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Feverfew

Scientific Name(s): Tanacetum parthenium Schulz-Bip.
Common Name(s): Altamisa, Bachelor's button, Chamomile grande, Chrysanthemematricaire, European feverfew, Feather-fully, Featherfew, Featherfoil, Febrifuge plant, Feddygen fenyw, Feverfew, Flirtroot, Grande chamomile, Midsummer daisy, Mutterkraut, Nosebleed, Santa Maria, Vetter-voo, Wild chamomile, Wild quinine

Clinical Overview

See also: Dulera

Use

Feverfew is primarily known for use in prophylactic treatment of migraine headaches and associated nausea and vomiting; however, evidence to support this use is inconclusive. Feverfew has numerous other pharmacological actions, including inhibition of prostaglandin synthesis, blockage of platelet granule secretion, effects on smooth muscle, antitumor activity, inhibition of serotonin release, inhibition of histamine release, and mast cell inhibition, but information from clinical trials is limited.

Dosing

Feverfew is generally given for migraine headaches at a daily dosage of 50 to 150 mg of dried leaves, 2.5 fresh leaves with or after food, or 5 to 20 drops of a 1:5, 25% ethanol tincture. Though optimal doses of feverfew have not been established, an adult dosage of parentholide 0.2 to 0.6 mg/day is recommended for the prevention of migraine. However, parthenolide has not been confirmed as a major active principle for migraine. Numerous feverfew products are commercially available; most are standardized to parthenolide 0.7% in tablet or capsule dosage forms.

Contraindications

Feverfew is contraindicated in patients allergic to other members of the Asteraceae family, such as aster, chamomile, chrysanthemum, ragweed, sunflower, tansy, and yarrow. Due to its potential antiplatelet effects, it is not recommended for use in patients undergoing surgery. Patients with blood-clotting disorders should consult their health care provider prior to using products containing feverfew.

Pregnancy/Lactation

Avoid use because of documented adverse effects. Pregnant women should not use the plant because the leaves possess emmenagogue activity (ejection of the placenta and fetal membranes) and may induce abortion. It is not recommended for breast-feeding mothers or for use in children younger than 2 years of age.

Interactions

None well documented.

Adverse Reactions

Patients withdrawn from feverfew may experience ill effects often known as "postfeverfew" syndrome. Handling fresh feverfew leaves may cause allergic contact dermatitis. Swelling of the lips, tongue, and oral mucosa, in addition to mouth ulceration, have been reported with feverfew use. GI effects, such as abdominal pain, nausea, vomiting, diarrhea, indigestion, and flatulence, may also occur.

Toxicology

No studies of chronic toxicity have been performed on the plant. The safety of long-term use has not been established.

Botany

Native to the Balkan Peninsula, feverfew is now found in Australia, Europe, China, Japan, and North Africa. In the mid-nineteenth century, feverfew was introduced in the United States. The plant grows along roadsides, fields, waste areas, and along the borders of woods from eastern Canada to Maryland and westward to Missouri. Feverfew is a short, bushy, aromatic perennial that grows 0.3 to 1 m in height. Its yellow-green leaves are usually less than 8 cm in length, almost hairless, and pinate-bipinnate (chrysanthemum-like). Its yellow tubular florets, each with 10 to 20 white rays, bloom from July to October and are about 2 cm in diameter. They resemble those of chamomile (Matricaria chamomilla), for which they are sometimes confused, and have a single layer of white outer-ray florets.5, 9, 10, 11

Historically, the plant has been placed into 5 different genera; therefore, some controversy exists as to which genus the plant belongs. Former botanical names include Chrysanthemum parthenium (L.) Bernh., Leucanthemum parthenium (L.) Gren and Gordon, Pyrethrum parthenium (L.) Bernh., and Matricaria parthenium (L.).5, 12 Feverfew is a member of the daisy (Asteraceae) family that includes aster, chamomile, chrysanthemum, ragweed, sunflower, tansy, and yarrow.

