Placebo-Controlled Trial of Feverfew in Migraine Prevention
J. Murphy, S. Heptinstall, J.R.A. Mitchell,
The Lancet, July 23, 1988
of Medicine, University Hospital, Nottingham
The use of feverfew (Tanacetum parthenium) for migraine prophylaxis
was assessed in a randomised, double-blind, placebo-controlled
crossover study. After a one-month single-blind placebo run-in,
72 volunteers were randomly allocated to receive either one capsule
of dried feverfew leaves a day or matching placebo for four months
and then transferred to the other treatment limb for a further
four months. Frequency and severity of attacks were determined
from diary cards which were issued two months; efficacy of each
treatment was also assessed by visual analogue scores. 60 patients
completed the study and full information was available in 59.
Treatment with feverfew was associated with a 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. Visual analogue scores also indicated a significant
improvement with feverfew. There were no serious side-effects.
Die Anwendung von Mutterkraut (Tanacetum
parthenium) in der Migräne-Prophylaxe wurde mit einer
randomisierten, doppelblind angelegten und placebo-kontrollierten
Crossover-Studie geprüft. Nach einer einmonatigen einfachblinden
Placebo-Verabreichung, wurden 72 Freiwillige zufällig in zwei
Gruppen aufgeteilt, die entweder vier Monate lang täglich eine
Kapsel Mutterkraut-Blätter oder Placebo erhielten. Danach wurde
jeder Patient für weitere vier Monate der jeweils anderen Behandlung
unterworfen. Die Häufigkeit und Schwere der Anfälle wurde über
2 Monate täglich festgehalten. Die Wirksamkeit der beiden Behandlungsmethoden
wurde nach Befragung der Patienten numerisch gewichtet. 60 Patienten
beendeten die Studie, von 59 konnten alle Befunde ermittelt werden.
Die Behandlung mit Mutterkraut war begleitet mit einer Verringerung
der Zahl und der Schwere der Anfälle im jeweiligen 2-Monatszeitraum.
Nicht verändert waren das Ausmaß der Übelkeit und die Dauer der
einzelnen Attacken. Auch die Übertragung der Befunde in numerische
Werte ergab eine signifikante Verbesserung nach Behandlung mit
Mutterkraut. Besondere Nebenwirkungen wurden nicht beobachtet.
aromatic plant known as feverfew (Tanacetum parthenium) was used
in monastic times as an antipyretic1. Over the past
decade it has regained its former status as a medicinal herb and
the leaves are a popular lay remedy for migraine prevention. The
plant is rich in a family of compounds known as sesquiterpene
lactones, principally parthenolide2. The intensity
of interest in feverfew in the UK was shown when 25.000 replies
were received in response to an offer of further information in
a national newspaper3. Both fresh and dried leaves
are ingested and several commercial preparations are available.
pathogenesis of migraine remains unknown, but abnormal platelet
behaviour has been implicated4. During an attack platelets
release serotonin5 and a pathogenic role for this process
is supported by the value of serotonin antagonists in migraine
prevention (pizotifen7, methysergide8) and
of ergotamine in acute treatment. In-vitro studies have shown
that feverfew extract inhibits serotonin release from platelets9,
if this response occurs in vivo, it might explain the clinical
benefit reported in migraine10.
have been few clinical studies of feverfew. In a double-blind
study, Johnson et al11 examined the effects of withdrawal
of feverfew from regular users who felt its use to be beneficial.
The deterioration in migraine in those changed to placebo provides
indirect evidence of efficacy, but, by virtue of the self-selection
of these patients, the effect of feverfew on migraineurs generally
could not be assessed. We now report the results of a prospective
double-blind placebo-controlled trial of feverfew in migraine
open meeting, organised in association with the local migraine
self-help group and publicised by the media, was attended by 150
people. From this group and from those responding directly to
the media publicity, 190 individuals volunteered for the study.
