Description

Medicinal Parts

The medicinal parts are the herb of the plant.

Flower and Fruit

The 5 to 20 composite flower heads are in a dense corymb. The epicalyx has a diameter of 6 to 8 mm. The lingual florets are white and female. The ray florets are 2.5 to 7 mm. The achenes are 1.2 to 1.5 mm and 5- to 8-ribbed.

Leaves, Stem, and Root

The plant is a strongly aromatic perennial. The leaves are pinnatisect to pinnatifid and yellowish-green. The basal and lower cauline leaves are more or less ovate with 3 to 7 oblong-elliptical to ovate segments, which are subpinnately divided. They are crenate or entire-margined.

Habitat

The plant originated in southeastern Europe and is now found all over Europe, Australia, and North America.

Production

Feverfew leaves are the leaves of Tanacetum parthenium. The plant is cut before full flowering. It is dried in thin layers in the shade, at temperatures not exceeding 35º C.

Other Names

Featherfew, Featherfoil, Midsummer Daisy

Actions & Pharmacology

Compounds

Volatile oil (0.75%): chief constituents are L-camphor, trans-chrysanthyl acetate, including, camphene, p-cymene, gamma-terpinene, D-germacrene, linalool, borneol, terpinenes-4-ol

Sesquiterpene lactones: especially parthenolide, and also 3-beta-hydroxy-parthenolide, costunolid, reynosin, 8-beta-hydroxy-reynosin, tanaparthin-alpha-peroxide, canin, artecanin, secotanapartholide A

Flavonoids: including apigenin-7-0-glucuronide, chrysoeriol-7-0-glucuronide, luteolin-7-0-glucuronide, luteolin-7-0-glucoside, tanetin

Polyynes: presumably only in fresh plants

Effects

Sesquiterpene lactones, especially parthenolide, are the active compounds in Feverfew. Parthenolide, although a key determinant of biological activity for Tanacetum parthenium leaf extracts, is not the sole pharmacologically active constituent. Other sesquiterpene lactones such as 3-beta-hydroxyparthenolide, secotanapartholide A, canin and artecanin, contain an alpha-methylene butyrolactone unit responsible for antisecretory (anti-inflammatory) activity (Groenewegen, 1986). Physiochemical methods were used to measure partholide in several purported commercial Feverfew products. The results found a wide variation in partholide content and in some products, partholide was not detected (Heptinstall, 1992).

Crude chloroform extracts of fresh Feverfew leaves (rich in sesquiterpene lactones) and of commercially available powdered leaves (lactone-free) produce a dose-dependent inhibition of thromboxane B2 and leukotriene B4 (eicosanoids) for an anti-inflammatory effect (Sumner, 1992). Anti-inflammatory properties of Feverfew also consist of inhibition of cellular phospholipases, which prevents release of arachidonic acid (Makheja, 1982). Parthenolide and chrysanthenyl acetate have also been shown to inhibit prostaglandin synthetase (Pugh, 1988). Extracts of Feverfew also inhibit granule secretion in blood platelets and polymorphonuclear leukocytes (Heptinstall, 1985).

Major flavonol and flavone methyl ethers (tanetin) of the herb inhibit the major pathways of arachidonate metabolism in leukocytes (Williams, 1999).

Feverfew extract and parthenolide inhibit human blood aggregation and serotonin (5-HT) secretion by platelets (Groenewegen, 1990). The extract does this through neutralizing cellular sulfhydryl-affecting substances, which are properties of monocyte adherence (Krause, 1990). The chloroform extract of the Feverfew leaf contains an unidentified substance capable of producing a selective, open-channel block of voltage-dependent potassium channels, which results in an antispasmodic effect (Barsby, 1993). Feverfew extract inhibited anti-IgE-induced histamine release in a unique way, which concludes that Feverfew extract contains a novel type of mast cell inhibitor (Hayes, 1987).

The actions of Feverfew's components most likely to contribute to its benefit in migraine as shown in vitro or in animal tests are inhibition of prostaglandin synthesis (Sumner et al, 1992; Williams et al, 1995), blocking platelet granule secretion (Marles et al, 1992), and decreasing vascular smooth muscle spasm (Barsby et al, 1992; Barsby et al, 1993a; Barsby et al, 1993b). One preliminary human study has confirmed a platelet granule secretion decreasing action (Biggs et al, 1982). It has also shown antitumor (Hoffmann et al, 1977; Lee et al, 1971) and mast-cell inhibitory activity (Hayes & Foreman, 1987) in preliminary in vitro tests.