History

The feverfew herb has a long history of use in traditional and folk medicine, especially among Greek and early European herbalists. The ancient Greeks called the herb Parthenium, supposedly because it was used medicinally to save the life of someone who had fallen from the Parthenon during its construction in the 5th century BC. The name may derive from use in treating menstrual cramps in young girls, because the word parthenos means virgin in the Greek language. Perhaps the common English name feverfew was derived from a feathery plant known as featherfew.5, 11

The first century Greek physician Dioscorides used feverfew as an antipyretic. Feverfew also was known as "medieval aspirin" or the "aspirin" of the 17th century. In 1633, the plant was recommended for use to treat headaches in Gerard's Herbal.5, 7, 9, 13

The plant has been used to treat arthritis, asthma, constipation, dermatitis, earache, fever, headache, inflammatory conditions, insect bites, labor, menstrual disorders, potential miscarriage, psoriasis, spasms, stomachache, swelling, tinnitus, toothache, vertigo, and worms. Feverfew also has been used as an abortifacient, as an insecticide, and for treating coughs and colds. Traditionally, the herb has been used as an antipyretic, from which its common name is derived.5, 10, 13, 14, 15

In Central and South America, the plant has been used to treat a variety of disorders. The Kallaway Indians of the Andes mountains value its use for treating colic, kidney pain, morning sickness, and stomachache. Costa Ricans use a decoction of the herb to aid digestion, as a cardiotonic, an emmenagogue, and as an enema for worms. In Mexico, it is used as an antispasmotic and as a tonic to regulate menstruation. In Venezuela, it is used for treating earaches.5 In Danish folk medicine, feverfew is used as an antiepileptic.16 The leaves are ingested fresh or dried, with a typical daily dosage of 2 to 3 leaves. The bitter taste is often offset by the addition of sweeteners. Feverfew also has been planted around houses to purify the air because of its strong, lasting odor; a tincture of its blossoms is used as an insect repellant and balm for bites.2 It has been used as an antidote for opium overdose.1

Chemistry

The chemistry of feverfew is well defined. The most important biologically active principles are sesquiterpene lactones, principally parthenolide. Parthenolide is found in the superficial leaf glands (0.2% to 0.5%), but not in the stems, and comprises up to 85% of the total sesquiterpene content.5, 12, 17, 18 Factors such as the geographical location of seed origin, stage of plant growth at harvest, plant parts used, and duration and condition of storage can all affect the parentholide content.7 A study revealed that degradation of parthenolide in a feverfew solution follows a first-order reaction. It was also discovered that parthenolide was stable when the environmental pH was between 5 to 7 but unstable at a pH of 3 or less. The effects of temperature on the degradation of parthenolide were also measured. The content remained constant after 6 months of storage in a refrigerator. However, at 25°C (80°F), the feverfew slowly degraded after 3 months, with decomposition occurring after 1 or 2 months if stored at 40°C (104°F) or higher. Increases in humidity were also associated with increased degradation of parthenolide.18

Flavonoids

The following flavonoids have been isolated: 6-hydroxykaempferol 3,6-dimethyl ether, 6-hydroxykaempferol 3,6,4′-trimethyl ether (tanetin), quercetagetin 3,6-dimethyl ether, quercetagetin 3,6,3′-trimethyl ether (accompanied by isomeric 3,6,4′-trimethyl ether), apigenin (also apigenin 7-glucuronide), luteolin (also luteolin 7-glucuronide), chrysoeriol, santin, jaceidin, and centaureidin.22, 23, 24, 25, 26

Sesquiterpene lactones

More than 30 sesquiterpene lactones have been identified in feverfew. In general, there are 5 different types of sesquiterpene lactones, which may be classified by chemical ring structures. Feverfew contains eudesmanolides, germacranolides, and guaianolides. Parthenolide is a germacranolide.5

Researchers have also isolated the following sesquiterpene lactones: artecanin, artemorin, balchanin, canin, costunolide, 10-epicanin, epoxyartemorin, 1-beta-hydroxyarbusculin, 3-beta-hydroxycostunolide, 8-alpha-hydroxyestagiatin, 8-beta-hydroxyreynosinn, 3-beta-hydroxyparthenolide, manolialide, reynosin, santamarine, secotanaparthenolide A, secotanaparthenolide B, tanaparthin-alpha-peroxide, and 3,4-beta-epoxy-8-deoxycumambrin B.13 Other members of this class have been isolated and possess spasmolytic activity, perhaps through an inhibition of the influx of extracellular calcium into vascular smooth muscle cells.5, 19, 20, 21

