduced amounts in the extract compared with the dried, whole plant material, may contribute to the anti-migraine activity due to its prostaglandin inhibition (de Weerdt et al., 1996; Heptinstall and Awang, 1998).

Animal

Anti-nociceptive (Jain and Kulkarni, 1999); anti-inflammatory (Jain and Kulkarni, 1999); inhibits collagen-induced bronchoconstriction (Keery and Lumley, 1986).

In vitro

Anti-inflammatory (Williams et al., 1995; Brown et al., 1997); inhibits mast cell release of histamine (Hayes and Foreman, 1987); inhibits blood platelet secretion of serotonin (Heptinstall et al., 1985; Groenewegen and Heptinstall, 1990); anti-thrombotic potential (Voyno-Yasenetskaya et al., 1988; Groenewegen and Heptinstall, 1990; Löesche et al., 1987); inhibits prostaglandin synthesis (Pugh and Sambo, 1988); inhibits serotonin release (Béjar, 1996; Marles et al., 1992); inhibits eicosanoid synthesis (Sumner et al., 1992); alters vascular responses (Barsby et al., 1992, 1993a, 1993b); inhibits neutrophil phagocytosis (Williamson et al., 1988); antibacterial (Hayes and Foreman, 1987); cytotoxic (O’Neill et al., 1987).

Mechanism of Action

May inhibit platelet behavior through the neutralization of sulphydryl groups on enzymes of proteins implicated in platelet aggregation and secretion (Heptinstall et al., 1987).

Sesquiterpene lactones and non-sesquiterpene lactones inhibit eicosanoid synthesis by inhibiting 5-lipoxygenase and cyclo-oxygenase in leukocytes (Sumner et al., 1992). Tanetin may contribute to anti-inflammatory properties by inhibiting the generation of pro-inflammatory eicosanoids (Williams et al., 1995; Hoult et al., 1995).

Parthenolide and other sesquiterpene lactones in extracts of fresh leaves appear to irreversibly and nonspecifically inhibit smooth muscle contractions (Barsby et al., 1993a). In contrast, chloroform extracts of dried feverfew leaves, containing no parthenolide, produce reversible smooth muscle contractions via a selective open-channel block of voltage-dependent potassium channels (Barsby et al., 1993b).

Inhibits collagen-induced bronchoconstriction by inhibiting phospholipase A2 activity (Keery and Lumley, 1986).

Parthenolide, and other sesquiterpene lactones inhibit serotonin release from bovine platelets. Serotonin has been implicated in the pathogenesis of migraines (Marles et al., 1992).

Parthenolide, michefuscalide, and chrysanthenyl acetate can inhibit prostaglandin synthetase, which catalyzes the conversion of arachadonic acid to prostaglandins (Pugh and Sambo, 1988).

Extract inhibits histamine release from rat peritoneal mast cells (Hayes and Foreman, 1987).

Blocks secretory activity in blood platelets and polymorphonuclear leukocytes (PMNs) (Heptinstall et al., 1985).

Inhibits the release of serotonin from platelets and platelet aggregation (Heptinstall et al., 1985).

Inhibits neutrophil phagocytosis and degranulation (Williamson et al., 1988).

Extract inhibits mitogen-induced, human peripheral-blood mononuclear cell proliferation and cytokine-mediated responses (O’Neill et al., 1987).

Contraindications

Feverfew is contraindicated when the patient is allergic to members of family Asteraceae (Compositae), which includes feverfew (Tanacetum parthenium), ragweed (Ambrosia spp.), chrysanthemums (Chrysanthemum spp.), marigolds (Calendula officinalis), chamomile (Matricaria spp.), yarrow (Achillea spp.), and daisies (ESCOP, 1996, Hausen and Osmundsen, 1983; Newall et al.,1996). Not recommended for children under two years old (Awang, 1993). Contraindicated for presurgical patients due to possible anti-PAF activity (Brinker, 2001).

Pregnancy and Lactation: Not for use in pregnancy or lactation (Awang, 1993). Contraindicated during pregnancy because it may act as an emmenagogue in early pregnancy (Brinker, 2001).

