Tanacetum (Tanaceti parthenii herba)

Table of contents

Table of contents ................................................................................................................... 2

1. Introduction....................................................................................................................... 4

1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof . 4

1.2. Information about products on the market in the Member States .............................. 8

1.3. Search and assessment methodology.................................................................... 9

2. Historical data on medicinal use ...................................................................................... 10

2.1. Information on period of medicinal use in the Community ...................................... 1 1

2.2. Information on traditional/current indications and specified substances/preparations .1 3

2.3. Specified strength/posology/route of administration/duration of use for relevant

preparations and indications..................................................................................... 1 3

3. Non-Clinical Data ............................................................................................................. 14

3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal

preparation(s) and relevant constituents thereof ......................................................... 1 4

3.1.1. Studies on parthenolide.................................................................................. 1 5

3.1.1.1. Antitumoral activity..................................................................................... 1 5

3.1.1.2. Anti-inflammatory activity............................................................................ 1 7

3.1.1.3. Antimicrobial activity................................................................................... 1 8

3.1.1.4. Antioxidant activity ..................................................................................... 1 8

3.1.1.5. Effects on smooth muscle contractility ........................................................... 1 8

3.1.1.6. Antimigraine effects .................................................................................... 1 8

3.1.2. Studies on extracts........................................................................................ 1 9

3.1.2.1. Antimicrobial activity................................................................................... 1 9

3.1.2.2. Anti-inflammatory, analgesic and antipyretic activities ..................................... 1 9

3.1.2.3. Effects on vessels and smooth muscle cells..................................................... 2 1

3.1.2.4. Antithrombotic activity ................................................................................ 2 2

3.1.2.5. Antioxidant activity ..................................................................................... 2 3

3.1.2.6. Antimigraine effects .................................................................................... 2 3

3.1.3. Studies on the essential oil ............................................................................. 2 4

3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal

preparation(s) and relevant constituents thereof ......................................................... 2 4

3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal

preparation(s) and constituents thereof ..................................................................... 2 4

3.4. Overall conclusions on non-clinical data............................................................... 2 4

4. Clinical Data ..................................................................................................................... 25

4.1. Clinical pharmacology ....................................................................................... 2 5

4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s)

including data on relevant constituents ...................................................................... 2 7

4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s)

including data on relevant constituents ...................................................................... 2 7

4.2. Clinical Efficacy ................................................................................................ 2 7

4.2.1. Dose response studies.................................................................................... 2 7

4.2.2. Clinical studies (case studies and clinical trials).................................................. 2 8

4.2.3. Clinical studies in special populations (e.g. elderly and children)........................... 3 6

4.3. Overall conclusions on clinical pharmacology and efficacy ...................................... 3 6

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5. Clinical Safety/Pharmacovigilance................................................................................... 36

5.1. Overview of toxicological/safety data from clinical trials in humans.......................... 3 6

5.2. Patient exposure .............................................................................................. 3 7

5.3. Adverse events and serious adverse events and deaths ......................................... 3 8

5.4. Laboratory findings .......................................................................................... 3 9

5.5. Safety in special populations and situations ......................................................... 3 9

5.6. Overall conclusions on clinical safety ................................................................... 3 9

6. Overall conclusions .......................................................................................................... 40

Annex .................................................................................................................................. 40

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1. Introduction

1.1. Description of the herbal substance(s), herbal preparation(s) or

combinations thereof

 Herbal substance(s)

Tanacetum parthenium herba consists of the dried, whole or fragmented aerial parts of Tanacetum

parthenium (L.) Schultz Bip. It contains no less than 0.20% of parthenolide (C 15 H 20 O 3 ; Mr 248.3),

calculated with reference to the dried drug. It has a camphoraceous odour (Ph. Eur. 6 th edition 2008).

The genus Tanacetum includes about 50 species, of those only T. santolinoides (D.C.) grows in Egypt

(El- Shazly et al. 2002).

T. parthenium (L.) Schulz Bip., also known as feverfew, is a member of the Compositae family

( Asteraceae ). It is an aromatic, hardy annual herb with chrysanthemum-like leaves and daisylike

flowers that grows prolifically in gardens and other open spaces. It is indigenous to South-East Europe,

as far East as the Caucasus, but commonly found throughout Europe and the United States of America

(WHO monograph 2004).

The leafy, more or less branched stem has a diameter of up to 5 mm. It is almost quadrangular,

longitudinally channelled, and slightly pubescent. The leaves are ovate, 2 to 5 cm long, sometimes up

to 10 cm, yellowish-green, petiolate and alternate. They are pinnate or bipinnate, deeply divided into

five to nine segments, each with a coarsely crenate margin and an obtuse apex. When present, the

flowering heads are 12 to 22 mm in diameter with long pedicels (Ph. Eur. 6 th edition 2008).

Beneficial properties have been associated with consumption of the leaves or aerial parts.

Overview on main active compounds and common qualitative/quantitative characterisation

Sesquiterpenes

The most significant components present in feverfew leaves are a complex series of sesquiterpene α-

methylenebutyrolactones which are stored in the glandular trichomes on leaves, flowers and seeds.

Some of the detected sesquiterpene lactones are known to have biological actions such as cytotoxicity,

growth regulation and antimicrobial effects and they cause allergic contact dermatitis. An exocyclic α-

methylene function of the sesquiterpene lactones, which may react with sulphydryl groups of proteins,

seems to be responsible for these activities (Milbrodt et al. 1997). The predominant sesquiterpene

lactone present in feverfew is a germacranolide, parthenolide (PN), which has been indirectly linked

to the anti-migraine action of feverfew preparations (Figure 1). This compound appears to have been

first isolated from T. parthenium . Later, the same compound, initially named champakin, was also

isolated from the roots of Michelia champaca . It has been supposed that PN is produced by feverfew as

a defensive compound. This compound is located in glands on the underside of the leaves in growing

plants, in which position it can express its antimicrobial properties. PN contains a highly electrophilic α-

methylene-γ-lactone ring and an epoxide residue capable of interacting rapidly with nucleophilic sites

of biological molecules. More recent studies have revealed that it also has anti-microbial, anti-

inflammatory and anticancer activities, which may depend on a wide range of PN-stimulated

intracellular signals (Won et al. 2004; Pajak et al. 2008).

Feverfew leaf from parthenolide-free sesquiterpene lactone chemotypes has never been clinically

tested for effectiveness in migraine prophylaxis (Dennis & Awang 1998). Levels of PN in the dried

leaves can be as high as 1%. The remaining sesquiterpene lactones are generally present in much

smaller quantities, typically <1 mg/kg. During the growth of T. parthenium the percentage of PN is the

highest at an early stage (just before the formation of stems). The yield of PN in the plant gradually

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increases until the plant is in full bloom. However, PN is present in the leaves and flower heads, but

not in the stems.

Drying at ambient temperature and lyophilisation seems to have no negative influence on the yield of

PN.

Figure 1. Chemical structure of parthenolide (from WHO monograph).

Since the PN content greatly varies depending on the part used and the season, it has been proposed

to distinguish two qualities of feverfew: A) Tanaceti parthenii folium (feverfew leaf), harvested at an

early stage before the formation of the stems and B) Tanaceti parthenii herba (feverfew herb),

harvested at full bloom, with a minimum PN content of 0.50% and 0.20% respectively, calculated on a

dry weight basis (Hendriks et al. 1997).

The aerial parts of feverfew contain a rich mixture of mono- and sesquiterpenes compounds.

Sesquiterpenes contained in the aerial parts are germacrene D, β-farnesene and camphor (the most

abundant monoterpene in feverfew). In the roots, β-farnesene and bicyclogermacrene are present. The

aerial parts contain also smaller amounts (<10 mg kg -1 ) of chrysanthenyl acetate, the epimeric cis-

chrysanthenol (plus the derived acetic, angelic and isovaleric esters), the isomeric cis-verbenol (an

oxidized relative), 4,β-acetoxy-chrysanthenone, bornyl acetate and the corresponding angelate ester.

Non-terpenoid spiroketal enol ethers are other substances that are present in small quantities in the

aerial parts (Knight 1995).

The presence of different sesquiterpene lactones depends on the habitat of the plant (Milbrodt et al.

1997).

Parthenolide metabolites

Other reported germacranolides are PN metabolites: 3β-hydroxyparthenolide, costunolide (common

component of the Compositae), 3β-hydroxycostunolide, artemorin and 3β-hydroxyanhydroverlotorin.

They are probably formed by epoxidation and/or allylic oxidation of PN. Related epoxides are

represented by epoxyartemorin and anhydroverlolorin-4α,5β-epoxide. Costic acid methyl ester and

reynosin have also been found in small quantities. Some sesquiterpenes belong to the biosynthetically

closely related guaianolide family: 8α-hydroxyestafìatin, with the corresponding isobutyl and angeloyl

esters.

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Other compounds

The roots of T. parthenium contain the coumarinic compound isofraxidin (Kisiel & Stojakowska 1997).

Melatonin was identified in four samples from feverfew leaves and a commercial preparation was

tested by Murch. The authors of the study suggested that melatonin in plant tissues may explain the

antimigraine effects of feverfew (Murch et al. 1997).

Lipophilic flavonoids in the leaf and flower of T. parthenium were identified as methyl ethers of the

flavonols 6-hydroxykaempferol and quercetagetin. A number of other flavones such as apigenin,

luteolin and chrysoeriol and their glucuronides, and glycosides such as apigenin 7-glucuronide, luteolin

7-glucuronide, luteolin 7-glucoside and chrysoeriol 7-glucuronide in feverfew extracts have been found.

Apigenin and two flavone glucuronides are present in glandular trichomes on the lower epidermis of

the flowers. The vacuolar flavonoids are dominated by the presence of apigenin and luteolin 7-

glucuronides. Other substances found are tanetin (previously thought to be a new structure and now

formulated as the known 6-hydroxykaempferol 3,6,4 '-trimethyl ether (Williams 1995)) and the other

three flavonol methyl esters as respective 6-O-methyl ethers instead of 7-O-methyl ethers (Williams

1999) and two closely related flavonols, jaceidin and centaureidin (Long et al. 2003). The major

flavonol and flavone methyl ethers inhibit the major pathways (cyclo-oxygenase and 5-lipoxygenase)

of arachidonate metabolism in leukocytes (Williams et al. 1999).

Moreover, antioxidant polyphenolic acids were isolated and characterised as 3.5-, 4.5- and 3.4-di-O-

caffeoylquinic acids ( Wu et al. 2007).

Feverfew oil

The analysis of feverfew oil showed the presence of many monoterpenes as α-pinene, camphene, β-

pinene, sabinene, myrcene, α-fellandrene, α-terpinene, p-cymene, γ-terpinene, terpinolene, terpinen-

4-ol and α-terpineol. Among them, the oxidized monoterpenes are very well represented especially

camphor, trans-chrysanthenyl acetate, linalool, linalyl acetate and bornyl acetate. The essential oil is

mostly composed of camphor and trans-chrysanthenyl acetate amounting up to 70% of the whole oil

content. These are the main components of the oil. Among other monoterpenic components, there is a

greater amount of p-cymene (4.77%), linalool (2.28%) and camphene (1.96%). Sesquiterpenic

lactones are not qualitatively or quantitatively present as monoterpenes. Among the sesquiterpenic

compounds there are: β-caryophyllene (1.96%), trans-β-farnesene, germacrene (1.49%) and δ-

cadinene. The phenyl propanic compound eugenol is also present (1.09%) (Kalodera et al. 1997).

 Herbal preparation(s)

The powdered herbal substance is yellowish-green and is widely used (Ph. Eur. 6 th edition 2008).

Herbalists and naturopathic doctors in the UK favoured the use of the tincture and extracts of feverfew.

Feverfew extract with a standardized PN content of at least 250 micrograms per daily dose has been

recommended for the treatment and prevention of migraine.

Researchers also paid attention to the other chemical components of feverfew leaf as possible

responsible agents for feverfew’s anti-migraine effect. Dutch researchers of feverfew leaf extract,

evidently focusing on its essential oil, suggested that the content of trans-chrysanthenyl acetate might

be significant (De Weerdt 1996; Hendricks 1996). This constituent declines markedly during the

extraction process from 0.25% to just 0.017%; the relevance of this difference has not been

determined. Trans-chrysanthenyl acetate and camphor, in contrast, are monoterpenes that are

regarded as characteristic constituents of T. parthenium , whose content in the essential oil has not

shown to vary significantly.

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PN was found to be the main constituent of the biologically active sesquiterpene lactones in ethanol

and aqueous extracts of feverfew. The sesquiterpene lactone content of ethanol extracts (ca. 0.5%)

were higher than those of the aqueous ones (ca. 0.3%) (Gromek et al. 1991).

Commercial preparations of feverfew leaves are known to vary widely in the PN content, as shown by

various authors. Feverfew products from the European markets have been simultaneously analysed by

HPLC, NMR and biological methods and all were consistent in showing a high variability of the PN

content (Heptinstall et al. 1992). Mean PN levels of commercial preparations of feverfew leaves

exhibited a range from non-detectable to 1.68% ± 0.97 (per dry weight) based on HPLC-UV-MS

(Cutlan et al. 2000).

Nelson et al. (2002) studied the PN content in capsules containing 25 to 500 mg of feverfew leaf,

available to consumers, by means of HPLC. The quantity of feverfew leaf in each capsule was similar to

that declared on the label. However, the PN content per dosage form varied 150-fold (from 0.02 to 3.0

mg), while percentage of PN varied 5.3-fold (from 0.14% to 0.74%). Therefore, if a person consumes

the daily dose recommended on the label, the intake of dried feverfew leaf would range from 225 to

2246 mg/day, a 10-fold variation, while intake of PN would range from 0.06 to 9.7 mg/day, a 160-fold

variation.

Taking into consideration the large variations observed in the PN contents and daily intake as

recommended by labelling in commercial feverfew products, as well as that therapeutic efficacy has

only been shown for preparations of feverfew that contain PN, it is suggested that manufacturers of

feverfew products should use measurements of PN for standardization and quality control (Heptinstall

et al. 1992). Among the proposed references for establishing quality control of feverfew preparations,

a minimum level of 0.2% PN in dried leaves was adopted by the Ph. Eur. and the French Ministry of

Health.

Possible differences in physico-chemical properties of extracts from different sources were investigated

in the USA on selected formulations of several commercial feverfew extracts. Flowability,

hygroscopicity, compressibility and compactibility were studied in order to develop and validate a

suitable extraction method. HPLC was used to determine the PN content of several commercial

feverfew extracts. The results of the investigation showed that the extracts exhibited poor to very poor

flowability. Hygroscopicity and compactibility varied greatly with the source. Moreover, no extracts

contained the PN content labelled. Even different batches from the same manufacturer showed a

significantly different PN content (Jin et al. 2007).