Volatile oils

Twenty-three compounds, representing 90% or more of the volatile oils, have been identified from feverfew. The primary components include camphor (56.9%), camphene (12.7%), rho-cymene (5.2%), and bornyl acetate (4.6%). Other components identified include tricylene, alpha-thujene, alpha-pinene, beta-pinene, alpha-phellandrene, alpha-terpinene, gamma-terpinene, chrysantheone, pinocarvone, borneol, terpinen-4-ol, rho-cymen-8-ol, alpha-terpineol, myrtenal, carvacrol, eugenol, trans-myrtenol acetate, isobornyl 2-methyl butanoate, and caryophyllene oxide.27

Other chemical constituents

The coumarin isofraxidin and an isofraxidin drimenyl ether named 9-epipectachol B have been isolated from the roots of the plant, as well as (2-glyceryl)-0-coniferaldehyde.28, 29

Uses and Pharmacology

Anticancer activity

Mechanisms of action are poorly understood but may include (1) cytotoxic action associated with interruption of DNA replication by the highly reactive lactone ring, epoxide, and methylene groups of parthenolide through inhibition of thymidine incorporation into DNA; or (2) oxidative stress, intracellular thiol depletion, endoplasmic reticulum stress, capase activation, and mitochondrial dysfunction.5, 56, 57

In vitro data

Parthenolide and similar lactones displayed anticancer activity against several human cancer cell lines, including human fibroblasts, human laryngeal carcinoma, human cells transformed with Simian Virus 40, human epidermoid cancer of the nasopharynx, human melanoma, and anti-Epstein-Barr early antigen activity. Additionally, an ethanolic extract of feverfew inhibited the growth of 2 human breast cancer lines, human glioblastoma cell lines, and 1 human cervical cancer cell line. Of all the constituents of feverfew tests, parthenolide demonstrated the greatest inhibitory effect.58 Another in vitro study demonstrated that parthenolide was effective at inhibiting the proliferation of human lung carcinoma, human medulloblastoma, human colon adenocarcinoma, and human umbilical vein endothelial cells.59 Results from another study suggest that parthenolide given in combination with hyperthermia (ie, heat) may increase thermosensitization of human lung adenocarcinoma cells via induction of apoptosis or cell cycle arrest through inhibition of nuclear factor (NK)-kappa-B activation.60 One study documents how parthenolide may influence and enhance the effectiveness of paclitaxel.5, 32, 39, 42, 61, 62, 63, 64, 65

Clinical data

Parthenolide is being investigated in early clinical studies for a therapeutic role in cancer.105

Anti-inflammatory activity

A proposed mechanism of action involves parthenolide inhibition of the NF-kappa-B pathway by blocking I-kappa-B kinase (IKK-beta), an activator of NF-kappa-B.6, 30 The IKK-beta complex plays an important role in pro-inflammatory cytokine-mediated signaling. Additionally, a component of essential oil, trans-chrysanthenyl acetate, is a known inhibitor of prostanglandin synthetase and may contribute to anti-inflammatory effects, especially when used for the treatment of migraine headaches.31

In vitro and animal data

Feverfew appears to be an inhibitor of prostaglandin synthesis. Extracts of the above-ground portions of the plant suppress prostaglandin production; leaf extracts inhibit prostaglandin production to a lesser extent. Neither the whole plant nor leaf extracts inhibit cyclooxygenation of arachidonic acid, the first step in prostaglandin synthesis. Chloroform leaf extracts, rich in sesquiterpene lactones, inhibit production of inflammatory prostaglandins in rat and human leukocytes. Inhibition was irreversible and the effect was not due to cytotoxicity. Studies have shown that lipophilic compounds other than parthenolide may be associated with anti-inflammatory activity, particularly with reducing human neutrophil oxidative burst activity.18, 32, 33

Tanetin, a lipophilic flavonoid found in the leaf, flower, and seed of feverfew, blocks prostaglandin synthesis. Aqueous extracts do not contribute to feverfew's anti-inflammatory activity, but do prevent the release of arachidonic acid and inhibit in vitro aggregation of platelets stimulated by adenosine 5′-diphosphate (ADP) or thrombin. Whether or not these extracts block the synthesis of thromboxane, a prostaglandin involved in platelet aggregation, is controversial. Results suggest that feverfew's inhibition of prostaglandin synthesis differs in mechanism from that of salicylates.23, 24, 34, 35, 36