Adverse Effects

Allergic contact dermatitis can occur when feverfew is handled (Brinker, 2001). Mouth ulceration and swelling of the tongue, lips, and oral mucosa have also been reported (Hausen, 1992; Murphy et al., 1988). Abdominal pains and indigestion have been reported for feverfew users who have chewed the leaves over a period of years (Hausen, 1992; Murphy et al., 1988). Diarrhea, flatulence, nausea, and vomiting were rare, but resulted in the discontinuation of treatment (ESCOP, 1996; Hausen, 1992). Although long-term toxicity data are presently unavailable, no serious side effects have been noted in patients taking the plant for a period of years (Hausen et al., 1992; Johnson et al., 1985; Murphy et al., 1988).

Drug Interactions

No adverse side effects were noted in a large number of individuals taking feverfew together with other medications (ESCOP, 1996). Due to the pharmacology, speculative theories suggest that feverfew should not be consumed with anticoagulants or antiplatelet agents like aspirin or warfarin (Brinker, 2001; Bratman and Kroll, 1999). However, these theories have not been proven in a clinical or scientific setting (Boon and Smith, 1999).

American Herbal Products Association (AHPA) Safety Rating

Class 2b: Not to be used during pregnancy (McGuffin et al., 1997). Note: Mouth ulceration and gastric disturbances have been reported in 6–15% of users, usually in the first week of use (McGuffin et al., 1997).

Regulatory Status

Canada: The Canadian Health Protection Branch has issued Drug Identification Numbers (DIN) to dried-leaf products containing a minimum of 0.2% parthenolide with certification of botanical identity. The Feverfew Leaf Labeling Standard permits the following indications: “Traditional Herbal Medicine (THM) to help prevent recurring migraine headaches and associated nausea and vomiting” (Awang, 1998b; Health Canada, 1997; Leung and Foster, 1996).

European Union: Dried aerial part, containing not less than 0.2% of parthenolide, is official in the European Pharmacopoeia 3rd ed. Supplement 2001 (Ph.Eur., 2001).

France: THM approved for specific indications (Bradley, 1992). Fresh or dried aerial parts are official in the French Pharmacopoeia (ESCOP, 1996).

Germany: Not reviewed by the German Commission E. No monograph in the German Pharmacopoeia (DAB).

Sweden: Classified as a natural product (De Smet et al., 1993). As of January 2001, no feverfew products are listed in the Medical Products Agency (MPA) “Authorised Natural Remedies” (MPA, 2001).

Switzerland: No feverfew products are licensed herbal medicines. No monograph in the Swiss Pharmacopoeia.

U.K.: Not on the General Sale List and no product licenses granted (Bradley, 1992).

U.S.: Dietary supplement (USC, 1994). Dried leaf and dried powdered leaf are official in the United States National Formulary (USP, 2002).

Clinical Review

Six trials are outlined in the following table “Clinical Studies on Feverfew”, including a total of 279 participants. All five of the trials examining feverfew’s effects on migraine demonstrate some positive effects, but one trial examining feverfew’s effects on arthritis found no apparent benefit. Three of the five migraine studies were randomized, double-blind, and placebo-controlled (R, DB, PC) (de Weerdt et al., 1996; Murphy et al., 1988; Johnson et al., 1985). In one of these studies the participants used a feverfew extract but did not experience a reduction in the number of migraine attacks; however, they were able to use fewer drugs during the period they took the feverfew (de Weerdt et al., 1996). Awang (1998b) has theorized that the therapeutic effect of feverfew is due to an unidentified plant constituent that may have been lost or degraded in the extract made from the feverfew material used in the de Weerdt (1996) study. Further, the leaves of the plant used in the study were not cultivated from certified seeds (Awang, 1998b). By comparison, the studies using dried feverfew leaf found a reduced number and severity of migraine attacks (Palevitch et al., 1997; Murphy et al., 1988; Johnson et al., 1985). Feverfew consistently reduced vomiting and nausea associated with migraine (Palevitch et al., 1997; Murphy et al., 1988; Johnson et al., 1985). A recently published literature review concludes that the efficacy of feverfew for the prevention of migraine has not been established beyond reasonable doubt (Pittler et al., 2000). One trial found that feverfew did not benefit women with rheumatoid arthritis (Pattrick et al., 1989).

Branded Products

Studies conducted were based on generic, not specific products.

References

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