Another investigation was conducted by the same group of researchers with the aim to evaluate the

stability of PN in feverfew solutions versus powdered feverfew (solid state). They further explored the

compatibility between commonly used excipients and PN in feverfew. Feverfew extract solution was

diluted with different pH buffers to study the solution stability of PN.

Powdered feverfew extract was stored at 40°C/0% to 75% relative humidities (RH) or 31% RH/5 to

50°C to study the influence of temperature and relative humidity on the stability of PN in feverfew solid

state. In addition, binary mixtures of feverfew powered extract and different excipients were stored at

50°C/75% RH for excipient compatibility evaluation.

The degradation of PN in feverfew solution appeared to fit a typical first-order reaction. PN is

comparatively stable when the environmental pH is in the range of 5 to 7, but becomes unstable when

pH is less than 3 or more than 7.

PN degradation in feverfew in the solid state does not fit any obvious reaction model. Both moisture

content and temperature play important roles affecting the degradation rate. After 6 months of

storage, PN in feverfew remains constant at 5°C/31% RH. However, ~40% PN in feverfew can be

degraded if stored at 50°C/31% RH. When the moisture changed from 0% to 75% RH, the degradation

of PN in feverfew increased from 18% to 32% after 6-month storage at 40°C. The authors concluded

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that PN in feverfew exhibits good compatibility with commonly used excipients under stressed

conditions in a 3-week screening study (Jin et al. 2007). Since the active constituents are unknown, it

is recommended that preparations containing the whole leaf (dried or fresh) should be used. Since the

PN stability can vary with storage conditions, feverfew should be stored in a cool, dry environment and

in a well-closed container, protected from light and humidity (Heptinstall et al. 1992).

 Combinations of herbal substance(s) and/or herbal preparation(s) including a description of

vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products

assessed, where applicable.

Combination products have been designed and their effects on migraine prophylaxis studied.

A study with a daily dose of riboflavin 400 mg, magnesium 300 mg and feverfew 100 mg was

conducted. Authors concluded that no significant positive effects were observed (Maizels et al. 2004).

1.2. Information about products on the market in the Member States

Regulatory status overview

Member State

Regulatory Status

Comments (not

mandatory field)

Austria

MA

TRAD

Other TRAD

Other Specify: No licensed HMPs

Belgium

MA

TRAD

Other TRAD

Other Specify: Food supplements

(multicomponent herbal

tea)

Bulgaria

MA

TRAD

Other TRAD

Other Specify:

Cyprus

MA

TRAD

Other TRAD

Other Specify:

Czech Republic

MA

TRAD

Other TRAD

Other Specify: No licensed HMPs

Denmark

MA

TRAD

Other TRAD

Other Specify: Single preparations and

combination authorised

in the past. MAs

withdrawn by the

Companies.

Estonia

MA

TRAD

Other TRAD

Other Specify: No licensed HMPs

Finland

MA

TRAD

Other TRAD

Other Specify: No licensed HMPs

France

MA

TRAD

Other TRAD

Other Specify: Single preparations and

fixed combination

Germany

MA

TRAD

Other TRAD

Other Specify: No licensed HMPs

Greece

MA

TRAD

Other TRAD

Other Specify:

Hungary

MA

TRAD

Other TRAD

Other Specify: A single preparation on

the market from1993 to

2005

Iceland

MA

TRAD

Other TRAD

Other Specify:

Ireland

MA

TRAD

Other TRAD

Other Specify:

Italy

MA

TRAD

Other TRAD

Other Specify: Food supplements

Latvia

MA

TRAD

Other TRAD

Other Specify: Food supplements

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Member State

Regulatory Status

Comments (not

mandatory field)

Liechtenstein

MA

TRAD

Other TRAD

Other Specify:

Lithuania

MA

TRAD

Other TRAD

Other Specify: Food supplement

(capsules containing

Tanaceti herba, Vitis

vinifera et Zingiberis

officinale extract)

Luxemburg

MA

TRAD

Other TRAD

Other Specify:

Malta

MA

TRAD

Other TRAD

Other Specify:

The Netherlands

MA

TRAD

Other TRAD

Other Specify: No licensed HMPs

Norway

MA

TRAD

Other TRAD

Other Specify:

Poland

MA

TRAD

Other TRAD

Other Specify: No products available on

the market

Portugal

MA

TRAD

Other TRAD

Other Specify: No licensed HMPs

Romania

MA

TRAD

Other TRAD

Other Specify:

Slovak Republic

MA

TRAD

Other TRAD

Other Specify: No licensed HMPs

Slovenia

MA

TRAD

Other TRAD

Other Specify: No licensed HMPs

Spain

MA

TRAD

Other TRAD

Other Specify: Single preparation and

fixed combinations

Sweden

MA

TRAD

Other TRAD

Other Specify: No licensed HMPs

United Kingdom

MA

TRAD

Other TRAD

Other Specify: Feverfew products are

currently available for

the following indication:

“A traditional herbal

medicinal product for the

prevention of migraine

headaches based on

traditional use only”. The

hard capsules contain as

active ingredient

powdered feverfew.

MA: Marketing Authorisation

TRAD: Traditional Use Registration

Other TRAD: Other national Traditional systems of registration

Other: If known, it should be specified or otherwise add ’Not Known’

This regulatory overview is not legally binding and does not necessarily reflect the legal status of the

products in the MSs concerned.

1.3. Search and assessment methodology

This assessment report reviews the scientific literature data available for T. parthenium and from the

WHO monograph, European Pharmacopoeia monograph, PubMed, EMA library, internet as well as

available information on products marketed in the European Community, including pharmaceutical

forms, indications, posology and methods of administration.

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The keywords “ Tanacetum parthenium ”, “Tanaceti herba”, “ Chrysanthemum parthenium”, “feverfew”,

“parthenolide” in all text fields were used.

Clinical studies conducted on the effects of parthenolide or other single active principles were excluded.

2. Historical data on medicinal use

Feverfew has been described since ancient times as having beneficial medicinal effects and has been

recommended for centuries for its medicinal properties.

The herb has also been known under other names such as Matricaria parthenium (L.), Leucanthenum

parthenium (L.) Gren. and Gordon, Pyrethrum parthenium (L.), Chrysanthemum parthenium (L.).

The origin of the term parthenium is not certain. According to the ancient Greek author Plutarch,

following an incident occurred in the 5 th century, feverfew was used to save the life of a person fallen

from the Parthenon during its construction. Another explanation is based on the Greek word parthenios

meaning 'virgin', probably because of the reputation of the herb as an antidote for women's ailments

(Groenewegen et al. 1992).

Feverfew is derived from the Old English name 'febrifuge' from the Latin 'febrifugia', pointing to one of

its benefits in reducing fever. In some other European countries this herb is referred to as

'motherherb" for example, 'Mutterkraut' in Germany, indicating its acclaimed beneficial properties in

various women's conditions. Other names for feverfew include featherfoil, flirtwort and bachelor's

buttons.

The use of feverfew as a medicinal plant can be traced back to the Greek herbal 'Materia Medica' by

Dioscorides and was successively described by Dodoens in 1619, by Gerard in 1636 and Culpeper in

1650.

It has been used for 'intermittent fevers' and for a variety of other conditions and disorders including

toothache, rheumatism, psoriasis, insect bites, asthma, stomach ache, menstrual problems and

treatment of miscarriage. During the 17 th century, it was also used for aiding the ejection of after

births and still births, cleansing the kidneys and bladder, strengthening the womb as well as for the

treatment of vertigo, spots, wind, colic, and for the treatment of disturbances due to the excessive use

of opium. Other uses recommended in the ancient times were the alleviation of St. Antoine’s fire,

inflammatory processes and hot swellings (Knight 1995).

Ancient uses of feverfew may be categorized broadly into three main groups:

1. treatment for fever, headache and migraine;

2. women's conditions such as difficulties in labour, threatened miscarriage, and regulation of

menstruation;

3. relief of stomach ache, toothache and insect bites (Groenewegen et al. 1992).

Bibliographic evidence for a traditional use of feverfew for migraines and headaches are partially

traceable in monographs and old texts on herbals (Table 1).

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Table 1. Monographs on feverfew

Source Indications

Dose

Dried herb

equivalent/day

BHP

1990

Migraine prophylaxis

n/s

-

BHP

1996

Migraine prophylaxis

n/s

-

Barnes

et al.

2007

Traditional uses

migraine

vertigo

tinnitus

arthritis

fever

menstrual disorders

difficulty during labour

stomach ache

toothache

insect bite

- Leaf (fresh) 2.5 leaves

daily

- Leaf (freeze-dried)

50 mg daily

- Aerial parts (dried) 50–

200 mg daily equivalent

to 0.2-0.6 mg

parthenolide daily

- ≈125 mg*

- 50 mg

- 50–200 mg

Modern uses

prevention and treatment of

migraine

ESCOP

2003

Prophylaxis of migraine

Adult daily dose: 50–120

mg of powdered feverfew

50–120 mg

BHP= British Herbal Pharmacopoeia

ESCOP= European Scientific Cooperative on Phytotherapy

n/s = not stated

The uterine stimulant effect may explain the folk uses of the plant as abortifacient, emmenagogue and

in certain labour difficulties but conflicts with the folk use of the drug in threatened miscarriage (Rateb

et al. 2007). This contradictory information supports the common warning of the producers avoiding

use of feverfew during pregnancy.

2.1. Information on period of medicinal use in the Community

T. parthenium has a long history of usage in Europe to prevent headache and migraine, for relief in

arthritis and for treatment of psoriasis. In recent years, it has become popular also in the United States

of America.

Because of all its folk fields of application, feverfew has been long referred to as a ‘medieval aspirin'.

In 1772 John Hill claimed that 'in the worst headache this herb exceeds whatever else is known'

(Heptinstall 1988).

Today's use started in late 1970s when the British press reported that a group of migraine sufferers

from Wales had found relief from attacks after taking the leaves of the plant for some time. Studies

carried out reported that patients were successfully using the herb in the prophylaxis of both migraine

and arthritis (Knight 1995). Thus the interest in feverfew grew quickly, bringing it back into the

limelight from obscurity since the Middle Ages. A number of investigations have now been carried out

on the plant's in vitro biological actions and the chemical components responsible for these actions.

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Following the success of feverfew in migraine, the herb was also tried in many other conditions and it

has now been claimed (but not scientifically proven) to be effective in arthritis, psoriasis and stress,

among others (Groenewegen et al. 1992).

Feverfew products have been widely available in the UK as herbal remedies exempt from licensing

under section 12 (2) of Medicines Act 1968. Since April 2007 hard capsules containing 100 mg of

powdered feverfew herb have been registered according the new traditional herbal medicinal products

registration scheme according to art. 16c of the directive 2001/83/EC as amended.

Feverfew products are currently available in the UK as herbal remedies for oral use for the following

indication: “A traditional herbal medicinal product for the prevention of migraine headaches based on

traditional use only”. They can be bought without prescription from pharmacies and other outlets. The

hard capsules contain as active ingredient powdered feverfew.

Between the early 1970’s and 1988, feverfew products held product licenses in the UK. This

information was obtained from the MHRA under a Freedom of Information Act enquiry. Information on

indication and posology was not available as these details for “product licenses of right” are not held on

the MHRA electronic database (Table 2).

Table 2. Licensed feverfew HMPs since the early 1970s in the UK (data from MHRA).

Licence no.

Product name

Date granted

Date cancelled

PLR 00250/5674

Liquid Extract Feverfew

Herb

Assumed to be the

early 1970’s

13/02/1977

PLR 00250/5843

Tincture Feverfew

Assumed to be the

early 1970’s

27/05/1975

PLR 0076/5631

Feverfew Liquid Extract

Assumed to be the

early 1970’s

28/10/1976

PLR 01252/5448

Chrysanth. Parthen.

Liquid Extract

Assumed to be the

early 1970’s

11/05/1979

PLR 02167/5183

Feverfew Extract

Assumed to be the

early 1970’s

17/07/1979

In Spain, the powdered herbal substance is registered as a traditional herbal medicinal product since

1991, in form of capsules both as a single preparation and in fixed combinations containing 200 mg of

T. parthenium and 100 mg of Anthemis nobilis or 150 mg of T. parthenium and 150 mg of Artemisia .

In France, the powdered herbal substance has been authorised as a traditional medicinal product since

1991, the dry extract (solvent: ethanol 30% V/V, DER 4.5-5.5:1) since 1994 and the comminuted

herbal substance was authorised from 1996 to 2000.

In Denmark, medicinal products containing Tanaceti extracts (0.1-0.2 mg) quantified to PN (0.1-0.2

mg) in form of tablets were on the market from 1990 to 2004.

An extract corresponding to 0.1 mg of partenolide had been authorised as a medicinal product from

1993 to 2002 and an extract containing 0.2 mg of PN had been authorised from 1997 to 2004. As a

fixed combination with Achillea millefolium herba and Populus tremula, the extract corresponding to 1

mg of PN had been authorised from 1993 to 2000. No further information on the type of the above

mentioned extracts is available. All these products were withdrawn by the Companies and no

information about their possible presence on the EU market as food supplements is available.

In Hungary capsules containing 50 mg of feverfew herb (Chrysanthemi parthenii herba) quantified to

0.4% parthenolid content were on the market from 1993 to 2005.

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Food supplements are on the market in Italy, Latvia and Lithuania. In Belgium, an herbal tea

containing 11 herbal components is on the market as a food supplement; however that will have to

undergo a revision phase according to the new directive 2004/24/EC on THMPs.

In the light of the above evidences, it can be concluded that feverfew herbal medicinal products for

migraines have been available for more than 30 years in the European Union and the medicinal use of

feverfew for migraine and headaches in Europe is documented since centuries.

2.2. Information on traditional/current indications and specified

substances/preparations

The powdered herbal substance is registered in the UK as “a traditional herbal medicinal product used

for the prevention of migraine headaches based on traditional use only” (ATC code N02CX), in Spain as

“a traditional herbal medicinal products used in case of headache”. In France single preparations

containing the comminuted or powdered herbal substance or the dry extract (ethanol 30% V/V, DER

4.5-5.5:1) are authorised as medicinal products traditionally used in the prevention of headaches. A

fixed combination with Artemisia vulgaris was authorised from 1995 to 2007 as a medicinal product

traditionally used in painful periods.

In Hungary, capsules containing feverfew herb are used to reduce the frequency of migraine

headaches, to relieve the associated symptoms (pain, nausea, vomiting and vision disturbances) and

to relief of headaches occurring prior or during menstruation.

In Denmark, the extract corresponding to 0.1 mg or 0.2 mg PN were authorised as an herbal

medicinal product for the prevention of milder forms of migraine, when a doctor has excluded other

reasons for the condition (ATC code N02CX). The fixed combination of the Tanaceti extract containing

0.1 mg PN plus Achilleae millefolii herba and Populus tremula (Gitadyl) was authorised as a non-

steroidal anti-inflammatory drug (ATC code M01A).