Phospholipase A2 inhibition in platelets has been documented. Inhibition of prostaglandin synthetase also has been shown for parthenolide.6, 37, 38

To maintain anti-inflammatory effects while minimizing skin sensitization, a parthenolide-depleted (PD) extract of feverfew was developed. To ensure parthenolide was removed, over 1,200 patients were patch-tested for skin sensitization. The PD-feverfew inhibited the activity of 5-lipoxygenase, phosphodiesterase-3, and phosphodiesterase-4. It also inhibited the release of pro-inflammatory mediators, such as nitric oxide, prostaglandin E2, and tissue necrosis factor (TNF)-alpha from macrophages and TNF-alpha IL-2, IFN-gamma, and IL-4 from human peripheral blood mononuclear cells. However, it was ineffective in the inhibition of cyclooxygenase-1 or -2.6

The anti-inflammatory effects of feverfew may be caused by a cytotoxic effect. Feverfew extracts were found to inhibit mitogen-induced tritiated thymidine uptake by human peripheral blood mononuclear cells, interleukin 2-induced tritiated thymidine uptake by lymphoblasts, and prostaglandin release by interleukin 1-stimulated synovial cells. Parthenolide also blocked tritiated thymidine uptake by mitogen-induced human peripheral blood mononuclear cells.39

In a genomic approach with the use of microarray analysis, approximately 400 genes in human monocytic THP-1 cells were identified that were consistently regulated by feverfew extracts. Of these, 245 were up-regulated genes and 155 were down-regulated with feverfew extracts. Most of the identified genes were involved in cellular metabolism, including regulation of metabolism and alcohol, nucleotide, and lipid metabolism. When tested if feverfew extracts could interfere with cytokine production in THP-1 cells, it was discovered that cells pretreated with feverfew extracts had a reduction in lipopolysaccharide-mediated TNF-alpha release in a dose-dependent fashion.40

Antioxidant effects

Feverfew parthenolide-free extract is suggested to have antioxidant and anti-inflammatory activity. Specifically, its antioxidant effects have been demonstrated through inhibition of smoke and ultraviolet-induced DNA damage, apoptosis, and through scavenging free radicals.67

In vitro data

A parthenolide-depleted formulation of feverfew was assessed for its antioxidant effects on primary normal human keratinocytes and dermal fibroblasts. It possessed more radical scavenging activity against a large range of oxygen-reactive species including oxygen, hydroxyl, peroxynitrate, and ferric radicals compared with ascorbic acid. Specifically, it had a 5-fold greater radical scavenging activity for oxygen and hydroxyl and 3-fold activity for ferric radicals compared with ascorbic acid. In the presence of cigarette smoke, parthenolide-depleted feverfew protected the keratinocyte against the production of cigarette smoke–induced oxygen reactive species.68 Thus, feverfew products, specifically those depleted of parthenolide for the avoidance of skin reactions, may be beneficial for its antioxidant effects.

Chemotherapeutic activity

In vitro data

Parthenolide inhibited the growth of gram-positive bacteria, yeast, and filamentous fungi.5

A hydroalcoholic extract of feverfew inhibited the growth of Leishmania amazonesis at a concentration (IC50) of 29 mcg/mL, while a dichloromethane fraction inhibited growth at an IC50 of 3.6 mcg/mL. Parthenolide has also inhibited Mycobacterium tuberculosis and Mycobacterium avium at a minimum inhibitory concentration of 16 and 64 mcg/mL.51