Allergen Diagnostic Test

Feverfew has been used successfully to test for allergenicity in other members of the Compositae family. Allergenicity to members of the Compositae occurred in 118 of 3,851 tested individuals (3.1%) in one group. Seventy percent of those reacting to Compositae reacted to Feverfew specifically (Hausen, 1996). Feverfew has been known to cross-react with tansy, yarrow, marguerite, aster, sunflower, laurel, and liverwort (Frullania) (Schmidt, 1986; Hausen & Osmundsen, 1983).

Analgesic Effects (Against Migraine)

A Cochrane review is inconclusive to establish efficacy of Feverfew for migraine headache prevention. Dried or freeze-dried leaves, but not ethanolic extracts, reduce the frequency and severity of migraine headaches. Nausea and vomiting were significantly less severe during Feverfew administration compared to placebo (Gerber, 1997). Although parthenolide is considered by some to be the active agent, the actual active component is unknown and parthenolide content may simply represent a portion of the activity, or assurance that a certain percentage of the actual active ingredient is present.

Anti-inflammatory Effects

Findings support a prostaglandin-related anti-inflammatory action for Feverfew. Feverfew has been shown to suppress 86% to 88% of prostaglandin production, but does not inhibit cyclooxygenase (Miller, 1998). Lipophilic extracts rich in sesquiterpene lactones inhibit production of inflammatory prostaglandins in rat and human leukocytes (Sumner et al, 1992; Heptinstall, 1988). Phospholipase inhibition in platelets in vitro has also been directly documented (Makheja & Bailey, 1982). Inhibition of prostaglandin synthetase has been shown in vitro for parthenolide and related lactones (Pugh & Sambo, 1988). The anti-inflammatory effects of Feverfew may be due to a cytotoxic effect (O'Neill et al, 1987).

Antiplatelet Effects

Platelet aggregation was not significantly affected by Feverfew in 10 subjects (Biggs et al, 1982). Parthenolide and Feverfew have been shown to inhibit platelet serotonin (5-HT) secretion in vitro (Marles et al, 1992; Groenewegen & Heptinstall, 1990, Groenwegen et al, 1986). Feverfew may inhibit 5-HT release via sulfhydryl group (SHG) neutralization (Krause et al, 1990). Lactone-rich Feverfew extracts reduced platelet granule secretion in response to several chemical stimulants to a greater extent than high-dose nonsteroidal anti-inflammatory drugs (Heptinstall et al, 1985). Feverfew extract dose-dependently inhibited uptake and release of arachidonic acid (AA) into or from platelet membrane phospholipids (Loesche et al, 1988). Feverfew has been shown to interfere with the initial step of thomboxane synthesis, inhibiting the release of the arachidonic acid substrate from platelet phospholipids, and resulting ultimately in decreased platelet aggregation (Makheja & Bailey, 1981).

Antispasmodic Effects

Feverfew extracts have spasmolytic activity in that they make smooth muscle nonselectively less responsive to agents such as norepinephrine, acetycholine, bradykinin, prostaglandin, histamine, and serotonin (Diamond, 1987).

Antitumor Effects

Parthenolide and similar lactones are cytotoxic to several human cancer cell lines (Hoffmann et al, 1977; Lee et al, 1971). Parthenolide inhibits thymidine incorporation into DNA (Woynarowski et al, 1981; Woynarowski & Konopa, 1981) and inhibits DNA polymerase function in vitro (Hall et al, 1978). Animal and human studies have not been conducted to confirm these results. Parthenolide, the primary active component in Feverfew, exhibited dose-dependent cytostasis and cytotoxicity when tested in human lymphoma line (TK6) and mouse fibrosarcoma cell line (MN-11). It is postulated that cytostasis occurs due to the reversible inhibition of protein kinases (Ross et al, 1999).

Effects Against Rheumatoid Arthritis

Current evidence does not support the traditional use of Feverfew to treat rheumatoid arthritis.

Clinical Trials

Migraine

A carbon dioxide-based Feverfew extract MIG-00 was found to be safe and effective for migraine prophylaxis when used in a dosage of 6.25 mg 3 times daily for up to 4 months, according to a 2005 randomized, double-blind, placebo-controlled, parallel-group clinical phase III study. The 170 participants (MIG-99, n=89; placebo, n=81) all fulfilled the International Headache criteria for migraine, and were treated for 16 weeks at multiple study centers after a 4-week baseline period. Migraine frequency decreased from 4.76 by 1.9 attacks monthly in the MIG-99 group and by 1.3 attacks in the placebo group, a significant difference (P=0.0456). This was a favorable benefit-risk ratio for the Feverfew treatment, given its effectiveness and adverse event profile (8.4% versus 10.2% for placebo (Diener et al, 2005).