Feverfew is used mainly for migraine, arthritis, rheumatic diseases and allergies. It has also been used

in the treatment of tinnitus, vertigo, fever, difficult labour, toothache, insect bites and asthma.

In folk medicine, feverfew has been used for cramps, as a tonic, a stimulant, a digestive substance,

blood detoxicant, migraine prophylaxis, intestinal parasites and gynecological disorder. The herb is also

used as a wash for inflammation and wounds, as a tranquilizer, an antiseptic and as a mouthwash

following tooth extraction. It is used externally as an antiseptic and insecticide.

The herbal infusion has been used for dysmenorrhea. In postpartum care, it has been used to reduce

bleeding (lochia) (PDR monographs 2007).

2.3. Specified strength/posology/route of administration/duration of use

for relevant preparations and indications

Feverfew has been administered in a variety of ways, both for internal and external use.

It has been used as a dried powder taken with honey (presumably because of its bitter taste), or as a

bath using decoction made with wine (for the women's conditions) or as syrup. In most cases, it was

advised to use the leaves, but for some conditions it was suggested to use the flowers (Groenewegen

et al. 1992).

Feverfew is supplied as whole or fragmented herbal substance for decoction or infusion or powdered or

as extracts in capsules, tablets, tinctures and drops.

Herbal tea as an infusion: 2 teaspoons of the herbal substance per cup, brew for 15 minutes. Three

cups to be taken daily for dysmenorrhea (PDR monograph 2007).

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A stronger infusion, made with doubled amount and allowed to steep for 25 minutes, is used for

washes (PDR monograph 2007).

It is commonly taken orally in tablets or capsules, often with food to disguise its bitter taste. The

stated amounts of feverfew per tablet or capsule for different products generally vary from 25 to 250

mg (Heptinstall 1988).

The daily dose of feverfew has not been clearly defined yet. Jin et al. (2007) suggests a daily dose of

50-250 mg feverfew dried leaf containing at least 0.2% PN and not exceeding the equivalent of 4 mg

PN daily.

For the treatment of migraine, 200 to 250 mg daily (standardized on 0.2% PN content) is used or

25 mg of freshly dried powdered feverfew extract that corresponds to 0.1 mg of sesquiterpene

lactones (PDR monograph 2007). Positive effects were recorded in a few clinical studies with the

posology of about 100 mg daily of feverfew extract.

The powdered herbal substance for oral use is administered in form of capsules. The recommended

dosage in the UK is 1 capsule containing 100 mg to be taken once daily for three months, in Hungary

two capsules containing 50 mg 2 times daily for two months, in France 1 capsule containing 260 mg 3

times daily and in Spain 1 or 2 capsules containing 200 mg/capsule up to 3 times daily.

The comminuted herbal substance had been used in form of herbal tea; in France the posology was 1

to 2 sachets daily (1 sachet containing 1.35 g).

The dry extract (ethanol 30% V/V, DER 4.5-5.5:1) is administered in capsules containing 200

mg/caps, 1 to 2 daily (FR).

An extract corresponding to 0.1 mg PN was orally used in Denmark in tablets, 2-3 times daily together

with the meals. Another extract corresponding to 0.2 mg PN was administered in tablets for oral use

1-2 times daily together with the meals (DK).

The recommended dosage for the fresh material varies from 1 to 3 leaves (25 to 75 mg) once or twice

daily (Heptinstall 1988).

Feverfew leaves are used mainly in the prophylaxis both of migraine and arthritis but sometimes in

single high doses to control the migraine attacks. The estimated period of use as a prophylactic agent

varies from instant relief to over a period of months in case of migraine. An average of 7 days is

claimed for the relief of arthritis pain and an average of 14 to 28 days to reduce the inflammation and

improve the mobility (Groenewegen et al. 1992).

3. Non-Clinical Data

3.1. Overview of available pharmacological data regarding the herbal

substance(s), herbal preparation(s) and relevant constituents thereof

Feverfew has been largely investigated for its traditional uses in medicine such as treatment of fever,

headache, migraine, stomach ache, insect bites, bronchitis, arthritis, cold, as an abortifacient, and for

alleviating menstrual cramps (Rateb et al. 2007).

The main active constituent in feverfew is the sesquiterpene lactone PN that contains a highly

electrophilic α-methylene-γ-lactone ring and an epoxide, which are able to readily interact with

nucleophilic sites of biological molecules (Won et al. 2004).

PN inhibits platelet aggregation and serotonin release from platelets granules and it is a well

documented inhibitor of the transcription factor NF-κB. The inhibition of NF-κB in cancer cells has

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become one of the major strategies in anticancer therapy. According to numerous data, PN is also the

inhibitor of IκB kinases complex (IKC), with the sustained cytoplasmic retention of NF-κB (Zhang et al.

2009).

Pharmacodynamics

This section is constituted of three separate paragraphs on studies describing effects of PN, extracts

and essential oil activity.

3.1.1. Studies on parthenolide

Studies on PN have shown that this compound possesses several biological properties such as

antitumoral, anti-microbial and anti-inflammatory activities. PN exerts effects also on smooth

contractile activity and it has been also studied for its antimigraine properties.

3.1.1.1. Antitumoral activity

PN has been shown to withdraw cells from cell cycle or to promote cell differentiation and finally to

induce programmed cell death. Recent advances in molecular biology indicate that this sesquiterpene

lactone might evoke the above-mentioned effects by indirect action on genes. In particular, it has been

shown that PN inhibits NF-κB- and STATs-mediated anti-apoptotic gene transcription. The pro-

apoptotic activity of PN seems to be associated with stimulation of the intrinsic apoptotic pathway with

the higher level of intracellular ROS (reactive oxygen substances) and modifications of Bcl-2 family

proteins (conformational changes of Bak and Bax, Bid cleavage). On the other hand, PN also amplifies

the apoptotic signal through the sensitization of cancer cells to extrinsic apoptosis, induced by TNF-α.

These properties suggest that PN could be further studied as a promising metabolic inhibitor to retard

tumorigenesis and to suppress tumor growth (Pajak et al. 2008).

Glioblastomas are difficult to treat and frequently aggressive and fatal. Treatment of glioblastoma cells

with PN resulted in rapid apoptosis through caspase 3/7 without a suppression of NF-κB activity. On

the basis of these results and due to its apparent potential for crossing the blood brain barrier for the

treatment of migraines, it has been suggested that PN or its derivatives may represent a new class of

compounds that will be useful in the treatment of brain tumors (Anderson & Bejcek 2008).

PN inhibits cell growth irreversibly at concentrations above 5.0 µM and an exposure time of 24 h. At

lower concentrations the effect is reversible; PN acted as a cytostatic over multiple cell generations for

mouse fibrosarcoma (MN-ll) and human lymphoma (TK6) cell lines (Ross et al. 1999).

Transcription factors such as NF-κB provide powerful targets for drugs to use in the treatment of

cancer. PN, inhibitor of NF-κB activity, markedly increases the degree of human leukaemia HL-60 cell

differentiation into monocytes via the inhibition of NF-κB activity and evidence has been provided that

inhibition of NF-κB activation can be a pre-requisite to the efficient entry of promyelocytic leukaemia

cells into a differentiation pathway (Kang et al. 2002).

The anticancer property of PN was tested in an UVB-induced mouse skin cancer model. The authors

examined the cancer chemopreventive property of PN using a combination of in vivo and in vitro

approaches. First, the anticancer effect of PN in an UVB-induced skin cancer model was tested. Mice

fed with PN (1 mg/day) showed a delayed onset of papilloma incidence, a significant reduction in

papilloma multiplicity (papilloma/mouse) and sizes when compared with the UVB-only group. The

molecular mechanism(s) involved in its anticancer effects using cultured JB6 murine epidermal cells

were next investigated. Non-cytotoxic concentrations of PN significantly inhibited UVB-induced

activator protein-1 DNA binding and transcriptional activity. In addition, PN pre-treatment also

inhibited c-Jun-N-terminal kinase (JNK) and p38 kinase activation. Impaired AP-1, JNK and p38

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signalling led to the sensitization of JB6 cells to UVB-induced apoptosis. These data confirmed the

anticancer property of PN in an animal model and provided evidence that the inhibitory effects on AP-1

and mitogen-activated protein kinases could serve as one of the underlying mechanisms for the cancer

chemopreventive property of PN (Won 2004).

Another research demonstrated that PN is able to induce robust apoptosis in primary human acute

myeloid leukemia (AML) cells and blast crisis chronic myeloid leukaemia (CML) cells while sparing

normal hematopoietic cells. Furthermore, analysis of progenitor cells using in vitro colony assays as

well as stem cells using the nonobese diabetic/severe combined immunodeficient xenograft model

showed, that PN also preferentially targets AML progenitor and stem cell populations. Notably, in

comparison to the standard chemotherapy drug cytosine arabinoside (Ara-C), it was observed that PN

is much more specific to leukemia cells. The molecular mechanism of PN mediated apoptosis is

strongly associated with inhibition of nuclear factor KB (NF-κB), proapoptotic activation of p53, and

increased reactive oxygen species (ROS). On the basis of these findings, the authors proposed that the

activity of PN triggers leukemia stem cells (LSC)-specific apoptosis (Guzman et al. 2005).

To investigate PN anticancer activity in ultraviolet B (UVB)-induced skin cancer in SKH-1 hairless mice,

the role of protein kinase C (PKC; the subtypes novel PKCd and atypical PKCz) in the sensitization

activity of PN on UVB-induced apoptosis has been studied. The results have demonstrated that PN

sensitizes UVB-induced apoptosis via PKC-dependent pathways (Won et al. 2005).

The effects of PN induced apoptosis in pre-B acute lymphoblastic leukemia (ALL) lines, including cells

carrying the t(4; 11) (q21; q23) chromosomal translocation were investigated. PN induced rapid

apoptotic cell death distinguished by loss of nuclear DNA, externalization of cell membrane

phosphatidylserine and depolarization of mitochondrial membranes at concentrations ranging from 5 to

100 µM. Using reactive oxygen species (ROS)-specific dyes, an increase in nitric oxide and superoxide

anion was detected in the cells by 4 h after exposure to PN. Parthenolide-induced elevation of

hypochlorite anion was observed only in the two (4; 11) lines. Data suggest that PN may have

potential as a potent and novel therapeutic agent against pre-B ALLs (Zunino et al. 2007).

Parada-Turska et al. (2007) determined the effect of PN on proliferation of three human cancer cell

lines: human lung carcinoma (A549), human medulloblastoma (TE671), human colon adenocarcinoma

(HT-29) and human umbilical vein endothelial cells (HUVEC) in vitro . Cell proliferation was assessed by

means of 3-(4.5-dimethylthiazol-2-yl)-2.5-diphenyltetrazolium bromide (MTT) assay. PN inhibited

proliferation of all three types of cancer cells (A549, TE671, HT-29) and HUVEC with the following IC50

values (in µM): 4.3, 6.5, 7.0 and 2.8 respectively.

The inhibitory activity of PN and golden feverfew extract against two human breast cancer cell lines

(Hs60ST and MCF-7) and one human cervical cancer cell line (SiHa) was determined in vitro . Feverfew

ethanolic extract inhibited the growth of all three types of cancer cells with a half-effective

concentration (EC50) of 1.5 mg/ml against Hs605T, 2.1 mg/ml against MCF-7, and 0.6 mg/ml against

SiHa. Among the tested constituents of feverfew (i.e., PN, camphor, luteolin and apigenin), PN showed

the highest inhibitory effect with an EC50 against Hs605T, MCf-7 and SiHa of 2.6 µg/ml, 2.8 µg/ml and

2.7 µg/ml, respectively. Interactions between PN and flavonoids (apigenin and luteolin) in feverfew

extract were also investigated to elucidate possible synergistic or antagonistic effects. The results

revealed that apigenin and luteolin might have moderate to weak synergistic effects with PN on the

inhibition of cancer cell growth of Hs605T, MCF-7 and SiHa (Wu et al. 2006a).

Studies of intensive immunotherapy revealed several metabolic inhibitors, such as cycloheximide,

actinomycin D, anisomycin, harringtonine and other metabolic inhibitors, which are able to modulate

the resistance of various cancer cells to cytokine induced cell death. However, the clinical use of

several tumor cell death promoting agents is limited, because they act non-specifically and are often

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cytotoxic. In turn, due to its low toxicity PN seems to be the ideal agent in future anti-cancer

immunotherapy.

3.1.1.2. Anti-inflammatory activity

The protein tyrosine kinase (PTK) inhibitors radicicol and herbimycin A inhibit the expression of the

mitogen-inducible cyclooxygenase (COX-2) and proinflammatory cytokines. Radicicol and herbimycin A

possess polarized double bonds which can conjugate sulphydryl groups of proteins. PN contains α-

methylene-gamma-lactone (MGL) and an epoxide in its structure. These moieties can interact with

biological nucleophiles such as a sulfhydryl group. Hwang et al. (1996) showed that PN inhibits the

expression of COX-2 and proinflammatory cytokines (TNFα and IL-1) in lipopolysaccharide (LPS)-

stimulated macrophages. The structure-function relationship indicates that the MGL moiety confers the

inhibitory effect. PN suppressed LPS-stimulated protein tyrosine phosphorylation in the murine

macrophage cell line (RAW 264.7). This suppression was correlated with its inhibitory effect on the

expression of COX-2 and the cytokines.

Excessive nitric oxide production by inducible nitric oxide synthase (iNOS) in stimulated inflammatory

cells is thought to be a causative factor of cellular injury in inflammatory disease states. Compounds

inhibiting iNOS transcriptional activity in inflammatory cells are potentially anti-inflammatory. It has

been demonstrated that PN exerts potent dose-dependent inhibitory effects on the promoter activity of

the iNOS gene in THP-1 cells. PN suppressed iNOS promoter activity at concentrations higher than 2.5

mM, with an IC50 of about 10 mM. A tumor-promoting phorbol ester, 12-O-tetradecanoylphorbol-13-

acetate (TPA), significantly increased the iNOS promoter-dependent reporter gene activity, and the

TPA-induced increase in iNOS promoter activity was effectively suppressed by PN, with an IC50 of

approximately 2 mM. These findings may further explain the anti-inflammatory property of PN (Fukuda

et al. 2000).

In order to identify the molecular mechanisms of parthenolide's anti-inflammatory activity, a PN

affinity reagent was synthesized by Kwok et al. (2001) and shown to bind directly to and inhibit IUB

kinase L (IKKL), the kinase subunit known to play a critical role in cytokine-mediated signalling.