Research has suggested that malignant stem cells are the source for several types of cancers in humans. These cell types exhibit unique properties that will not allow chemotherapy to be effective. In fact, administration of chemotherapy in the treatment of leukemia not only targets the leukemic stem cells, but also normal stem cells. Parthenolide has been investigated for its use in the treatment of leukemia. Specifically, parthenolide inhibits NF-kappa-B, a nuclear factor that plays a vital role in cell survival, and selectively destroys the leukemic cells to cause apoptosis in primary human acute myeloid leukemia (AML) cells and in blast crisis chronic myeloid leukemia (CML) cells.52, 53 Parthenolide targeted AML progenitor and leukemic stem cells when analyzed using in vitro colony-forming assays in a nonobese diabetic/severe combined immunodeficient xenograft mouse model.54 In addition, another study of cell lines from patients diagnosed with pre-B cell acute lymphoblastic leukemia (ALL) containing the chromosomal translocation t(4;11)(q21;q23) and those without the translocation determined that parthenolide was able to induce apoptosis accompanied by mitochondrial dysfunction. Additionally, those cells with the chromosomal translocation were more sensitive to parthenolide than the cells without this translocation. Parthenolide also enhanced the production of nitric oxide and superoxide anion in all of the ALL cells.55 Thus, parthenolide may be a future treatment option for patients with leukemia to selectively destroy the leukemic stem cells while sparing normal stem cells.

Cystic Fibrosis

In cystic fibrosis, there is an excessive inflammatory response due to the dysregulated production of proinflammatory cytokines including TNF-alpha, IL-1-beta, IL-6, and IL-8. These cytokines are dependent on the transcription factor NF-kappa-B for secretion. Phosphorylation of its inhibitor, I-kappa-B by the enzyme IKK-beta leads to the activation of NF-kappa-B, which ultimately facilitates the transcription of NF-kappa-B-dependent genes. In vitro data suggest that parthenolide inhibits IKK and can directly inactivate NF-kappa-B.66

In vitro data

In an in vitro model, the effects of pretreatment with parthenolide on 2 cell lines with defective and normal cystic fibrosis transmembrane conductance regulator (CFTR) were assessed. Pretreatment with parthenolide inhibited IL-8 production associated with IKK activity inhibition and ultimately inhibition of NF-kappa-B translocation to the nucleus.66

In vivo data

Another study evaluated parthenolide's effects in an in vivo model using CFTR knockout mice. Parthenolide inhibited the degradation of I-kappa-B and NF-kappa-B activation. In addition, parthenolide decreased cytokine production and polymorphonuclear influx into the lung.66

Effects on platelets

In vitro and animal data

Extracts of feverfew inhibit platelet 5-HT secretion via neutralization of sulfhydryl groups inside or outside the cell and prevent prostaglandin synthesis. The sesquiterpenes in feverfew contain the alpha-methylenebutyrolactone unit capable of reacting with sulfhydryl groups. Feverfew extracts are not only potent inhibitors of serotonin release from platelets but also of polymorphonuclear leukocyte granules, providing a possible connection between the claimed benefit of feverfew in migraines and arthritis.5, 12, 30, 36, 46, 47, 48, 49

Effects on vascular smooth muscle

In vitro and animal data

Chloroform leaf extracts of feverfew inhibited the contraction and relaxation of rabbit aorta. The inhibition was concentration- and time-dependent, noncompetitive, and irreversible, occurring with or without the presence of endothelium. The leaf extracts inhibited contractions induced by potassium depolarization much less. Only fresh leaf extracts, as compared with dried powdered leaves (available commercially), inhibited the effects on smooth muscle, which was likely due to a higher concentration of parthenolide. Experiments in rat and rabbit muscle using chloroform extract from fresh leaves suggest feverfew may inhibit smooth muscle spasms by blocking open potassium channels.41, 42, 43

Researchers have demonstrated that parthenolide noncompetitively inhibited serotonin (5-HT)-mediated spasmogenic response of indirect-acting 5-HT agonists in isolated rat stomach fundus preparation. Parthenolide noncompetitively antagonized the contractions elicited by the serotonergic action of fenfluramine and dextroamphetamine on the fundal tissue. The mechanism of action associated with parthenolide does not involve inhibition of 5-HT2 receptors directly, but rather occurs at the level of 5-HT stored in vesicles of the intramural neurons of fundal tissue.44

Rat aortic vascular smooth muscle cells were isolated and treated with varying concentrations of parthenolide (10, 20, and 30 mcmol/L). The treatment with parthenolide inhibited the proliferation of vascular smooth muscle cells via cell cycle arrest at the G0/G1 phase and decreased the cell population at the S phase.45

Inhibition of histamine release

In vitro data

A chloroform extract of feverfew inhibited histamine release from rat peritoneal mast cells in a different manner from established mast cell inhibitors, such as cromoglycate and quercetin. The exact mechanism of action has not been determined but may be mediated by entry of calcium into mast cells.50

Migraine headache, prophylactic treatment

Feverfew action does not appear to be limited to a single mechanism. Plant extracts affect a wide variety of physiologic pathways. Some of these mechanisms have been discussed previously, including inhibition of prostaglandin synthesis, decrease of vascular smooth muscle spasm, and blockage of platelet granule secretion.