Less promising results were generated by a randomized, placebo-controlled 2004 trial that found a placebo (riboflavin 25 mg) to be comparable in effectiveness for migraine prophylaxis to a combination drug of Feverfew 100 mg, riboflavin 200 mg, and magnesium 300 mg. Forty-nine patients completed the 3-month trial with a 1-month run-in phase, which allowed for 120 patients to be randomized. The authors concluded that the findings only add to the already conflicting evidence for the efficacy of Feverfew and the other substances studied, as there was no significant difference between the two regimens in terms of percentage of migraines reduced, number of migraine days, migraine index, or other parameters measured. The response of placebo (riboflavin) exceeded that of findings in other trials, suggesting a possible role for this substance in migraine prophylaxis (Maizels et al, 2004).

A 2004 Cochrane Collaboration systematic review of evidence from double-blind and randomized controlled trials examining the efficacy of Feverfew in preventing migraine headache found insufficient evidence of superiority over placebo for this purpose. While the review cited studies that showed some efficacy, the authors noted that overall the evidence was mixed and the methodological quality of the trials included in the review was unsatisfying. It appears from the data that with only mild and transient adverse events reported in the trials examined, it can be concluded that Feverfew presents no major safety problems (Pittler 2004).

Among those studies cited in the Cochrane review was a 1997 trial in which dried whole leaf Feverfew capsules were found to be effective in reducing migraine symptoms in a double-blind, placebo-controlled trial of 57 subjects. None of the participants had taken Feverfew prior to entry into the study. Two 50-mg Feverfew capsules were administered during active treatment phases. Pain intensity, vomiting, photophobia, and phonophobia were all significantly lower during Feverfew treatment compared to baseline (in the run-in, uncontrolled period, p<0.001 for all symptoms) or placebo (during the double-blind period, p<0.01, p<0.01 and p<0.017, respectively). Adverse effects were not reported (Palevitch et al, 1997).

The efficacy of dried Feverfew leaves for migraine prophylaxis was assessed in another randomized, placebo-controlled, double-blind, crossover study cited by the Cochrane review. The study consisted of 72 patients with classic or common migraine headaches for more than 2 years. The effect of 1 capsule daily of Feverfew was determined by the use of diary cards and visual analog scores. Duration of treatment was 4 months. After this time, Feverfew was associated with a reduction in number and severity of attacks in each 2-month period. The degree of vomiting was also reduced in the Feverfew treatment group. A significant improvement in the visual analog scale was also observed in the Feverfew treatment group (Murphy, 1988).

Also cited by the Cochrane review was a study in which patients already taking Feverfew for migraine prophylaxis were randomized in a double-blind, placebo-controlled trial. The placebo groups had a significant increase in the frequency and severity of headache, nausea, and vomiting with the emergence of untoward effects during the early months of treatment. There was no change in the frequency or severity of symptoms of migraine in the Feverfew treatment group, thus suggesting that Feverfew may be taken prophylactically to prevent attacks of migraines (Johnson, 1985).

Rheumatoid Arthritis

A double-blind, placebo-controlled study evaluated the use of dried chopped Feverfew (70 mg to 86 mg) in patients with symptomatic rheumatoid arthritis. There were 41 patients involved in the study, and they were observed during a 6-week period. Variables assessed in the study included stiffness, pain (visual analog scale), grip strength, articular index, full blood count, erythrocyte sedimentation rate, urea, creatinine, C-reactive protein, complement breakdown products, rheumatoid factor titre, immunoglobulins (IgG, IgA, IgM), functional capacity, and patient and observer global opinions. While grip strength improved significantly in the Feverfew group compared to the placebo group, there were no other important differences in clinical or laboratory variables between the groups during the study period (Pattrick, 1989).

Supplement Form

A placebo-controlled study employing capsules of ethanol extract of Feverfew could not confirm the results of the previous studies using whole leaf. (De Weerdt et al, 1996).