119 satisfied the entry criteria and 76-23 with classical and
53 with common migraine-agreed to participate. All patients gave
informed consent and the protocol was approved by the hospital
ethical committee. Those eligible for the study were adults with
migraine (as defined by Blau12) of more than two years
duration with at least one attack a month. Patients were excluded
if they were receiving treatment for conditions other than migraine
except for women taking oral contraceptives, who were included
if their treatment had been unchanged for at least three months.
Women of childbearing age not receiving adequate contraception
study group consisted of 20 men and 56 women whose ages ranged
from twenty-four to seventy-two years (mean forty-six). 70 (92%)
had previously consulted a general practitioner about their migraine
and 19 (25%) had been referred to a hospital consultant. 37 (47%)
had already tried conventional migraine prophylaxis and 39 (51%)
had received ergotamine; only 17 (22%) had received neither form
of therapy. 18 (23%) had previously tried feverfew, of whom 11
thought it helpful. On entry to the study 5 were still taking
feverfew, 4 propranolol, and 3 pizotifen. All migraine-related
drugs were stopped at the beginning of the trial.
a one-month single-blind placebo run-in period, patients were
randomly allocated to receive either one capsule of feverfew daily
or matching placebo for four months. They were then transferred,
with no intervening washout period, to the other treatment limb
for the final four months.
were assessed every two months for the double-blind phases of
the study. A diary of migraine symptoms was provided for each
of these periods in which patients recorded the number and duration
of individual attacks, the severity of headache, and any associated
features. The severity of headache was graded as follows: 0 =
no pain; 1 = mild, not interfering with daily activities; 2 =
severe, reducing working capacity; 3 = very severe, requiring
rest in bed. Nausea and vomiting were also recorded: 0 = no nausea
or vomiting; 1 = nausea only; 2 = vomited once; 3 = vomited repeatedly.
Details of visual or focal neurological features and working days
lost through migraine were noted.
patients’ overall impressions of each two-month treatment period
were assessed in two ways. A 10 cm visual analogue scale was used
to represent an individual`s range of migraine, with "worst
ever" and "best ever" as the two extremes. Measurement
in millimetres from the "worst ever" end produced a
score ranging from 0 to 100, with higher scores indicating a better
period for migraine. Patients also graded each treatment period
by choosing one for five reponses: A = much worse; B = worse;
C = same; D = better; E = much better. at the end of the study
patients were asked to indicate which of the two four-month periods
of treatment they regarded as more effective.
I - COMPARISON OF MEAN (SEM) NUMBER AND DURATION OF ATTACKS IN
EACH TWO-MONTH PERIOD
of attacks (h)
NS = Not
presence of mouth ulceration, reported to be a side-effect of
feverfew13, was elicited by direct questioning at each
visit. Other side-effects were elicited by recording the response
to a standard question: "Have you noticed any problems with
the treatment?" Urinalysis for blood and protein (BM-Test-5L,
Boehringer Mannheim) and routine haematological and biochemical
tests were done during the run-in and at the end of each treatment
phase; blood pressure and pulse rate were recorded at the same
visits. Blood pressure (right arm, Hawksley random-zero sphygmo-manometer,
all treasurements in duplicate) was measured supine after resting
for 5 min, and erect after standing for 2 min; pulse rate was
determined by radial palpation for 30 s after each blood pressure
plants were propagated from original plants which had been selected
for their high anti-secretory activity (see below). They were
grown under glass, watered daily, and fed weekly with a high nitrogen,
high potassium feed. The plants were kept at 20-24°C and received
sixteen hours of light a day from fluorescent tubes. Leaves were
gathered weekly throughout the year and were taken from the shoots
of non-flowering plants.
II - ATTACKS OF STATED SEVERITY ON EACH TREATMENT
0 (no pain)
3 (very severe)
no of attacks
were washed in clean cold water, soaked in a solution of 0-5%
(v/v) sodium hypochlorite for 10 min to reduce bacterial contamination,
and rinsed in copious amounts of fresh cold water. They were then
blot-dried on large sheets of absorbent paper and transferred
to a drying cabinet at 37°C. After four days, the dried leaves
were placed in polythene containers and stored at 4°C until required.