Clinical data

A great deal of interest has focused on the activity of feverfew in the treatment and prevention of migraine headaches.69 The first modern, public account of its use as a preventative for migraine appeared in a 1978 article in the British health magazine Prevention about a patient who suffered from severe migraine headaches since 16 years of age. At 68 years of age, she began using 3 leaves of feverfew daily, and after 10 months, her headaches ceased completely.70

A study in 8 patients treated with feverfew and 9 placebo-control patients found that fewer headaches were reported by patients taking feverfew for up to 6 months of treatment. Patients in both groups self-medicated with feverfew for several years before enrolling in the study. The incidence of headaches remained constant in those patients taking feverfew but increased almost 3-fold in patients who switched to placebo during the trial (P < 0.02).71 The abrupt discontinuation of feverfew caused incapacitating headaches in some patients. Nausea and vomiting were reduced in patients taking feverfew, but the statistical analysis has been questioned.72 These results were confirmed in a placebo-controlled study in 72 patients suffering from migraine.73 On the basis of their research, investigators predicted that feverfew may be useful not only for classical migraine and cluster headaches, but also for premenstrual, menstrual, and other headaches.70

Studies at the City of London Migraine Clinic revealed that the experimental observations may not be clinically relevant to migraine patients taking feverfew. Ten patients who had taken extracts of the plant for up to 8 years to control migraine headaches were evaluated for physiologic changes that may have been related to the plant. The platelets of all treated patients aggregated characteristically to ADP and thrombin similarly to those of control patients. However, aggregation in response to serotonin was greatly attenuated in the feverfew users.74

The clinical efficacy and safety of 3 dosage regimens of a carbon dioxide (CO2) feverfew extract, each given 3 times daily, were compared with placebo in a double-blind, multicenter, randomized, controlled trial. One hundred forty-seven patients suffering from migraine with or without aura according to International Headache Society criteria were treated. The primary end point was the total number of migraine attacks during the last 28 days of treatment compared with the 4-week baseline period. Secondary end points were total and average duration, intensity of migraine attacks, and number of days with accompanying migraine symptoms. There were no statistically significant effects for primary or secondary end points. Furthermore, a dose-response relationship was not observed. Subgroup analysis of 49 patients with at least 4 migraine attacks during the baseline period showed a significant effect with the 6.25 mg dose compared with placebo (P = 0.02).75

Following this study, a randomized, double-blind, placebo-controlled, multicenter, parallel-group study assessed the efficacy of the feverfew CO2 extract (MIG-99) in 170 patients (intention-to-treat) suffering from migraine headaches. They were randomized to receive feverfew 6.25 mg 3 times daily or placebo for 16 weeks. Migraine frequency declined from 4.8 attacks to 2.9 attacks (−1.9 ± 0.2) in patients treated with feverfew compared with 3.5 attacks (−1.3 ± 0.2) with placebo at weeks 5 through 12. The number of migraine attacks per 28 days was less in the feverfew group.76

A Cochrane review of evidence from double-blind, randomized, controlled trials was inconclusive in establishing the efficacy of feverfew for preventing migraine headaches. A total of 5 randomized, placebo-controlled, double-blind trials (343 patients) met the inclusion criteria. Results from the meta-analysis reported insufficient evidence to conclude whether feverfew was superior to placebo in reducing the frequency and severity of migraine attacks, incidence and severity of nausea and vomiting, and global assessment of efficacy in patients with migraine headaches. The dosage form varied in the trials, and thus may have impacted the results. Three trials administered dried powdered feverfew leaf extract at 50 to 100 mg/day for 8 to 24 weeks; 1 trial administered an alcoholic feverfew extract 143 mg/day for 8 weeks; 1 trial administered a CO2 extract (2.08 mg vs 6.25 mg vs 18.75 mg 3 times daily for 12 weeks). The 2 studies with the highest methodological quality administered the alcoholic and CO2 extract and reported no benefit, while the studies with lower methodological quality administered the dried powdered leaf extract and reported a favorable response.14

Feverfew has been studied in combination with other products for the treatment of migraine headaches.77, 78, 79 Poor methodology (low number of participants and open-label design) and the use of feverfew with other natural products makes attribution of the study findings to feverfew itself, problematic.