Indications & Usage

Unproven Uses

Feverfew is used mainly for migraine, arthritis, rheumatic diseases, and allergies. Feverfew has also been used in the treatment of tinnitus, vertigo, arthritis, fever, difficulty during labor, toothache, insect bites, and asthma. In folk medicine, Feverfew is used for cramps, as a tonic, a stimulant, a digestive agent, and a blood purifier. Other uses in folk medicine include migraine prophylaxis, digestion problems, intestinal parasites and gynecological disorders. The herb is also used as a wash for inflammation and wounds, as a tranquilizer, an antiseptic, and following tooth extraction as a mouthwash. The infusion is used for dysmenorrhea. In postnatal care, Feverfew is used to reduce lochia. The drug is used externally as an antiseptic and insecticide.

Contraindications

Pregnancy

Feverfew is not to be used during pregnancy.

Breastfeeding

Not be used during breast-feeding.

Pediatrics

Not to be used in children under two years of age.

Precautions & Adverse Reactions

Based on questionnaires completed by 300 Feverfew users, the overall incidence of minor side effects is around 20% (Murdoch, 1989). Feverfew inhibits platelet aggregation and caution should be used in patients on other platelet aggregation inhibitors such as aspirin and dipyridamole (Miller, 1998).

The drug has a high potential for sensitization via skin contact. Occupational or direct exposure has caused eczema and allergic dermatitis. Feverfew has been known to cross-react with Tansy, Yarrow, Marguerite, Aster, Sunflower, Laurel, and Liverwort (Schmidt, 1986; Guin & Skidmore, 1987; Paulsen, 1998). Other adverse reactions include abdominal pain, diarrhea, lip swelling, mouth ulcers (from chewing leaf), and glossitis (from chewing leaf) (Klepser & Klepser, 1999; Murdoch, 1989; deSmet & Vulto, 1987).

Cardiovascular

Transient increases in heart rate have occasionally been reported (Murdoch, 1989).

Hypersensitivity

Allergenicity to members of the Compositae family occurred in 118 of 3,851 tested individuals (3.1%) in one group. Seventy percent of those reacting to Compositae reacted to Feverfew specifically (Hausen, 1996). Another study of 686 European patients showed a 4.5% Compositae hypersensitivity (Paulsen et al, 1993).

Musculoskeletal

Feverfew contains sesquiterpenes (parthenolide and cynaropicrin), which have been shown to induce toxic and irreversible inhibition of smooth muscle contractility when there are high concentrations in the tissue (Hay, 1994).

Post-Feverfew Syndrome

About 10% of migraine patients who abruptly stop taking Feverfew may experience rebound headaches, insomnia, muscle stiffness, joint pain, fatigue, nervousness, and tension (Miller, 1998; Murdoch, 1989; Baldwin, 1987).

Drug Interactions

Moderate Risk:

Anticoagulants, low molecular weight heparins, thrombolytic agents

Concurrent use may result in increased risk of bleeding. Clinical Management: If Feverfew is taken with any of these drugs, monitor for signs and symptoms of excessive bleeding.

Antiplatelet agents

Concurrent use may result in increased risk of bleeding. Clinical Management: If Feverfew is taken with an antiplatelet drug, monitor for signs and symptoms of excessive bleeding to determine if platelet function has been adversely affected by feverfew.

Nonsteroidal Anti-inflammatory Agents

Concurrent use may result in increased risk of adverse effects from the nonsteroidal antiinflammatory agent (i.e., gastrointestinal, renal effects). Clinical Management: Avoid concomitant use of Feverfew with nonsteroidal anti-inflammatory agents.

Dosage

Mode of Administration

Feverfew preparations are used both internally and externally.

How Supplied

• Capsules – 80 mg, 100 mg, 380 mg, 384 mg, 400 mg, 500 mg, 1000 mg
• Tablets – 12 mg (standardized to 600 mcg sesuiterpine lactone content)
• Liquid Extract
• Fresh leaf: ∼25 mg

Preparation

To make an infusion, use 2 teaspoonfuls of the drug per cup, allow to steep for 15 minutes. To make a strong infusion, double the amount and allow to steep for 25 minutes.

Daily Dosage

• Capsules – 200 to 250 mg daily for the treatment of migraines; the usual standardization level is 0.2% parthenolide content (Brown, 1996). Freshly dried powdered Feverfew of 25 mg is approximately equal to 0.1 mg of sesquiterpine lactones (SL) (Mervyn,1986).
• Fresh leaf – 1 to 3 leaves (25 to 75 mg) once or twice daily has been recommended (Johnson et al, 1985; O'Hara, 1998).
• Unproven uses – 3 cups of the infusion are taken per day. The stronger infusions are used for washes.

Storage

Store the herb in sealed containers.

Literature