Mutation of cysteine 179 in the activation loop of IKKL abolished sensitivity towards PN. Moreover, the

authors showed that parthenolide's in vitro and in vivo anti-inflammatory activity is mediated through

the K-methylene Q-lactone moiety shared by other sesquiterpene lactones. According to the authors,

PN targets this kinase complex providing a possible molecular basis for the anti-inflammatory

properties.

The NO donor glyceryl trinitrate (GTN) provokes delayed migraine attacks when infused into

migraineurs and also causes iNOS expression and delayed inflammation within rodent dura mater.

Sodium nitroprusside, a NO donor as well, also increases iNOS expression. As inflammation and iNOS

are potential therapeutic targets, Reuter et al. (2002) examined transcriptional regulation of iNOS

following GTN infusion and the consequences of its inhibition within dura mater. They show that

intravenous GTN increases NO production within macrophages, iNOS expression is preceded by

significant nuclear factor kappa B (NF-κB) activity, as reflected by a reduction in the inhibitory protein-

IkBα (IκBα) and activation of NF-κB after GTN infusion. IκBα degradation, NF-κB activation and iNOS

expression were attenuated by PN (3 mg/kg). These findings suggested that GTN promotes NF-κB

activity and inflammation with a time course consistent with migraine attacks in susceptible

individuals. Based on results with this animal model, the authors concluded that blockade of NF-κB

activity can provide a novel transcriptional target for the development of anti-migraine drugs.

Pharmacological control of interleukin-12 (IL-12) production may be a key therapeutic strategy for

modulating immunological diseases dominated by type-1 cytokine responses. Kang et al. (2001)

showed that PN potently inhibited the lipopolysaccharide-induced IL-12 production in a dose-

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dependent manner. The authors suggested that PN-induced inhibition of IL-12 production in

macrophages may explain some of the biological effects of PN including its anti-inflammatory activity.

The massive hyperplasia of synovial fibroblasts is one of the most striking features of rheumatoid

arthritis. The effect of PN on the proliferation of rabbit synoviocytes cell line HIG-82, rheumatoid

arthritis fibroblast-like synoviocytes (RA-FLS) and human skin fibroblasts (HSF) in vitro was

investigated. Cell proliferation was assessed by means of 3-(4.5- dimethylthiazol-2-yl)-2.5-

diphenyltetrazolium bromide and 5′-bromo-2′-deoxy-uridine methods. PN inhibited proliferation of

HIG-82 and human RA-FLS, whereas the proliferation of HSF was inhibited less effectively (Parada-

Turska et al. 2008).

3.1.1.3. Antimicrobial activity

PN showed significant activity against the promastigote form of L. amazonensis with 50% inhibition of

cell growth at a concentration of 0.37 µg/ml. For the intracellular amastigote form, PN reduced by 50%

the survival index of parasites in macrophages when it was used at 0.81 µg/ml. The purified compound

showed no cytotoxic effects against J774G8 macrophages in culture and did not cause lysis in sheep

blood when it was used at higher concentrations that inhibited promastigote forms. Sodium dodecyl

sulfate-polyacrylamide gel electrophoresis with gelatin as the substrate showed that the enzymatic

activity of the enzyme cysteine protease increased following treatment of the promastigotes with the

isolated compound. This finding was correlated with marked morphological changes induced by PN,

such as the appearance of structures similar to large lysosomes and intense exocytic activity in the

region of the flagellar pocket, as seen by electron microscopy. These results provided new perspectives

on the development of leishmanicidal activities of PN (Tiuman et al. 2005).

3.1.1.4. Antioxidant activity

A study was performed to investigate the protective effect of PN against oxidative stress-induced

apoptosis of human lens epithelial (HLE) cells and the possible molecular mechanisms involved. HLE

cells (SRA01-04) were incubated with 50 µM H202 in the absence or presence of different doses of PN

(10, 20 and 50 µM). The expression of caspase-3 and caspase-9 induced by H202 in HLE cells was

significantly reduced by PN both at the protein and mRNA levels, and the activation of caspase-3 and

caspase-9 was also suppressed by PN in a dose-dependent manner. The authors concluded that PN

prevents HLE cells from oxidative stress-induced apoptosis through inhibition of the activation of

caspase-3 and caspase-9, suggesting a potential protective effect against cataract formation (Yao et al.

2007).

3.1.1.5. Effects on smooth muscle contractility

Extracts of feverfew and PN inhibit smooth muscle contractility in a time-dependent, non-specific and

irreversible manner. The hypothesis that this toxic effect is caused by the presence of the potentially

reactive α-methylene function in the sesquiterpene lactone was tested on rabbit isolated aortic ring

preparations. The α-methylene functions in PN were chemically inactivated by reaction with cysteine.

The results showed the characteristic smooth muscle inhibitory profile for PN but not for the compound

lacking this functional group or by cysteine inactivated compounds. Thus the α-methylene function is

critical for this aspect of the toxic pharmacological profile of the sesquiterpene butyrolactones (Hay et

al. 1994).

3.1.1.6. Antimigraine effects

Although migraine is a complex neurovascular disorder, serotonin based mechanisms are central to its

pathophysiology. Antimigraine drugs interact predominantly with receptors of 5-HT1 and 5-HT2

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classes. 5-HT2B and 5-HT2A receptor antagonists such as methysergide, cyproheptadine, and

mianserin have been shown to be effective in migraine prophylaxis. PN at a concentration of 1 x 10 -5

mol/L was observed to be a potent inhibitor of neuronal release of 5-HT but without any significant

direct effect on 5-HT2B and 5-HT2A receptor sites in both fundus, and ileum when the tissues were

incubated for 30 min. Increasing the incubation time to 1.5 h resulted in a potent inhibition of both

responses to exogenous 5-HT and neuronal release of 5-HT via d-fenfluramine. At a higher

concentration (5 x 10 -5 mol/L), PN followed a similar trend as with 30-min incubation but its

antiserotonergic effect was much more striking when a 1.5-h incubation period was provided. The

above results indicate that the antagonism at the 5-HT receptor sites is very slow (Mittra et al. 2000).

In another report by Bejar et al. (1996) no 5-HT2B blocking action was noted with PN (1 x 10 -5 mol/L),

whereas a significant inhibition of neuronally released 5-HT was seen.

3.1.2. Studies on extracts

Extracts of T. parthenium (L.) showed antimicrobial, analgesic, anti-inflammatory, antipyretic,

antispasmodic, antithrombotic, antioxidant and uterine-stimulant activities in addition to the in vitro

cytotoxic effects. The effect of extracts on vessels and smooth muscle cells and antimigraine

properties has also been studied.

3.1.2.1. Antimicrobial activity

The activity of crude extracts, fractions and PN (pure compound) obtained from T. parthenium against

two forms of the parasite Trypanosoma cruzi was investigated. One thousand grams of dried aerial

parts were sequentially extracted by exhaustive maceration in ethanol/water 9:1. The powder resulting

from lyophilization, soluble in water, was termed the aqueous crude extract (WCE). The residue was

dissolved in ethanol or ethyl-acetate. Activity against epimastigote forms was observed for aqueous

(WCE), ethanolic (ACE) and ethyl-acetate (ECE) crude extracts, fractions and PN, and a progressive

increase in the antitrypanosomal effect was observed in the course of the purification process. These

extracts were assayed for their activity against epimastigote forms of T. cruzi . At 1000 µg/ml, all the

crude extracts showed similar effects inhibiting more than 90% of the parasites’ growth. At low

concentrations, ACE was the most effective extract. The pure compound showed IC50/96h and

IC90/96h of 0.5 μg/ml and 1.25 μg/ml, respectively. The cytotoxic effect of PN in LLMCK2 cells was

3.2 μg/ml (CC50/96h) and the selectivity index was 6.4. No haemolysis was detected for the pure

compound. The internalization index of T. cruzi in LLMCK2 cells was reduced to almost 51% at the

concentration of 2 µg/ml of PN and 96.6% at 4 μg/ml. Scanning and transmission electron microscopy

permitted observation of morphological modifications and ultrastructural alterations (Izumi et al.

2008).

Other investigations showed that the ethanolic extracts possess high activity against all Gram positive

bacteria, on some Gram negative bacteria and on some fungi (Kalodera et al. 1997).

3.1.2.2. Anti-inflammatory, analgesic and antipyretic activities

The alcoholic extracts of flowers and leaves and PN showed significant analgesic, anti-inflammatory

and antipyretic activities which confirmed the folk use of feverfew herb for treatment of headache,

fever, common cold and arthritis. These effects are attributed to the sesquiterpene lactones and

flavonoids present in the leaves and/or flowers (Milbrodt et al. 1997). The roots showed no or mild

biological activities due to the absence of sesquiterpene lactones and flavonoids; thus confirming the

hypothesis of these compounds as active constituents.

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Feverfew inhibits human blood platelet aggregation and secretion induced by a number of agents

in vitro and this may be related to the beneficial effects in migraine. The inhibitory activity of PN was

compared with that of crude feverfew leaves extract by Groenewegen & Heptinstall (1990). The effects

of both on [ 14 C]5-HT secretion from platelets and on platelet aggregation induced by a number of

different stimulants were determined. The activating agents studied included the phorbol ester PMA,

ADP, arachidonic acid, collagen, the thromboxane mimetic U46619, the calcium ionophore A23187, the

diacylglycerol analogue OAG and adrenaline. Powdered leaves were stirred with chloroform (feverfew,

50 mg/ml -1 , chloroform) for 30 min. The dried extract was re-suspended in an equal volume of PBS

(phosphate-buffered saline) to obtain a final solution concentration 50 mg/ml -1 PBS as derived from

feverfew. The results show that there are marked similarities between the effects of feverfew extract

and of PN on both [ 14 C]5-HT secretion and platelet aggregation, which is consistent with the effects of

feverfew extract on platelets caused by PN or similar compounds in the extract.

The effect of feverfew as a whole plant on an aqueous extract equivalent to 20 mg dried plant per ml,

has been examined on both cyclo-oxygenase and lipoxygenase activity in rat leucocytes in-vitro. At

10-25 µg ml -1 feverfew had no effect on the formation of arachidonate metabolites; while at the

highest concentrations (50-200 µg ml -1 ) it inhibited both cyclooxygenase and lipoxygenase metabolic

products (Capasso 1986).

A feverfew extract produced a dose-dependent inhibition of histamine release from rat peritoneal mast

cells stimulated with anti-IgE or the calcium ionophore A23187. The extract was obtained by extraction

of 1 g of air-dried leaves using chloroform (20 ml). Greater inhibition of anti-IgE-induced histamine

release was achieved with feverfew compared with the inhibition of A23187-induced release. Inhibition

of anti-IgE-induced histamine release by feverfew extract was observed when the drug was added

simultaneously with anti-IgE and the inhibitory activity increased only slightly when the drug was pre-

incubated with the cells for 5 min before anti-IgE stimulation. In this respect feverfew differs from

cromoglycate and quercetin. Feverfew extract inhibited anti-IgE-induced histamine release to the same

extent in the absence and or the presence of extracellular glucose. The authors concluded that

feverfew extract contains a novel type of mast cell inhibitor (Hayes & Foreman 1987).

Crude chloroform extracts of fresh feverfew leaves (rich in sesquiterpene lactones) and of

commercially available powdered leaves (lactone-free) produced dose-dependent inhibition of the

generation of thromboxane B2 (TXB2) and leukotriene B, (LTB,) by ionophore- and chemoattractant-

stimulated rat peritoneal leukocytes and human polymorphonuclear leukocytes. Approximate IC50

values were in the range 5-50 µg/ml, and inhibition of TXB2 and LTB, occurred in parallel. Isolated

lactones (PN, epoxyartemorin) were also inhibitory, with approximate IC50 values in the range 1-5

µg/ml, as were crude extracts treated with cysteine (to neutralize reactive α-methylene butyrolactone

functions of the sesquiterpenes). Inhibition of eicosanoid generation appeared to be irreversible but not

time-dependent. The authors concluded that feverfew contains a complex mixture of sesquiterpene

lactone and non-sesquiterpene lactone inhibitors of eicosanoid synthesis of high potency, and that

these biochemical actions may be relevant to the claimed therapeutic activity of the herb (Sumner et

al. 1992).

The bioactivity of feverfew leaf extracts has been analysed by use of a human polymorphonuclear

leukocyte (PMNL) bioassay to assess the relative contributions of solvent extraction and PN content to

the biological potency of the extract. Extracts prepared in acetone-ethanol contained significantly more

PN (mean ± s.d. 1.3 ± 0.2% dry leaf weight) than extracts in chloroform-PBS (phosphate-buffered

saline; 0.1 ± 0.0 4% dry leaf weight) or PBS alone (0.5 ± 0.1% dry leaf weight). Extract bioactivity

was measured as inhibition of phorbol 12-myristate 13-acetate-induced 5-amino-2.3-dihydro-l,4-

phthalazinedione (luminol)-enhanced PMNL chemiluminescence. Extracts inhibited phorbol 12-

myristate 13-acetate-induced oxidative burst by amounts which, if solely attributable to PN, indicated

PN concentrations for the respective solvent systems of 2.2 ± 0.6%, 0.2 ± 0.1% and 0.9 ± 0.1% dry

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leaf weight. The mean ratio of PN concentration to the PN equivalent/PMNL-bioactivity value for

acetone-ethanol and PBS extracts were both 1:1.7. The results indicated that PN, although a key

determinant of biological activity for T. parthenium leaf extracts based on the PMNL-bioassay, seems

not to be the sole pharmacologically-active constituent. The identical and elevated bioactivity-PN ratios

for both organic and aqueous-phase leaf extracts suggested that a proportion of the other bioactive

compounds have solubility similar to that of PN (Brown et al. 1997).

Oral administration of a water feverfew extract (composition unknown) led to significant anti-

nociceptive and anti-inflammatory effects against acetic acid-induced writhing in mice and

carrageenan-induced paw edema in rats, respectively. These responses were dose-dependent (10, 20,

40 mg/kg, p.o.). PN (1.2 mg/kg i.p.) also produced anti-nociceptive and anti-inflammatory effects.

Naloxone (1 mg/kg i.p.), an opiate antagonist, failed to reverse feverfew extract and PN-induced anti-

nociception. Feverfew extract in higher doses (40, 60 mg/kg p.o.) neither altered the locomotor

activity nor potentiated the pentobarbitone-induced sleep time in mice. It also did not change the

rectal temperature in rats. Feverfew extract exerted anti-nociceptive and anti-inflammatory effects

without altering the normal behaviour of animals (Jain & Kulkarni 1999).