Canada's Health Protection Branch granted a Drug Identification Number for a British feverfew (T. parthenium) product, allowing the manufacturer, Herbal Laboratories, Ltd, to claim that this nonprescription drug prevents migraine headaches. The agency recommends a daily dosage of 125 mg of a dried feverfew leaf preparation from authenticated T. parthenium containing at least parthenolide 0.2% for the prevention of migraine.80

Feverfew may produce an antimigraine effect in a manner similar to methysergide maleate (Sansert), a known 5-HT antagonist.81, 82

Several guidelines have been published discussing the place in therapy for feverfew in the treatment and prevention of migraines.104, 106, 107

The American Academy of Neurology and the American Headache Society Quality Standards Report lists the CO2 feverfew extract as probably effective (level B) for migraine prevention.106

Other pharmacological effects

Monoterpenes in the plant may exert insecticidal activity, and alpha-pinene derivatives may possess sedative and mild tranquilizing effects. Extracts of the plant also inhibit the release of enzymes from white cells found in inflamed joints, and a similar anti-inflammatory effect may occur in the skin, providing a rationale for the traditional use of feverfew in psoriasis.

The effect of feverfew on rheumatoid arthritis has been investigated in a 6-week double-blind, randomized, placebo-controlled trial. Forty-one women with rheumatoid arthritis were randomized to take placebo or feverfew 70 to 86 mg. Of 15 parameters tested, only grip strength improved significantly (P = 0.04) in the feverfew group compared with the placebo group. However, the dose of feverfew in this study may have been too small, and the parthenolide content was not standardized. Human synovial fibroblasts express an intracellular adhesion molecule-1 (ICAM-1) that has been implicated in the pathogenesis of rheumatoid arthritis. Feverfew extracts or purified parthenolide inhibited the increased expression of ICAM-1 on human synovial fibroblasts by cytokines IL-1, TNF-alpha, and interferon-gamma.13, 83, 84

Feverfew-containing products may be beneficial for treating dermatological conditions such as rosacea and atopic dermatitis.85, 86 Specifically, a parthenolide-free extract of feverfew was demonstrated to possess anti-inflammatory and antioxidant effects when used topically. In a 3-week study, 31 women ages 25 to 62 with a history of sensitive skin and/or atopic dermatitis topically applied a facial moisturizer containing parthenolide-free extract feverfew. The product significantly improved erythema, overall irritation, and tactile roughness as noted by the participants and investigators (P < 0.05).85

Feverfew may have a potential role as an antiepileptic agent. Specifically, an ethanolic extract of T. parthenium had high affinity for the gamma-aminobutyric acid (GABA-A)-benzodiazepine site. The flavonoid, apigenin, was isolated which may be responsible for these effects.16

Dosing

Feverfew generally is given for migraine at a daily dose of 50 to 150 mg of dried leaves, 2.5 fresh leaves with or after food, or 5 to 20 drops of a 1:5, 25% ethanol tincture. An optimal dose of feverfew has not been established. An adult dosage for the prevention of migraine headaches should be equivalent to 0.2 to 0.6 mg/day of parentholide; however, this compound has not been confirmed as a major active principle for migraine.83, 87 Patients may prefer to take feverfew with food due to its bitter taste. Beneficial effects may be noted within 4 to 6 weeks after initiation with feverfew. Upon discontinuation of feverfew, the dose should be gradually tapered to avoid the emergence of withdrawal symptoms. Feverfew should be stored in a cool, dry, dark environment to protect the parentholide content.7, 88 Potential variations in parthenolide content of 21 feverfew products were evaluated with a high pressure liquid chromatography (HPLC) system. It was discovered that while the quantity of feverfew found in each capsule was similar to what was stated on the label, the parthenolide content per dosage form varied 150-fold (0.02 to 3 mg). Additionally, the percentage of parthenolide varied 5.3-fold (0.14% to 0.74%). Human consumption of the recommended daily dosage of feverfew would therefore range from 225 to 2,246 mg/day, a 10-fold variation in the quantity, which would amount to 0.06 to 9.7 mg/day of parthenolide, a 160-fold variation.89 Patients should be aware that feverfew-containing products are not strictly regulated by the Food and Drug Administration.