Before the capsules were prepared, samples of each batch of leaves
were analysed for anti-secretory activity9 by quantifying
the inhibitory effect of chloroform extracts of the laeves on
14C-serotonin release from human platelets.
capsulets were prepared from finely powdered leaves in the hospital
pharmacy in accordance with standard guidelines14 and
stored at 4°C until dispensed (or discarded after five months
if unused). The amount of feverfew powder used per capsule varied
with the strength of the preparation, as judged by its anti-secretory
activity. Capsule weights ranged from 70 to 114 mg (mean. 82 mg)
and contained the equivalent of 2.19 (SD 0.63) µrnol parthenolide
III - ATTACKS ACCOMPANIED BY NAUSEA AND VOMITING ON EACH TREATMENT
nausea or vomiting
capsule therefore corresponded to about two medium-sized leaves.
Placebo capsules contained dried cabbage leaves which were similarly
prepared; the cabbage did not possess any anti-secretory activity.
was restricted to patients who completed the study. Unless otherwise
stated, mean values, and standrad errors are reported. Analysis
of variance was used to compare the number and duration of attacks,
the visual analogue scores, blood pressure, and pulse rate. The
homogeneity of variance was assessed with Cochraná test and logarithmic
transformation of the data was done as necessary. Contingency
tables were analysed by c 2 ,
with Pearson´s coefficient of contingency to quantify differences
of the 76 patients (79%) completed the study. 4 withdrew during
the placebo run-in and 12 after randomisation (6 on feverfews,
6 on placebo), 5 of the withdrawals after randomisation were because
of side-effects (2 feverfew, 3 placebo); 4 chose to withdraw because
of failure to improve (3 feverfew, 1 placebo) and 2 after development
of serious illness unrelated to the trial (both on placebo); and
1 patient defaulted from follow-up. Of the 60 remaining patients
who completed the study, 1 lost her migraine diary on two separate
occasions, so the results refer to the remaining 59.
was a 24% reduction (95% confidence interval 14-34%) in the number
of attacks during feverfew treatment but no significant alteration
in the duration of individual attacks (table I). there was a non-significant
tendency (p = 0.06) towards milder headaches with feverfew (table
II) and a significant reduction (p < 0.02) in nausea
and vomiting accompanying the attacks (table III). 68 working
days were lost through migraine during the feverfew phases vs
76 with placebo.
of the global assessments of efficacy showed that feverfew was
better than placebo. The visual analogue score (higher scores
indicate improvement) was 74 (2) on feverfew vs 60 (3) on placebo
(p < 0.0001).
1 compares the grading (five-point scale) of each two-month period.
The reponses on feverfew and placebo differed
(p < 0.001): 36% of all feverfew periods were graded as "much
better" for migraine and only 1% as "much worse"
compared with placebo values of 21% and 10%, respectively.
1 - Overall grading of the two-month treatment periods according
to the five-point scale, expressed as a percentage of the total
number of periods on each treatment.
completing the study (and stiff "blind" to therapy)
35 (59%) patients reported that a feverfew period was more effective
whereas only 14 (24%) chose placebo (p < 0.001). 10 patients
(17%) felt there was no difference between treatments.
2 - Effect of each treatment on the number of attacks throughout
= significant difference between feverfew and placebo, p<
the 17 patients with classical migraine were considered separately,
feverfew reduced the number of attacks by 32% from 4.3 (0.5) to
2.9 (0.4) (95% confidence interval 11-53%, p < 0.05), and increased
the visual analogue score from 57 (5) to 78 (4) (p < 0.01).