Both crude ethanol feverfew extracts and purified PN were examined for their ability to modulate

adhesion molecule expression in human synovial fibroblasts. Pre-treatment of synovial fibroblasts with

either feverfew extracts or purified PN could inhibit the expression of intercellular adhesion molecule-1

(ICAM-1) induced by the cytokines IL-1 (up to 95% suppression), TNF-α (up to 93% suppression) and,

less strongly, interferon-γ (up to 39% suppression). Inhibition of ICAM-1 was dose and time

dependent; as little as a 30-min pretreatment with feverfew resulted in inhibition of ICAM-1. The

decrease in ICAM-1 expression was accompanied by a decrease in T-cell adhesion to the treated

fibroblasts. The modulation of adhesion molecule expression may be an additional mechanism by which

feverfew mediates anti-inflammatory effects (Piela-Smith & Liu 2001).

Chen & Leung (2007) tested three different feverfew extracts to check possible differences in gene

response of human cells. The standard reference extract (SRE) was obtained by extraction of 2 g of

dried leaf powder with 20 ml of 90% ethanol under mild conditions (sonication for 30 min with no

evaporation or exposure to the air). A carbon dioxide supercritical fluid extract was prepared under

conditions giving a spectrum of components similar in ratio of concentration to the SRE which contains

most of the volatile components of feverfew including camphor, chrysantenylacetate and PN. A

negative control extract was prepared with the same extraction solvent and DER but under stress

condition (extraction or 19 days, moderate heat up to 50°C and evaporation). Both, a standard

reference ethanolic extract and the carbon dioxide supercritical fluid extract of feverfew exhibited

blockade on lipopolysaccharide-mediated TNF-α release. Extracts effectively suppressed also CCL2

(also known as monocyte chemoattractant protein l, MCP-I), suggesting that CCL2 is a potential

cellular target for feverfew's antimigraine effects.

3.1.2.3. Effects on vessels and smooth muscle cells

Barsby et al. (1992) showed that samples prepared from chloroform extracts of fresh leaves of

feverfew strongly inhibited responses of rabbit aortic rings to phenylephrine, 5-hydroxytryptamine,

thromboxane mimetic U46619 (9,11.dideoxy-11α,9α-epoxy-methano-PGF 2α ), and angiotensin II.

In contrast, the inhibition of potassium induced depolarization was much less pronounced. The

inhibition was concentration- and time-dependent, non-competitive, irreversible and also occurred in

endothelium-denuded preparations. The feverfew extracts also caused a progressive loss of tone of

pre-contracted aortic rings and appeared to impair the ability of acetylcholine to induce endothelium-

dependent relaxations of the tissue. These effects were mimiced by PN, obtained from the extract. The

results suggest a non-specific and potentially toxic response to feverfew on the vessels.

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Thakkar et al. (1983) demonstrated that phospholipase A activity, measured in homogenates and acid

extracts of smooth muscle cells from rat aorta and mesenteric artery, was inhibited by an extract from

the leaves of feverfew plant.

The effects of a chloroform feverfew extract of fresh leaves on potassium currents in smooth muscle

were studied by Barsby et al. (1993). The currents were recorded from single cells dissociated from the

rat anococcygeus and the rabbit ear artery using the whole-cell patch-clamp technique. When applied

to cells isolated from the rat anococcygeus, the extract reduced the inactivating voltage-dependent

potassium current in a concentration-related manner, with an IC50 value of 56 µg/ml -1 . A complete

block of the current occurred at 1 mg/ml -1 . In addition to reducing the peak current, feverfew

decreased the time to peak of the current and increased the rate of delay of the current. These effects

could be explained by the feverfew extract blocking open potassium channels. In single cells isolated

from rabbit ear artery, the feverfew extract again reduced the voltage-dependent potassium current,

whilst at the same time having no effect on the spontaneous ion of calcium-dependent potassium

channels. These results suggest that chloroform extracts of feverfew leaf contain an as yet unidentified

substance capable of producing a selective, open-channel block of voltage-dependent potassium

channels.

3.1.2.4. Antithrombotic activity

Chloroform and water extracts of feverfew inhibited secretory activity in blood platelets and

polymorphonuclear leucocytes (PMNs). Release of serotonin from platelets induced by various

aggregating agents (adenosine diphosphate, adrenaline, sodium arachidonate, collagen, aM U46619)

was inhibited. Platelet aggregation was consistently inhibited but thromboxane synthesis was not.

Feverfew also inhibited release of vitamin B12-binding-protein from PMNs induced by the

secretagogues formyl-methionyl leucy1-phenylalanine, sodium arachidonate and zymosan-activated

serum. Feverfew did not inhibit the secretion induced in platelets or PMNs by the calcium ionophore

A23187. The pattern of the effects of the feverfew extracts on platelets was different from that

obtained with other inhibitors of platelet aggregation. The effect on PMNs was more pronounced than

that has been obtained with very high concentrations of non-steroidal anti-inflammatory agents

(Heptinstall et al. 1985).

Loesche et al. (1988) demonstrated that chloroform feverfew leaves extract inhibits aggregatory and

secretory responses in human platelets and granulocytes, and such inhibition may be relevant to the

beneficial effects. It has been suggested that feverfew extracts inhibit platelet behaviour via effects on

platelet sulphydryl groups. In another study, researchers found evidence that feverfew inhibits uptake

as well as liberation of arachidonic acid into/from platelet membrane phospholipids.

The same group studied the effect of feverfew on the interaction of platelets with different types of

collagen immobilized plastic as well as on the integrity of endothelial cells monolayer in perfused rabbit

aorta. Feverfew leaves were dried in air, powdered and extracted with chloroform (20 ml/g leaves).

The extract was dried under nitrogen and the residue dissolved in phosphate-buffered saline. Feverfew

extract inhibited in a dose-dependent way deposition of platelets and inhibited the formation of

surface-bound aggregates. The results of the study indicate that feverfew extract may have

antithrombotic potential (Loesche at al. 1988).

Chloroform/methanolic and water extracts of the herb were found to inhibit mitogen-induced tritiated

thymidine ([3H]-TdR) uptake by human peripheral blood mononuclear cells (PBMC), interleukin 2 (IL-

2)-induced [3H]-TdR uptake by lymphoblasts and PGE2 release by interleukin 1 (IL-1)-stimulated

synovial cells. Both crude organic and acqueous extracts and PN proved cytotoxic to mitogen-induced

PBMC and IL-1 stimulated synovial cells, the cytotoxic effect being functionally indistinguishable from

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the inhibitory effects. The authors suggest that pharmacological properties of feverfew may thus be

due to cytotoxicity (O’Neill et al. 1987).

3.1.2.5. Antioxidant activity

A PN-depleted extract of feverfew (PD-feverfew), which was free of sensitization potential, was found

to possess free radical scavenging activity against a wide range of reactive oxygen species and with

greater activity than Vitamin C. In vitro , PD-feverfew restored cigarette smoke-mediated depletion of

cellular thiols, attenuated the formation of UV-induced hydrogen peroxide and reduced pro-

inflammatory cytokine release. In vivo , topical PD-feverfew reduced UV-induced epidermal hyperplasia,

DNA damage and apoptosis. In a clinical study, PD-feverfew treatment significantly reduced erythema

versus placebo 24 h post-UV exposure. The authors suggested that through the ability to scavenge

free radicals, preserve endogenous antioxidant levels, reduce DNA damage and induce DNA repair

enzymes, which can help repair damaged DNA, PN-depleted extract of feverfew may protect skin from

the numerous external aggressions encountered daily by the skin and reduce the damage to

oxidatively challenged skin (Martin et al. 2008).

In another study, the antioxidant activities of an ethanolic feverfew extract and its bioactive

components were determined in terms of their free radical-scavenging activities against the 1,1-

diphenyl-2-picrylhydrazyl (DPPH) radical and their Fe 2+ -chelating capacities. In addition, the bioactive

constituents in feverfew were determined by GC–MS and HPLC–UV. Feverfew powder extracted by

80% alcohol contained camphor, PN, luteolin and apigenin in 0.30 ± 0.08%, 0.22% ± 0.03%, 0.84%

± 0.10% and 0.68% ± 0.07%, respectively. Total phenolic content of the feverfew extract was

measured in 21.21 ± 2.11 μg gallic acid equivalent per mg dry material. The feverfew alcoholic extract

possessed a strong DPPH free radical-scavenging activity of 84.4% and moderate Fe 2+ -chelating

capacity of 53.1%. Luteolin also showed strong DPPH scavenging activity of approximately 80% at

0.52 mg/ml. PN exhibited weak DPPH scavenging activity of 15% and moderate Fe 2+ -chelating

capacity of nearly 60%. Similar moderate Fe 2+ -chelating activity (approximately 60%) was observed

for luteolin and apigenin at 2 mg/ml (Wu et al. 2006).

3.1.2.6. Antimigraine effects

To study the mechanism of antimigraine activity of T. parthenium , its extracts and PN were tested for

their effects on 5-HT storage and release, and stimulation of 5-HT2B and 5-HT2A receptors.

Dichloromethane feverfew extracts (containing 1x10 -5 mol/L PN and a number of other mono- and

sesquiterpenes) showed a potent inhibition of neuronally released 5-HT via d-fenfluramine. In rat

fundus and ileum incubated with the extract for 30 min, the 5-HT2B and 5-HT2A receptors were

blocked in a manner similar to cyproheptadine (a predominantly 5-HT2B receptor blocker) and

risperidone (a 5-HT2A/2C receptor blocker) (Mittra et al. 2000).

Tassorelli et al. (2005) studied the biological effects of different T. parthenium extracts and purified PN

in an animal model of migraine based on the quantification of neuronal activation induced by

nitroglycerin. The methanolic extract enriched in PN significantly reduced nitroglycerin-induced Fos

expression in the nucleus trigeminalis caudalis. Purified PN inhibited nitroglycerin induced neuronal

activation in additional brain nuclei and significantly, the activity of nuclear factor κB. These findings

suggest that PN is the component responsible for the biological activity of T. parthenium as regards its

antimigraine effect and provide important information for future controlled clinical trials.

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3.1.3. Studies on the essential oil

The essential oil showed bactericidal and fungicidal activity. Gram positive species demonstrated a

significantly lower sensitivity than the Gram negative ones, moulds, the dermatophytes and some

fungi. Regarding the Gram positive species, the essential oil has a strong bactericidal effect only on the

Bacillus species, while this effect is negligible on other species ( Sarcina flava , Staphylococcus aureus ,

Enterobacter sp.). The oil has a strong bactericidal effect on many of the Gram negative species:

Escherichia coli, Klebsiella oxitoca, Salmonella , sp., Shigella sonnei, Serratia marcescens and

Citrobacter freundii . On Candida tropicalis , C. pseudotropicalis and C. apicola , the essential oil has a

strong fungicidal effect. The microbicidal effect on moulds ( Aspergillus flavus , A. ochraceus , A. niger )

and dermatophytes ( Microsporum gypseum , Trichophyton mentagrophytes and Epidermophyton

floccosum ) has also been determined (Kalodera et al. 1997).

3.2. Overview of available pharmacokinetic data regarding the herbal

substance(s), herbal preparation(s) and relevant constituents thereof

No data available.

3.3. Overview of available toxicological data regarding the herbal

substance(s)/herbal preparation(s) and constituents thereof

Single/repeat dose toxicity, genotoxicity, carcinogenicity and local tolerance studies have not been

performed.

Reproductive toxicity

Yao et al. (2006) carried out a preliminary screen of a commonly used formulation of feverfew in order

to determine its potential for reproductive toxicity. The recommended human dose is 1 g/day. The

extract of feverfew used consisted of a commercial preparation of the dried leaf of the feverfew plant

extracted in 60% ethanol in a 1:2 dilution, giving a final concentration of 200 mg/ml feverfew

standardized to 0.7 mg/ml of PN. The reported teratogenic threshold of ethanol is 2 g/kg in the Long-

Evans rat, used in the study. The upper dose of the ethanol content of the feverfew concentrate was

therefore limited to 1.98 g/kg. This meant that the maximum dose of feverfew that could be delivered

to the rat was 839 mg/kg/day or 58.7 times the recommended human dose. Treated rats were dosed

with 12.8 ml/kg/day of a 65.2 mg/ml feverfew solution. Control rats received either 12.8 mg/kg of

distilled water or 20% (v/v) ethanol. Five female rats were orally dosed with 839 mg/kg feverfew daily

on either gestation days (GD) 1-8 or 8-15. Two pregnant rats became very sick (exhibited piloerection,

reduced mobility, reduced response to stimuli) before the 8 days of feverfew treatment were

completed. On GD20, rats were sacrificed and fetuses, placentae and ovaries were collected. The

fetuses were weighed and examined for malformations. While maternal weight gain appeared to be

reduced, ANCOVA analysis suggested that the difference was due to the litter size, rather than

treatment. Pre-implantation loss appeared increased but this was not statistically significant in the

feverfew GD 1-8 group. Fetuses exposed to feverfew from GD 8-15 were smaller than ethanol controls

perhaps as a result of the increased frequency of runts in treated litters. Feverfew induced toxicity

when GD 10.5 embryos were cultured for 26 h in rat serum to which extract was added. The results of

this preliminary study suggest that a comprehensive reproductive study of feverfew is warranted.

3.4. Overall conclusions on non-clinical data

Several non clinical investigations support feverfew traditional medicinal uses.

The sesquiterpene lactone PN containing an α-methylene-γ-lactone ring and an epoxide residue

capable of interacting rapidly with nucleophilic sites of biological molecules is considered the main

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active constituent. PN possesses anti-tumoral, anti-microbial, anti-inflammatory and antioxidant

activities. It inhibits platelet aggregation and platelet serotonin release and it is also an inhibitor of NF-

κB and IκB kinases complex.

The role of PN in the antimigraine effects of feverfew was investigated and antagonism of serotonin

receptors and inhibition of neuronally released 5-HT have been suggested for the mechanism of action.

Moreover, feverfew leaf extracts inhibit human blood platelet aggregation and secretion induced by a

number of agents in vitro and this may relate to the beneficial effects in migraine.

Alcoholic extracts of flowers and leaves showed significant analgesic, anti-inflammatory and antipyretic

activities. These effects are attributed to the presence of sesquiterpene lactones and flavonoids.

Antioxidant activities of ethanolic feverfew extracts have also been shown.

Water, ethanolic and ethyl-acetate extracts of T. parthenium showed significant antimicrobial, anti-

inflammatory, antinociceptive and antipyretic activity in vitro . Inhibition of histamine release and of

phospholipase A2, cyclo-oxygenase and lipoxygenase activity has been suggested for the mechanism

of action.

Chloroform extracts of fresh leaves of feverfew strongly inhibit responses of vessels to contracting

agents and both chloroform and water extracts of feverfew inhibit secretory activity in blood platelets

and polymorphonuclear leucocytes (PMNs) and release of serotonin from platelets induced by various

aggregating agents.

Both feverfew and PN inhibit smooth muscle contractility in a time-dependent, non-specific and

irreversible manner. The uterine stimulant effect of the plant agrees with the folk uses of the plant as

an emmenagogue and in dysmenorrhea.