There are no randomized clinical studies in children for the prevention of migraine headaches.90 Children younger than 2 years of age should not be treated with products containing feverfew.9

Pregnancy / Lactation

Avoid use because of documented adverse effects. Feverfew may promote menstruation and induce abortion,91, 92, 93 and has traditionally been used to cause ejection of the placenta and fetal membranes.94 In a rat model, 5 pregnant rats received 839 mg/kg of feverfew daily on either gestational days 1 through 8 or days 8 through 15. Those treated with feverfew on gestational days 8 through 15 produced offspring with lower fetal weights compared with those receiving the ethanol control. This result is likely due to a higher percentage of runts in the feverfew-treated mice.87

Interactions

Agents with antiplatelet properties: Herbs (anticoagulant/antiplatelet properties) may enhance the adverse/toxic effect of agents with antiplatelet properties. Bleeding may occur. Consider therapy modification.95, 96, 97, 98

Anticoagulants: Herbs (anticoagulant/antiplatelet properties) may enhance the adverse/toxic effect of anticoagulants. Bleeding may occur. Consider therapy modification.95, 96, 97, 98

Herbs (anticoagulant/antiplatelet properties): May enhance the adverse/toxic effect of other herbs (anticoagulant/antiplatelet properties). Bleeding may occur. Consider therapy modification.95

Nonsteroidal anti-inflammatory agents: Herbs (anticoagulant/antiplatelet properties) may enhance the adverse/toxic effect of nonsteroidal anti-inflammatory agents. Bleeding may occur. Consider therapy modification.95, 96, 97, 98

Salicylates: Herbs (anticoagulant/antiplatelet properties) may enhance the adverse/toxic effect of salicylates. Bleeding may occur. Consider therapy modification.95, 96, 97, 98

Thrombolytic agents: Herbs (anticoagulant/antiplatelet properties) may enhance the adverse/toxic effect of thrombolytic agents. Bleeding may occur. Consider therapy modification.95, 96, 97, 98

Adverse Reactions

Adverse reactions in patients administered feverfew 50 mg/day (roughly equivalent to 2 leaves) during 6 months of treatment were mild and did not result in discontinuation, with 4 of 8 patients experiencing no adverse effects. Heart rate increased dramatically (by up to 26 beats/min) in 2 patients. Patients who switched to placebo after taking feverfew for several years experienced a cluster of nervous system reactions (eg, fatigue, headaches, insomnia, joint pain, nervousness, poor sleep patterns, stiffness, tension) along with muscle and joint stiffness, often referred to as "postfeverfew syndrome."70, 99

In a larger series of feverfew users, 18% reported adverse effects, the most serious being mouth ulceration (11%). Feverfew can induce widespread inflammation of the oral mucosa and tongue, often with lip swelling and loss of taste. Dermatitis has been associated with this plant, specifically with the handling of fresh leaves. Two case reports describe women who developed dermatitis soon after using a facial moisturizer containing feverfew. The first case involved a 45-year-old woman with an eruption on her scalp and face, including the eyelids and behind the ears. The second patient was a 25-year-old woman with an eruption around the eyes. Upon patch testing, both women tested positive to various allergens including a sesquiterpene lactone mix and the moisturizer, leading to the conclusion that feverfew moisturizer was responsible for their dermatitis.50, 69, 100, 101 Other adverse effects have included nausea, vomiting, abdominal pain, diarrhea, indigestion, and flatulence.7

Toxicology

Because no studies of long-term toxicity have been performed on the plant, the safety of feverfew use has not been established. Pregnant women should not use the plant because the leaves possess potential emmenagogue activity. It is not recommended for breast-feeding women or for children.80

One study evaluated the potential genotoxic effects of long-term feverfew ingestion in 30 migraine sufferers. Analysis of the frequency of chromosomal aberrations and sister chromatid exchanges in circulating lymphocytes from patients who ingested feverfew for 11 months found no unexpected aberrations, suggesting that the plant does not induce chromosomal abnormalities.102

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