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.
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