A preliminary study, to determine its potential for reproductive toxicity, was conducted in the rat. The

dose of feverfew delivered daily corresponded to about 58.7 times the recommended human dose.

Treatment induced both maternal and embryo toxicity, however, the same authors considered the

study preliminary and suggested that a comprehensive reproductive study of feverfew is to be

warranted.

The essential oil possesses bactericidal and fungicidal properties.

In conclusion, PN and different preparations of T. parthenium show biological activities in vitro and in

vivo in experimental models. These findings support the traditional use in migraine prevention and in

minor pain syndromes such mild articular pain.

4. Clinical Data

4.1. Clinical pharmacology

Migraine Prophylaxis

Migraine is a recurrent moderate-to-severe headache that can be unilateral and often is characterised

by photophobia, phonophobia, nausea, vomiting, or aggravated by movement. Migraine is further

classified into migraine without aura, migraine with aura, basilar-type migraine, familiar or sporadic

hemiplegic migraine. These subtypes may be further classified as episodic or chronic.

Migraine is heterogeneous (among sufferers and between attacks) in frequency, duration and

disability. Some migraineurs have less than one attack a month while others have one or more attacks

a week. Some are quite disabled by their headaches, while others are not. Therefore, it is appropriate

to stratify the care of the migraine population by headache frequency, severity and level of disability.

Furthermore, prevention needs to be considered for those patients whose migraine has a substantial

impact on their lives.

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Migraine is considered a genetic disorder of neuronal hyper-excitability. The genesis of the attack is

linked to neuronal activation. Migraine headache has an incidence of 6% in men and 15% to 17% in

women (Bamford et al. 2009).

There are two ways to treat migraine headache: the acute therapy to terminate the headache when

needed and the preventive therapy, in which treatment is given chronically to reduce attack frequency,

severity and duration, to improve responsiveness to acute therapy, and to improve function and

reduce disability (Bamford et al. 2009).

The aim of a preventive treatment for migraine is to prevent or reduce the frequency and/or to

attenuate severity of new migraine attacks, to improve response to acute medications, to improve

patient function and to reduce disability.

Prophylactic drug treatment of migraine should be considered and discussed with the patient when one

or more of the following problems occur:

- quality of life, business duties, or school attendance are severely impaired;

- frequency of attacks per month is two or higher;

- migraine attacks do not respond to acute drug treatment;

- frequent, very long, or uncomfortable auras occur.

In summary, patients with high frequencies of migraine, high disability or impact from migraine, and

frequent users of acute migraine medications merit migraine prophylaxis in the form of daily

medication.

Migraine-preventive medications, at best, work in approximately half of patients to reduce migraine

frequency by about 50%. A careful establishment of expectations with the use of headache diaries is

crucial for determination of the therapeutic success. The treatment should be maintained for 2 to 3

months to evaluate effectiveness.

Medications with the best evidence for efficacy in the prevention of migraine are amitriptyline,

propranolol, timolol, valproate, and topiramate. Options available include alternative and

complementary therapies, optimized lifestyles with changes as necessary, dietary and substance

changes and drug prevention (Taylor 2009).

Although all migraine preventive medications are non-specific and have multiple potential mechanisms

for their effects, they often share a tendency to reduce central neuronal hyper-excitability by inhibiting

excitatory neurotransmitters, such as glutamate and norepinephrine, increasing inhibitory tone via

GABA, reducing the likelihood of cortical spreading depression or favorably altering channelopathies or

mitochondriopathies thought to be intrinsic to migraine pathophysiology (Bamford et al. 2009).

Use of feverfew in the migraine treatment

Feverfew leaf extracts inhibit human blood platelet aggregation and secretion induced by a number of

agents in vitro and this may relate to the beneficial effects in migraine. These effects are similar to

those shown for drugs preventing migraine attacks (i.e. tryptans). On this basis, use of T. parthenium

is not considered useful for acute therapy to terminate the headache but more suitable for the

prevention (or prophylaxis) of migraine attacks. In conclusion, it can be given chronically to reduce

attack frequency, severity and duration, to improve responsiveness to acute therapy, to improve

function and reduce disability. Since feverfew appears to have a relatively benign side effect profile, it

is considered as an option for migraine prophylaxis. Feverfew treatment has been assigned to ‘class B

recommendation’ within guidelines on management of migraine in clinical practice differentiating

between class A, B and C (Pryse-Phillips et al. 1998).

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4.1.1. Overview of pharmacodynamic data regarding the herbal

substance(s)/preparation(s) including data on relevant constituents

Feverfew has traditionally been used for fever, women’s ailments, inflammatory conditions, psoriasis,

toothache, insect bites, rheumatism, asthma and stomach-ache. During the last decades, it has also

been used for headache and migraine prophylaxis.

Feverfew extract enables the release of serotonin (5-hydroxytryptamin) from platelets induced by a

variety of aggregation agents. Moreover, both extracts of feverfew and pure PN inhibit the synthesis of

prostaglandins (Sumner et al. 1992).

A role of the sesquiterpene lactone PN in migraine prophylaxis was supported by in vitro studies

suggesting inhibition of serotonin release from blood platelets but this hypothesis is not commonly

shared. PN also markedly interferes with both contractile and relaxant mechanisms of blood vessels.

The pharmacological role of feverfew in the migraine pathophysiology is not completely understood.

4.1.2. Overview of pharmacokinetic data regarding the herbal

substance(s)/preparation(s) including data on relevant constituents

No data available.

4.2. Clinical Efficacy

4.2.1. Dose response studies

The efficacy and safety of T. parthenium (feverfew) in migraine prophylaxis-a double-blind,

multicentre, randomized placebo-controlled dose-response study

A study was designed with the primary objective to show a dose–response with a stable extract (MIG-

99) reproducibly manufactured with supercritical CO 2 from feverfew. Furthermore, the study provided

data on the safety and tolerability of MIG-99. In a randomized, double-blind, multicentre, controlled

trial, the clinical efficacy and safety of three dosages of MIG-99 (2.08 mg, corresponding to 0.17 mg

PN; 6.25 mg, corresponding to 0.5 mg PN; 18.75 mg, corresponding to 1.5 mg PN twice in a day) were

compared with placebo. The patients (n=147) suffered from migraine with and without aura according

to International Headache Society (IHS) criteria and were treated with one of the study medications for

12 weeks after a 4-week baseline period. During the active treatment period patients received either

2.08 mg MIG-99 (corresponding to 0.17 mg PN), 6.25 mg MIG-99 (0.5 mg PN), 18.75 mg MIG-99 (1.5

mg PN) or placebo. The primary efficacy parameter was the number of migraine attacks during the last

28 days of the treatment period compared with baseline. Secondary endpoints were total and average

duration and intensity of migraine attacks, mean duration of the single attack, number of days with

accompanying migraine symptoms, number of days with inability to work due to migraine as well as

type and amount of additionally taken medications for the treatment of migraine attacks. The design of

the study included a pre-planned adaptive interim analysis for patients with at least four migraine

attacks within the baseline period. With respect to the primary and secondary efficacy parameter, a

statistically significant difference was not found between the overall and the confirmatory intention-to-

treat (ITT) sample in the exploratory analysed four treatment groups. The frequency of migraine

attacks for the predefined confirmatory subgroup of patients (n=49) with at least four migraine attacks

during the baseline period decreased in a dose-dependent manner (P=0.001).

The highest absolute change of migraine attacks was observed under treatment with 6.25 mg t.i.d.

(mean ± SD = - 1.8 ± 1.5 per 28 days) compared with placebo (- 0.3 ± 1.9; P=0.02). Overall, 52 of

147 (35%) patients reported at least one adverse event.

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The incidence of adverse events in the active treatment groups was similar to that in the placebo

group, and no dose-related effect was observed in any safety parameter. MIG-99 failed to show a

significant migraine prophylactic effect in general. Accordingly, in the ITT analysis a dose–response

relationship could not be observed. MIG-99 was shown to be effective only in a small predefined

subgroup of patients with at least four attacks during the 28-day baseline period, where the most

favourable benefit–risk ratio was observed with a dosage of three capsules of 6.25 mg MIG-99 extract

per day. Due to a low number of patients, these findings need to be verified in a larger sample. The

incidence of adverse events was similar for all treatment groups. In conclusion, there were no

statistically significant effects for either primary or secondary outcome measures. Accordingly, a dose-

response relationship could not be observed. Subgroup analysis including patients with at least four

migraine attacks during baseline evaluations (n=49) showed a significant effect when the 6.25-mg

dose was compared with placebo (p=0.02) (Pfaffenrath et al. 2002) (Table 3).

4.2.2. Clinical studies (case studies and clinical trials)

Clinical studies with feverfew for prevention of migraine

 Efficacy of feverfew as prophylactic treatment of migraine.

A double blind placebo controlled trial including seventeen patients who already ate fresh leaves of

feverfew daily as prophylaxis against migraine was carried out. Patients who had suffered from

classical or common migraine for at least two years, with eight or fewer attacks per month, were

allocated randomly to receive either feverfew (freeze-dried leaves) or identical placebo capsules in

numbered packs. Diary cards were used to assess the frequency of migraine and the incidence of

nausea and vomiting. Patients were instructed how to record the various visual symptoms, nausea,

vomiting and headache (including times of onset and relief and any additional treatment) and to grade

them according to severity on diary cards provided for each period. The severity of nausea or vomiting

was recorded as: 0 = neither nausea nor vomiting; 1=nausea only; 2=vomiting, single episode;

3=vomiting, repeated episodes. Headache was scored: 0=no pain; 1=mild, unpleasant but not

affecting work or recreational activities; 2=severe, reducing ability to work or carry out recreational

activities; 3=incapacitating, unable to work or carry out recreational activities; 1=duration up to six

hours; 2=duration between six and 24 hours; 3=duration greater than 24 hours. Presence of usual

visual disturbance scored 1. Use of drugs was scored: 1=use of repeated doses of minor analgesics;

1=use of single dose of ergotamine; 2=use of repeated doses of ergotamine. The cards were reviewed

at intervals of one to two months throughout the study. Patients were instructed to take two capsules

every morning with food for six periods of four weeks. The mean daily dose of feverfew used by

patients before entry to the study was 2.44 leaves (roughly 60 mg). Hence, it was decided that the

dose of each capsule should be fixed at 25 mg and that each patient should receive two capsules daily.

Eight patients received capsules containing freeze dried feverfew powder and nine patients received

placebo. The results showed a significant (p<0.02) increase in the number of attacks per month in the

placebo group (mean, 3.1; standard error [SE], 0.8) compared with baseline, while attack frequency

remained constant in patients receiving feverfew (mean, 1.7; SE, 0.6). 42% and 79% of attacks were

associated with nausea and vomiting in the feverfew and placebo groups, respectively (p<0.05). The

incidence of bouts of nausea/vomiting was significantly (p<0.05) lower in the feverfew group than in

the placebo group (39 and 116, respectively). The global assessment of efficacy by patients indicated a

significant (p<0.01) difference in favour of feverfew: 6/8 patients in the feverfew group rated the

overall treatment effect as moderately good to excellent, while this result was reported by only 3/9

patients in the placebo group. This provided early evidence that feverfew taken prophylactically

prevents attacks of migraine (Johnson et al. 1985) (Table 4).

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 Randomised double-blind placebo-controlled trial of feverfew in migraine prevention.

The use of feverfew for migraine prophylaxis was assessed in a randomised, double blind, placebo-

controlled crossover study. After a one-month single-blind placebo run-in, 72 patients with common or

classical migraine were randomly allocated to receive either one capsule of a chloroform extract of

dried feverfew leaves a day or matching placebo for four months and then transferred to the other

treatment arm for a further four months. There was no wash-out period between the treatment

periods. Capsule weights ranged from 70 to 114 mg (mean 82 mg) and contained the equivalent of

2.19 (SD 0.63) μmol of PN per capsule. Frequency and severity of attacks were determined from diary

cards which were issued every two months; efficacy of each treatment was also assessed by visual

analogue scores. Sixty patients completed the study and full information was available in 59. The

results suggested a significant (p<0.005) difference in the number of attacks per 2-month period

during feverfew treatment (mean, 3.6; SE, 0.2) compared with placebo (mean, 4.7; SE, 0.3). Among

patients with classical migraine (n=17), the number of attacks per 2-month period was significantly (p

< 0.05) lower with feverfew (mean, 2.9; SE, 0.4) than with placebo (mean, 4.3; SE, 0.5); among

patients with common migraine (n=42), headache frequency was similar during the feverfew (mean,

3.9; SE, 0.3) and placebo (mean, 4.9; SE, 0.4) periods (p = 0.06). In the study population as a whole,

the total number of attacks rated as severe or very severe was 178/424 (42%) with feverfew and

258/559 (46%) with placebo. Nausea and vomiting accompanied the attacks in 207/424 (49%) and

313/559 (56%) cases treated with feverfew and placebo, respectively (p<0.02). The global

assessment of efficacy, measured on a 100-mm visual analogue scale with ’worst ever’ and ’best ever’

as the two extremes, indicated a significant (p<0.0001) difference in favour of feverfew compared with

placebo (mean, 74; SE, 2 versus mean, 60; SE, 3, respectively). Among patients with classical

migraine, global assessment scores were significantly (p<0.01) higher during treatment with feverfew

(mean, 78; SE, 4) than during treatment with placebo (mean, 57; SE, 5); among patients with

common migraine, scores for the two treatment periods were similar (mean, 72; SE, 2 for feverfew

and mean, 61; SE, 3 for placebo). In conclusion, treatment with feverfew was associated with a

reduction in the mean number and severity of attacks in both two-month periods, and in the degree of

vomiting, while the duration of individual attacks was unaltered. Visual analogue scores also indicated

a significant improvement with feverfew. There were no serious side-effects (Murphy et al. 1988)

(Table 5).

 Herbal medicines in migraine prevention: Randomized double-blind placebo-controlled crossover

trial of feverfew preparation.

De Weerdt et al. (1996) assessed 50 patients diagnosed according to the criteria of the International

Headache Society (IHS 1988). Patients suffering from migraine with or without aura received daily

either one capsule of an alcoholic feverfew extract (143 mg) or placebo in a randomised crossover

trial. The extract was obtained subjecting feverfew powder to 19 days of prolonged exposure to 90%

ethanol, moderate heat (up to 90°C) and evaporation. A 1-month placebo run-in phase was followed

by 2-month treatment periods. There was no wash-out period between the treatment periods. The

investigators reported that no significant effects on the number or severity of headaches were

observed (Table 6).

 Feverfew ( T. parthenium ) as a prophylactic treatment for migraine: A placebo-controlled double-

blind study.

