Randomised controlled trial of butterbur and cetirizine for treating seasonal allergic rhinitis

Those of us 'Wellness Consultants' who have been successfully using
Butterbur for many years now, are not surprised at it's recent success in
a Randomized Clinical Trial against Cetirizine, for the treatment of
Seasonal Allergic Rhinitis (SAR) ; as warmly indexed under Andreas
Schapowal et al : BMJ, 2002 Jan 19;324(7330):144-6 ***

Infact , many of us consistently feel that Butterbur may also be
exceedingly efficacious in Perennial Allergic Rhinitis (PAR)...and a whole
host of other related conditions too.

The highly laudable fact that Butterbur does not have any sedating
properties , therapeutically adds more icing to the cake.

Without wanting to be seen as being 'immensely over-excited' about
these momentously inspiring results, permit me to humbly provide a few
widely known excerpts on Butterbur; as placed in the public domain by the
Alternative Medicine Review , way back in 2001.

Admittedly, the Butterbur sample sizes are not as huge as those
portrayed in many other trials, but at least we are warmly provided with a
very welcome 'start' in the exponentially expanding field of Complementary
and Alternative Medicine (CAM) Research.

Listen...and Learn.

Petasites Hybridus (Butterbur).

Source : Alternative Medicine Review , 2001.

Introduction : Petasides hybridus (butterbur) is a perennial shrub,
found throughout Europe as well as parts of Asia and North America, that
has been used medicinally for centuries.

During the Middle Ages butterbur was used to treat plague and fever;
in the 17th century its use was noted in treating cough, asthma, and skin
wounds.[l,2]

The plant can grow to a height of three feet and is usually found in
wet, marshy ground, in damp forests, and adjacent to rivers or streams.
Its downy leaves can attain a diameter of three feet, making it the
largest of all indigenous floras, and their unique characteristics are
responsible for the plant's botanical and common names.

The genus name, Petasites, is derived from the Greek word petasos,
which is the felt hat worn by shepherds.[2] The common name of butterbur
is attributed to the large leaves being used to wrap butter during warm
weather.[3] Other common names include pestwurz (German), blatterdock, bog
rhubarb, and butter-dock.[2]

Currently, the primary therapeutic uses for butterbur are for
prophylactic treatment of migraines, and as an antispasmodic agent for
chronic cough or asthma. It has also been used successfully in preventing
gastric ulcers, and in treating patients with irritable bladder and
urinary tract spasms.[2,4]

Active Constituents: Extracts of Petasites hybridus are prepared from
the rhizomes, roots, and leaves. The main active constituents are two
sesquiterpenes, petasin and isopetasin. Petasin is responsible for the
antispasmodic properties of the plant by reducing spasms in smooth muscle
and vascular walls, in addition to providing an anti-inflammatory effect
by inhibiting leukotriene synthesis.

Prostaglandins are important mediators in the inflammatory process
and isopetasin's positive impact on prostaglandin metabolism contributes
to the effectiveness of Petasites extracts.

Extracts of the plant also contain volatile oils, flavonoids,
tannins, and pyrrolizidine alkaloids. As these alkaloids are believed to
be toxic to the liver and carcinogenic in animals, extracts are available
in which the pyrrolizidine alkaloids have been removed.[2]

Mechanisms of Action:The active constituents of Petasites have an
antispasmodic effect on vascular walls and appear to have an affinity for
cerebral blood vessels. Petasites' ability to reduce smooth muscle spasm
suggests it may be a useful therapeutic tool in treating urinary
disorders, menstrual cramps, migraine headaches, kidney stone disorders,
obstruction of bile flow, as well as other liver or gastrointestinal
disorders associated with smooth muscle spasm.[1]

The anti-inflammatory properties of butterbur extracts are attributed
to inhibition of lipoxygenase activity and down-regulation of leukotriene
synthesis, and are primarily due to the petasin content.[5].

Clinical Indications:

*Migraine Headache :Two clinical studies using 50 mg of a
standardized Petasites extract twice daily for 12 weeks demonstrated its
effectiveness as a prophylactic treatment for migraines. Both studies were
double-blind, placebo controlled, and involved a total of 128 patients.
The results of the two studies showed a significant reduction (as much as
60%) in frequency of migraine attacks compared to placebo. Other
improvements in the Petasites group included a reduction in the number of
days with migraines per month, a decrease in migraine-associated symptoms,
and diminished duration and intensity of pain. No adverse reactions were
reported in either study. Butterbur extract's high degree of efficacy and
excellent tolerability accentuates its value in the prophylactic treatment
of migraines.[6,7]

*Asthma/Bronchitis :Various parts of the butterbur plant have been
used for centuries to treat bronchial asthma and whooping cough, and in
folk medicine the leaves of the plant were used as a mucus-reducing cough
remedy.