There was no difference in the proportion of attacks associated
with an aura. For the 42 patients with common migraine, feverfew
reduced the number of attacks by 21 %, from 4.9 (0.4) to 3.9 (0.3)
(95% confidence interval 10-33%, p = 0.06) and increased the visual
analogue score from 61 (3) to 72 (2) (p < 0.01).
the 59 patients completing the study, 42 had never previously
taken feverfew. When this group was considered separately, feverfew
reduced the number of attacks from 4.5 (0.4) to 3.5 (0.3), a reduction
of 23% (p < 0.05, 95% confidence interval 10-35%). This improvement
was reflected in the mean visual analogue score, which rose from
64 (3) with placebo to 74 (2) with feverfew (p < 0.05).
2 and 3 show the numbers of attacks and visual analogue score
in the whole group throughout the nine months of the study. The
results suggest that the observed differences are attributable
to improvement with feverfew rather than to deterioration on its
were no differences between the mean erect and supine blood pressures
or heart rate on either treatment.
3 - Effect of each treatment on visual analogue score throughout
p < 0.05; ** p <
IV shows the reported side-effects with each treatment. Mouth
ulceration was more common during treatment with placebo, and
there was no overall excess of side-effects on feverfew. Analysis
of variance was used to compare laboratory investigations on each
treatment; no change was seen in haematological tests, urea, creainine,
electrolytes, blood sugar, or tests of liver function. There was
no difference in urinalysis on the two treatments.
IV - SIDE-EFFECTS ON EACH TREATMENT
withdrawal of a patient because of side-effects
with feverfew was clearly associated with a reduction in migraine
frequency, and in the vomiting associated with attacks;
there was also a trend towards a reduction in migraine severity.
3 patients withdrew from the study during a feverfew phase because
of failure to improve compared with 1 during a placebo phase,
but this finding would not account for the observed differences
between the remaining patients. Stopping regular feverfew has
been associated with deterioration in migraine symptoms11,
and with our crossover design, which did not include a washout
period between treatments, differences could have resulted from
feverfew; this possibility is not supported by the data shown
in figs 2 and 3.
sesquiterpene lactones (chiefly parthenolide) in feverfew are
responsible14 for the reduced secretory activity of
platelets and white cells in vitro9, possibly by neutralisation
of sulphydryl groups16. It is unclaer, however, whether
these observations have any bearing on the therapeutic effect
findings have wider implications. In common with other herbal
remedies, feverfew is exempt from the preliminary tests of safery
required in the UK by the 1968 Medicines Act. Although no serious
adverse effects have been recorded in long-term users of feverfew11,13,17,
these studies were retrospective and the patients were therefore
self-selected. Our approach has been pragmatic in that we were
asking our volunteers to do no more, under close medical supervision,
than they were prepared to do without such supervision. Patients
who take feverfew on their own initiative are likely to be seen
with increasing frequency by general practitioners, physicians,
and neurologists and further information is therefore required
both on the potentail benefits and on safery associated with its
use. In our study, treatment with feverfew did not produce any
adverse effects but the period of treatment (four months) was
short, especially since lifelong treatment may bei required for
migraine. Information is also needed on the quality of commercial
preparations of the herb. In one study18, wide differences
in the anti-secretory activity were measured in different commercial
products; activity was even undetectable in some brands, and,
as one would expect, in all homoeopathic preparations. Moreover,
the ability of feverfew to modify the natural history of migraine
serves as a reminder that active agents are still readily available
through health-food shops.
thank Mrs. S. Green for preparing the capsules and for her help
with analysing the results, Miss W. Antoinette Groenewegen for
helping with the assay for anti-secretory activity, and Mr. P.
H. Reilly for his advice on statistics. We also thank Dr. Brian
Power and staff of the Department of Botany at Nottingham University
for cultivating the feverfew plants, and the Nottingham and District
Migraine Self-Help Group.
should be addressed to J.J. M., Department of Medicine, University
Hospital, Queen´s Medical Centre, Nottingham NG7 2UH.
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