The crossover trial conducted by Palevitch et al. (1997) included 57 patients with migraine diagnosed

by medical examination (diagnostic criteria not specified). During the preliminary, open phase of the

trial, each patient received 100 mg feverfew daily for 2 months. The PN content of the dried leaves

was 0.2% as determined by HPLC. 50 mg of fine powdered leaves was packed in small gelatin

capsules. Powdered dry leaves of parsley ( Petroselinum crispum ), were prepared in the same way and

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served as the placebo control. Thereafter, in the double-blind crossover phase, one group received

placebo for 30 days, while the other continued taking feverfew. Patients in the active treatment group

were then transferred to the placebo arm and vice versa. There was no wash-out period between the

treatment periods. The severity of migraine attacks was measured by patients on a numerical scale of

0 (’no pain’) to 10 (’most severe pain’) and the severity of nausea and vomiting was assessed using a

numerical analogue scale and a questionnaire. The results of the preliminary, open phase showed a

significant decrease in migraine severity after treatment with feverfew compared with baseline

(p<0.001). In the first crossover phase there was a further reduction of migraine severity in the

feverfew group (mean, 1.5; SE, 0.7) and an increase in severity in the placebo group (mean, 1.6; SE,

0.9) (p<0.01). In the second phase of the crossover, these trends continued: migraine severity

decreased among patients taking feverfew (mean, 4.0; SE, 1.1) and increased among patients taking

placebo (mean, 1.4; SE, 1.1). In addition, there was a significant (p<0.001) difference in the severity

of nausea and vomiting in favour of feverfew (Table 7).

 Efficacy and safety of 6.25 mg t.i.d. feverfew CO 2 -extract (MIG-99) in migraine prevention, a

randomized, double-blind, multicentre, placebo-controlled study.

The efficacy and tolerability of a CO 2 -extract of feverfew (MIG-99, 6.25 mg t.i.d.) for migraine

prevention were investigated in a randomized, double-blind, placebo-controlled, multicentre,

parallel-group study. Patients (N=170 intention-to-treat; MIG-99, N=89; placebo, N=81) suffering

from migraine, according to the International Headache Society criteria, were treated for 16 weeks

after a 4-week baseline period. The primary endpoint was the average number of migraine attacks per

28 days during the treatment months 2 and 3 compared with baseline. Predefined secondary efficacy

parameters were the number of migraine attacks during each 28-day period of therapy, the clinical

global impression of efficacy (very good, good, moderate, none), change of migraine intensity, the

total duration of migraine attacks, mean duration of the single attack, number of migraine days,

number of attacks with confinement to bed or inability to work or accompanying migraine symptoms

per 28 days, number of migraine attacks with aura per 28 days, type and amount of analgesics and

migraine preparations taken and number of drop-outs due to insufficient efficacy. Safety parameters

included adverse events, laboratory parameters, vital signs and physical examination. The migraine

frequency decreased from 4.76 by 1.9 attacks per month in the MIG-99 group and by 1.3 attacks in

the placebo group (P=0.0456). Logistic regression of responder rates showed an odds ratio of 3.4 in

favour of MIG-99 (P=0.0049). Adverse events possibly related to study medication were 9/107 (8.4%)

with MIG-99 and 11/108 (10.2%) with placebo (P=0.654). The authors concluded that MIG-99 is

effective and shows a favourable benefit–risk ratio (Diener et al. 2005) (Table 8).

Table 3. Efficacy of feverfew as prophylactic treatment of migraine

Authors N° subjects

Randomization

and control

Endpoints

17 patients with migraine. 8

patients active treated

9 patients treated with

placebo

Randomization

Placebo

Double blind

Frequency and severity of headache,

nausea and vomiting.

Johnson

et al.

1985

Posology and Duration of

treatment

Statistical

analysis

Efficacy

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Authors N° subjects

Randomization

and control

Endpoints

The mean daily dose of

feverfew used by patients

before entry to the study

was 2.44 leaves (roughly 60

mg).

25 mg of freeze-dried

powdered feverfew leaves

twice/day

for six periods of four weeks

Yes

Those who received placebo 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 with respect to

the period before the treatment with

feverfew.

Table 4. Randomised double-blind placebo-controlled trial of feverfew in migraine prevention

Authors N° subjects

Randomization

and control

Endpoints

60 patients with history of

common or classical

migraine of at least 2 years'

duration

Randomization

Placebo

Double blind

Cross-over

Duration, frequency and severity

of attacks.

Visual analogue score.

Murphy et

al. 1988

Posology and Duration of

treatment

Statistical analysis Efficacy

About 82 mg (from 72 to

114 mg) a day of a

chloroform extract of dried

feverfew leaves for four

months

Yes

Reduction in the mean number

and severity of attacks in each

two-month period and in the

degree of vomiting; duration of

individual attacks was unaltered.

Table 5. Herbal medicines in migraine prevention: Randomized double-blind placebo-controlled

crossover trial of feverfew preparation

Authors N° subjects

Randomization

and control

Endpoints

50 patients with migraine

Randomization

Placebo

Cross-over

Frequency and severity of

migraine attacks

De

Weerdt

et al.

1996

Posology and Duration of

treatment

Statistical analysis Efficacy

143 mg daily of an ethanolic

extract

Yes

No significant effect in number or

severity of attacks

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Table 6. Feverfew ( Tanacetum parthenium ) as a prophylactic treatment for migraine: A placebo-

controlled double-blind study

Authors N° subjects

Randomization

and control

Endpoints

57 patients with migraine

Phase 1: open-labelled trial.

Two groups (A and B) both

received a daily dose of 100

mg feverfew for 60 days.

Phases 2 and 3: double-

blind controlled randomized

cross-over trial. Group A

( n =30) received feverfew

for an additional 30 days

and then shifted to placebo

treatment for 30 days (100

mg daily of ground

parsley).

Randomization

Placebo

Double blind

Cross-over

Severity of migraine attacks

Palevitch

et al.

1997

Posology and Duration of

treatment

Statistical analysis Efficacy

100 mg feverfew powdered

leaves daily for two months

Yes

Decrease of severity of attacks

both in the open labelled phase

and in the controlled phases.

Table 7. The efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis-a

double-blind, multicentre, randomized placebo-controlled dose-response study

Authors N° subjects

Randomization

and control

Endpoints

147 patients treated in four

parallel groups

Randomization

Placebo

Double blind

Primary parameter: number of

migraine attacks during the last

28 days of the treatment period

vs baseline period. Secondary

endpoints: total and average

duration and intensity, mean

duration of migraine attacks,

mean duration of the single

attacks.

Pfaffenrat

h

et al.

2002

Posology and Duration of

treatment

Statistical analysis Efficacy

MIG-99 (2.08 mg; 6.25

mg; 18.75 mg three times

daily) for 12 weeks

Yes

MIG-99 was shown to be effective

only in a small predefined

subgroup of patients with at least

four attacks during the 28-day

baseline period where the most

favourable benefit–risk ratio was

observed with a dosage of three

capsules of 6.25 mg MIG-99

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Authors N° subjects

Randomization

and control

Endpoints

extract per day.

Table 8. Efficacy and safety of 6.25 mg three times daily feverfew CO2-extract (MIG-99) in migraine

prevention, a randomized, double-blind, multicentre, placebo-controlled study

Authors N° subjects

Randomization

and control

Endpoints

MIG-99, N =89; placebo,

N =81

Randomization

Placebo

Double blind

Primary endpoint: average

number of migraine attacks per

28 days during the treatment

months 2 and 3 vs baseline.

Posology and Duration of

treatment

Statistical analysis Efficacy

Diener HC

et al.

2005

MIG-99 6.25 mg; three

times daily) for 16 weeks

Yes

The migraine frequency decreased

from 4.76 by 1.9 attacks per

month in the MIG-99 group and

by 1.3 attacks in the placebo

group ( P =0.0456). Logistic

regression of responder rates

showed an odds ratio of 3.4 in

favour of MIG-99 ( P =0.0049).

Reviews on clinical studies with feverfew for prevention of migraine

The first systematic review on feverfew as a preventive treatment for migraine was published by

Vogler et al. in 1998. Only randomized, placebo-controlled, double-blind trials were included. The

methodological quality of all trials was evaluated using the Jadad score.

Main results:

Five trials met the inclusion/exclusion criteria. The majority favoured feverfew over placebo. Three

studies reported positive results in favour of feverfew. In total, 216 patients were included, both men

and women suffering from classical and/or common migraine. The author concluded that the

effectiveness of feverfew in the prevention of migraine has still not been established beyond

reasonable doubt (Vogler et al. 1998).

Ernst published in the year 2000 a systematic review on the efficacy and safety of feverfew. Only

randomized, placebo-controlled, double-blind trials of feverfew mono-preparations for the prevention

of migraine in human subjects were included. Six trials met the inclusion/exclusion criteria. The

majority favoured feverfew over placebo. The data also suggested that feverfew is associated with only

mild and transient adverse effects and few other safety concerns. The author concluded that feverfew

is likely to be effective in the prevention of migraine and that there are no major safety problems

(Ernst & Pittler 2000).

A Cochrane review on feverfew for preventing migraine was released in 2004. The aim of the review

was to systematically evaluate the evidence from double-blind randomised controlled trials (RCTs)

assessing the clinical efficacy and safety of feverfew versus placebo for preventing migraine.

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Publications describing (or which might describe) double-blind RCTs of feverfew extract for migraine

were considered. Randomised, placebo-controlled, double-blind trials assessing the efficacy of feverfew

for preventing migraine were included. Trials using clinical outcome measures were included. Trials

focusing exclusively on physiological parameters were excluded. There were no restrictions regarding

the language of publication.

Five trials (343 patients) met the inclusion criteria. Results from these trials were mixed and did not

convincingly establish that feverfew is efficacious for preventing migraine. Only mild and transient

adverse events were reported in the included trials (Pittler & Ernst 2004).

The authors concluded that there is insufficient evidence from randomised, double-blind trials to

suggest an effect of feverfew over and above placebo for preventing migraine. It appeared from the

data reviewed that feverfew presents no major safety problems. It has been suggested that the lack of

efficacy may be due to the absence of the therapeutic constituents in the granulated feverfew leaves,

which were either not sufficiently extracted, or perhaps degraded during the preparation.

Another explanation suggests only a secondary role for serotonin in the etiology of migraine. Assuming

that whole-leaf preparations are effective, it would direct the attention towards feverfew constituents

other than PN (Awang 1998).

Another hypothesis suggests that an essential oil constituent of feverfew, chrysanthenyl acetate, may

be important. This component inhibits prostaglandin synthetase in vitro and seems to possess

analgesic properties. Other investigators agree that PN is not the only pharmacologically active

constituent in feverfew.

A link between the relatively high concentration of melatonin in different feverfew varieties and a

decrease in melatonin excretion during migraine attacks has also been suggested.

An alternative explanation for negative trial results is offered by the fact that some commercial

preparations are under-dosed, possibly due to the instability of the active constituents in these

extracts (Pittler & Ernst 2004).

Clinical studies with combination products

To determine the efficacy for migraine prophylaxis of a preparation containing a combination of

riboflavin, magnesium and feverfew a randomized double-blind placebo-controlled trial of a compound

providing a daily dose of riboflavin 400 mg, magnesium 300 mg and feverfew 100 mg was conducted.

The placebo contained 25 mg riboflavin. The study included a 1-month run-in phase and 3-month trial.

The protocol allowed for 120 patients to be randomized, with a pre-planned interim analysis of the

data after 48 patients had completed the trial.

Forty nine patients completed the 3-month trial. For the primary outcome measure, a 50% or greater

reduction in migraines, there was no difference between active and “placebo” groups, achieved by 10

(42%) and 11 (44%), respectively (P=.87). Similarly, there was no significant difference in secondary

outcome measures, for active versus placebo groups, respectively: 50% or greater reduction in

migraine days (33% and 40%, P=.63); or change in mean number of migraines, migraine days,

migraine index, or triptan doses. Compared to baseline, however, both groups showed a significant

reduction in number of migraines, migraine days and migraine index. This effect exceeds that reported

for placebo agents in previous migraine trials.

Author’s conclusion: riboflavin 25 mg showed an effect comparable to a combination of riboflavin 400

mg, magnesium 300 mg and feverfew 100 mg. The placebo response exceeds that reported for any

other placebo in trials of migraine prophylaxis and suggests that riboflavin 25 mg may be an active

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comparator. There is at present conflicting scientific evidence with regard to the efficacy of these

compounds for migraine prophylaxis (Maizels et al. 2004).

Feverfew and Salix alba (white willow) either alone or in combination have been shown to inhibit

binding to 5-HT 2A/2C receptors; feverfew failed to recognise 5-HT 1D receptors, whereas S. alba or the

combination did. It was hypothesised that S. alba in combination with feverfew may provide superior

migraine prophylactic activity compared with feverfew alone.

On this basis, a prospective, open-label study was performed in 12 patients diagnosed with migraine

without aura. Twelve weeks' treatment with a combination product (feverfew extract standardised on

PN ( > 0.2%) 300 mg plus S. alba extract standardised on salicilin ( > 1.5%) 300 mg) twice daily was

administered to determine the effects of therapy on migraine attack frequency (primary efficacy

criterion), intensity and duration (secondary efficacy criteria), and quality of life, together with the

tolerability for patients.

Attack frequency was reduced by 57.2% at 6 weeks (p<0.029) and by 61.7% at 12 weeks (p<0.025)

in nine of ten patients, with 70% patients having a reduction of at least 50%. Attack intensity was

reduced by 38.7% at 6 weeks (p<0.005) and by 62.6% at 12 weeks (p<0.004) in ten of ten patients,

with 70% of patients having a reduction of at least 50%. Attack duration decreased by 67.2% at 6

weeks (p<0.001) and by 76.2% at 12 weeks (p<0.00l) in ten of ten patients. Two patients were

excluded for reasons unrelated to treatment. Self-assessed general health, physical performance,

memory and anxiety also improved by the end of the study. The treatment was well tolerated and no

adverse events occurred.

Author’s conclusions: the remarkable efficacy of the combination product in this trial is not only

reducing the frequency of migraine attacks but also pain intensity and duration. Further investigation

of this therapy in a double-blind, randomised, placebo-controlled investigation involving a larger

patient population is necessary (Shrivastava et al. 2006).

Guideline for the non-pharmacologic management of migraine in clinical practice

To provide physicians and allied health care professionals with guidelines for the non-pharmacologic

management of migraine in clinical practice, a large full range and quality of non-pharmacologic

therapies available for the management of migraine was analysed. The objective of the guidelines was

the improvement in the non-pharmacologic management of migraine. The creation of the guidelines

followed a need of assessment by members of the Canadian Headache Society and included a

statement of objectives. Regarding the use of feverfew, two small randomized controlled trials were

considered to show the efficacy of feverfew (herb) in migraine prophylaxis. According to the Canadian

Headache Society, feverfew may be considered as an option for migraine prophylaxis because of its

relatively benign side effect profile (occasional mouth ulceration and contact dermatitis). Feverfew

treatment was assigned to class B recommendation, when differentiating between class A, B and C

recommendations (Pryse-Phillips et al. 1998).

Feverfew in rheumatoid arthritis

 Feverfew in rheumatoid arthritis: a double blind, placebo controlled study.

Feverfew is reputed by folklore to be effective in arthritis. Forty one female patients with symptomatic

rheumatoid arthritis received either dried powdered feverfew (70-86 mg) leaf (equivalent to 2-3 μmol

PN) or placebo capsules once daily for six weeks. One capsule of feverfew corresponded to two

medium sized leaves. Allocation was random and not known by patient or observer. Variables assessed

included stiffness, pain (visual analogue scale), grip strength, articular index, full blood count,

erythrocyte sedimentation rate, urea, creatinine, C reactive protein, complement breakdown products

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(C3dg), rheumatoid factor titre, immunoglobulins (IgG, IgA, IgM), functional capacity, and patient and

observer global opinions. One patient (placebo) withdrew after three days and was not included in the

analysis. Treatment and placebo groups (20 patients each) were well matched at entry. No important

differences between the clinical or laboratory variables of the groups were observed during the six

week period. This study therefore shows no apparent benefit from oral feverfew in rheumatoid arthritis

(Pattrick et al. 1989).

4.2.3. Clinical studies in special populations (e.g. elderly and children)

 Compositae dermatitis from airborne parthenolide

Feverfew is a member of the European Compositae plant family that are suspected of causing airborne

contact allergy. Its most important allergen is the sesquiterpene lactone PN. A study was designed to:

(i) assess the allergenicity of feverfew-derived monoterpenes and sesquiterpenes and their oxidized

products in feverfew-allergic patients, (ii) re-assess the role of PN and other sesquiterpene lactones in

airborne contact allergy. Feverfew-allergic patients were patch tested with extracts and fractions

containing volatile monoterpenes and sesquiterpenes as well as extracts of airborne particles from

flowering feverfew plants, obtained by fractionation of ether extracts, dynamic headspace and high-

volume air sampler (HIVAS) technique, respectively. Among 12 feverfew-allergic patients, 8 had

positive patch-test reactions to a HIVAS filter extract, while 2 tested positive to a headspace extract.

Subsequent analysis of the HIVAS extract by gas chromatography and mass spectrometry detected PN

in a concentration of 510 mg ml -1 in the HIVAS extract. Testing with a dilution series of PN showed

positive reactions down to 8x1 mg in selected patients. None of the 12 patients tested positive to

monoterpenes or sesquiterpenes, whether they were oxidized or not. The clinical results have proved

that some feverfew-allergic patients are sensitive to airborne particles released from the plant and

isolation of PN from the particle-containing HIVAS extract in allergenic amounts is strong evidence of

PN as the responsible allergen (Paulsen et al. 2007).

4.3. Overall conclusions on clinical pharmacology and efficacy

Based on the totality of evidence, including clinical trials and systematic reviews, feverfew should not

be considered as definitely effective (grade B evidence) nor as established safe in long-term use. Even

though some studies are positive, we consider their results inadequate to substantiate well established

use because the small number of patients, effects that were only lightly superior than placebo and the

different dosages used.

5. Clinical Safety/Pharmacovigilance

5.1. Overview of toxicological/safety data from clinical trials in humans

Feverfew was well tolerated in the included trials, and adverse events were generally mild and

reversible. Controlled studies have demonstrated no effect on blood pressure, heart rate or body

weight after 6 months of regular consumption of encapsulated dried feverfew leaf (Johnson et al.

1985). Two studies (Johnson 1985; Murphy 1988) reported a higher incidence of adverse events

during treatment with placebo than with feverfew. Feverfew did not appear to affect blood pressure,

heart rate, body weight or haematological and biochemical safety parameters (Pittler 2004).

During the study conducted in 1985 by Johnson at the City of London Migraine Clinic, roughly 10% of

patients who were switched to placebo after taking feverfew for several years appeared to experience

a genuine “post-feverfew syndrome”: a cluster of nervous system reactions including rebound of

migraine symptoms, anxiety, poor sleep patterns along with muscle and joint stiffness (Johnson 1985).

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It was a small study including seventeen patients that were already using the plant by eating fresh

leaves of feverfew daily as prophylaxis against migraine in the period before the beginning of the

clinical investigation.

In another study conducted by Pfaffenrath et al. (2002), the incidence of adverse events was similar

for all treatment groups.

Chewing feverfew leaves produces sometimes a more general inflammation of the oral mucosa and

tongue, accompanied by swelling of the lips and occasionally loss of taste. In Johnson’s 1983 survey of

300 feverfew users, mouth ulceration (aphthous ulcers) from chewing fresh leaves was reported by

11.3% of users, prompting discontinuance of treatment by some. Mouth ulceration is a systemic

reaction to Tanaceti Parthenii observed only in subjects chewing fresh leaves; it requires

discontinuation of the product. Inflammation of the mouth and tongue with swelling of the lips appears

to be a local reaction that may be overcome by using encapsulated herb products (WHO monograph

2004).

Abdominal pains and indigestion have been reported for feverfew users who chewed the leaves over a

period of years. Although long-term toxicity data are presently unavailable, no serious side effects

have been noted in patients taking the plant for several years. Digestive disturbances were

experienced by 6.5% of respondents (Dennis 1998, Johnson 1983).

The frequency of chromosomal aberrations and sister chromatid exchanges was determined from

lymphocyte cultures established from blood samples. Samples had been taken over a period of several

months in 30 migraine patients who had daily taken leaves, tablets or capsules of feverfew for more

than 11 consecutive months. They were compared to 30 feverfew non-user migraine patients who had

been individually age and sex matched. Matched pairs were sampled on the same date for two-thirds

of the cases, and the greatest difference in sampling time of the remainder was 20 days. Also, the

mutagenicity of urine samples from 10 feverfew user migraine patients was compared to that from 10

matched non-user migraine patients using the Ames Salmonella mutagenicity test system. Paired

samples were given on the same date. The mean frequency of chromosomal aberrations in the

feverfew user group was lower than that in the non-user group, both in terms of cells with breaks

(2.13% vs 2.76%) and in terms of cells with all aberrations (4.34% vs 5.11%). However, this

difference was small and not significant. The mean frequency of SCE in the feverfew exposed group

was lower than that in the control group (8.78 vs 8.80 SCE/cell ), but this difference was not significant

as determined by factorial analysis of variance (P =0.897). There was a highly significant variance

between the frequencies of SCE in the matched pairs of migraine patients, but this was not related to

age, sex or feverfew exposure. The mean number of revertants in the Ames mutagenicity assay was

greater for the urine of the feverfew user migraine patients than that of the non-user migraine

patients, in both strains of bacteria, with or without the inclusion of an S-9 metabolizing system.

However, the increases were small and insignificant. The data indicate that the prophylactic use of

feverfew for the alleviation of migraine symptoms affects neither the frequency of chromosomal

aberrations nor the frequency of SCE in the circulating peripheral lymphocytes. Also, the mutagenicity

of urine from feverfew user migraine patients is unaffected compared to urine from non-user migraine

patients detectable by the methods used in this study (Anderson et al. 1988).

5.2. Patient exposure

Feverfew has been ingested continuously by large numbers of people without indication of any chronic

toxicity effects (Dennis 1998). Anderson et al. (1988) found no substantial differences in the frequency

of chromosomal aberrations and sister chromatid exchanges in lymphocytes, or in the mutagenicity of

urine, in tests comparing migraine patients who used feverfew leaves, tablets or capsules chronically

with non-users of feverfew.

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Sesquisterpene lactones such as the feverfew constituent and PN are also known to cause contact

dermatitis (Dennis 1998, Johnson 1983).

5.3. Adverse events and serious adverse events and deaths

Allergy to Tanacetum and other plants from the Compositae family

Parthenium dermatitis, in its classical form, is known as airborne contact dermatitis and primarily

affects the exposed areas and the flexures. Other clinical patterns are a seborrheic pattern, widespread

dermatitis and exfoliative dermatitis.

The trend of the clinical pattern is changing. The classic airborne contact dermatitis may change to

photodermatitis resembling chronic actinic dermatitis or mixed pattern dermatitis. The allergens

responsible for contact dermatitis are sesquiterpene lactones and are present in the oleoresin fraction

of the leaf, the stem and the flower, and also in the pollen. The allergens can be extracted in various

solvents (such as acetone, alcohol, ether and water) and then used for patch testing. The acetone

extract of T. parthenium is better than the aqueous extract in eliciting contact sensitivity. The

treatment of T. parthenium dermatitis is mostly symptomatic. Topical steroids, antihistamines and

avoidance of T. parthenium are the mainstay of treatment for localised dermatitis. Systemic

corticosteroids and azathioprine are frequently needed for severe or persistent dermatitis (Sharma et

al. 2007).

A case of specific, delayed hypersensitivity induced by repeated contact with a wild form of feverfew in

a 63-year-old man who had suffered from recurrent dermatitis on his hands and forearms; most

marked on the dorsal side and on his face, mainly around the eyes, was reported in 1983. Cross-

reactions were elicited with 11 of 21 mostly Compositae plants containing chemically related

sesquiterpene lactones (Hausen & Osmundsen 1983).

Compositae dermatitis occurred in a 9-year-old boy with a strong personal and family history of atopy.

A positive patch test reaction was found for feverfew and other Compositae plants. The eruption

resembled atopic dermatitis morphologically but was prominent on the palms and face and

dramatically spared the area of the boy's feet covered by his shoes (Guin & Skidmore 1987).

Around 80% of patients with prurigo nodularis are atopic, even in the absence of eczema, and in 20%,

the condition starts after an insect bite. The association of contact dermatitis with prurigo nodularis

was documented in a study of 32 patients, 25 of whom had positive patch tests, including to ragweed.

Three case reports of prurigo-like lesions in contact dermatitis have been described. They were the

first reports of prurigo-nodularis-like lesions in patients with parthenium dermatitis. Azathioprine was

effective in both prurigo nodularis and parthenium dermatitis and was successful in 2 of the 3 patients

(Sharma & Sahoo 2000).

A 45-year-old woman presented an eruption involving her scalp and face, including her eyelids and

behind her ears. The eruption began at the end of August. It flared after she used a calming

moisturizer containing feverfew.

A second patient, a 25-year-old woman, presented complaining of a 1 month history of an eruption

around the eyes that started after she began using a moisturizer containing feverfew. Both patients

were patch-tested with the North American Contact Dermatitis Group series, cosmetic and plant series

and their own skin care products. The first patient had a + reaction to sesquiterpene lactone mix, a +

reaction to Compositae mix, a + reaction to PN, a + reaction to Tanacetum vulgare and a + reaction to

the calming moisturizer. Patient 2 had + reactions to sesquiterpene lactone, Compositae mix, and the

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same calming moisturizer. It is thought that both of these eruptions are a result of contact dermatitis

from the Compositae plant family (Killoran et al. 2007).

5.4. Laboratory findings

No data available.

5.5. Safety in special populations and situations

Occupational or direct exposure has caused eczema and allergic dermatitis.

Feverfew cross reacts with Tansy, Yarrow, Marguerite, Aster, Subflower, Laurel and Liverwort (PDR

monograph 2007).

Withdrawal and rebound

Post-feverfew syndrome. About 10% of migraine patients who abruptly stop taking feverfew fresh

leaves may experience rebound headache, insomnia, muscle stiffness, joint pain, fatigue and

nervousness (PDR monograph 2007).

Drug interactions

Some theoretical potential risks have been suggested:

- feverfew inhibits platelet aggregation and it has been suggested that caution should be used in

patients treated with other inhibitors of platelet aggregation such as aspirin and dipyridamole (PDR

monograph 2007);

- moderate risk of bleeding may result by interactions with anticoagulants, low molecular weight

heparins, thrombolytic agents and antiplatelet agents (PDR monograph 2007);

- moderate risk of adverse reactions (i.e. gastrointestinal, renal effects) may result by interactions with

nonsteroidal anti-inflammatory agents (PDR monograph 2007).

However, no drug interaction has been reported in people taking feverfew.

Use in pregnancy and lactation

In view of its traditional reputation for emmenagogic effect and to affect the menstrual cycle (Herbal

Medicines 2007), feverfew preparations should not be consumed by pregnant or lactating women.

Use in children and adolescents

Because of lack of information on the plant’s effect, it has to be advised that children and adolescents

should not be treated with feverfew.

5.6. Overall conclusions on clinical safety

Data from clinical studies show that feverfew is well tolerated and adverse events were generally mild

and reversible. In view of its traditional reputation for emmenagogic effect, feverfew preparations are

contraindicated in pregnant or lactating women. Because of the lack of data, feverfew treatment is not

recommended in children and adolescents. Moderate risks may result from interactions with drugs or

substances influencing blood coagulation and platelets aggregation. Rebound symptoms may appear

after stop taking feverfew. Exposure to feverfew may cause eczema and allergic dermatitis.

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6. Overall conclusions

Tanacetum parthenium , also known as “feverfew”, is a member of the Compositae family and it has

been described since ancient times as having beneficial medicinal effects. The plant parts used for

medicinal use are the dried leaves or the dried aerial parts.

Several investigations support feverfew’s traditional medicinal uses. Feverfew herbal medicinal

products for migraines have been available for more than 30 years in the European Union and the

medicinal use of feverfew for migraine and headaches in Europe is well documented for centuries.

The sesquiterpene lactone parthenolide is considered the main active constituent. Parthenolide inhibits

platelet aggregation and platelets serotonin release. It has also been shown that parthenolide has

antinflammatory effects through the inhibition of NF-κB and the IκB kinases complex.

Feverfew appears to be safe and well tolerated for the indication proposed and side effects are

generally mild and reversible. Despite the wide use, no serious adverse reaction was reported. The

analysis of data from clinical studies shows that side effects associated with its use such as nausea,

heartburn, constipation, flatulence, abdominal bloating and diarrhoea are rarely reported and their

frequency is similar to that of placebo. The occurrence of frequent mouth ulceration has been reported,

but it has successively become clear that it is associated with chewing of feverfew fresh leaves. Such

events are not reported from clinical studies in which feverfew was encapsulated. This may be

plausible because such preparations do not come into contact with the Langerhans cells of the skin oral

mucosa. Potential problems of sensitisation caused by allergens can be avoided by the use of capsules.

The proposed medicial use for Tanaceti parthenii herba is:

“Traditional herbal medicinal product for the prophylaxis of migraine headaches”.

Due to the lack of sufficient data on long term use and based on the knowledge that prolonged intake

can provoke rebound effects when feverfew is withdrawn, the duration of use of two months seems to

be suitable for self-medication.

Annex

List of references

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Herbal Medicines for Human Use

Herbal Medicines
for Human Use