Butterbur's ostensible effectiveness in treating upper respiratory
disorders such as asthma and bronchitis is attributed to the antispasmodic
properties of the petasin constituent. The plant's anti-inflammatory
action would also help calm the reactive airways seen in both asthma and
bronchitis.[2]

A Polish clinical study conducted in 1998 examined the influence of
Petasites on lung ventilation and bronchial reactivity in patients
suffering from asthma or chronic obstructive bronchitis. The study
included three test groups and two control groups. Test Group A exhibited
an improvement in forced expiratory volume (FEV1) three hours after an
oral dose of 600 mg Petasites extract. Group B experienced a significant
decrease in bronchial reactivity two hours after receiving an oral dose of
600 mg Petasites extract. Group C patients were treated for 14 days and
received 600 mg of the extract three times daily. Some patients (n=10)
were also given corticosteroids due to disease severity. All three groups
exhibited a decrease in bronchial reactivity, but the patients in Group C
who received no corticosteroids had the most pronounced results.[8] These
results indicate Petasites might be helpful in improving lung ventilation
in patients with asthma or chronic obstructive bronchitis.

*Gastrointestinal Disorders : Butterbur's use as an antispasmodic for
gastrointestinal conditions dates back to the Middle Ages. The leaves and
rhizomes were used to treat spasms of the digestive tract associated with
colic, plague, and bile flow obstruction.[9,10].

A German study conducted in 1993 found ethanolic extracts of
Petasites hybridus blocked ethanol-induced gastric damage and reduced
ulcerations of the small intestine caused by indomethacin, an anti-
inflammatory drug used to treat arthritic conditions. The results of this
study were attributed to inhibition of lipoxygenase activity and
leukotriene biosynthesis.[11].

Safety : Until recently, side effects from Petasites extracts had not
been reported. In September 2000, a study conducted in Taiwan noted the
petasin constituent, responsible for many of butterbur's pharmacological
properties, inhibited the production of testosterone in rat testicular
cells, but did not speculate whether this effect would be applicable in
humans.[12]. The plant's pyrrolizidine alkaloids are thought to cause
liver damage and to be carcinogenic in animals; however, extracts are
commercially available in which the pyrrolizidine alkaloids have been
removed.

There are no known interactions with either pharmaceutical or over-
the-counter anti-inflammatory agents; however, use of Petasites extracts
during pregnancy and lactation is contraindicated.[1].

Dosage : Typically, Petasites extracts are standardized to contain a
minimum of 7.5 mg of petasin and isopetasin. The adult dosage ranges from
50-100 mg twice daily with meals. When used to treat migraines,
administration is prophylactic and supplementation should be carried out
daily for four to six months and then tapered until migraine incidence
begins to increase. Dosage regimens for asthma and gastrointestinal
disorders are as yet undefined, dictating the need for further research.

References

[1.] Eaton J. Butterbur, herbal help for migraine. Nat Pharm
1998;2:1,23-24.

[2.] Mauskop, A. Petasites hybridus: ancient medicinal plant is
effective prophylactic treatment for migraine. Townsend Lett 2000;202:104-
106.

[3.] Grieve M. Butterbur. In: Leyel CF, ed. A Modern Herbal,
electronic version. New York, NY: Dover Publications, Inc. 1971.

[4.] Reglin F. A clinical review: Petadolex [R] (Standardized
Butterbur Extract), Praxis-Telegram, Nr. 1/98:13-14.

[5.] Bickel D, Roder T, Bestmann HJ, Brune K. Identification and
characterization of inhibitors of peptido-leukotriene synthesis from
Petasites hybridus. Planta Med 1994;60:318-322.

[6.] Mauskop A, Grossmann WM, Schmidramsl H. Petasites hybridus
(butterbur root) extract is effective in the prophylaxis of migraines.
Results of a randomized, double-blind trial. J Head Face Pain 2000;40:4.

[7.] Grossmann WM, Schmidramsl H. An extract of Petasites hybridus is
effective in the prophylaxis of migraine. Int J Clin Pharmacol Ther
2000;38:430-435.

[8.] Ziolo G, Samochowiec L. Study on clinical properties and
mechanism of action of Petasites in bronchial asthma and chronic
obstructive bronchitis. Pharmaceutica Acta Helvetica 1998;72:359-380.

[9.] Lindauerova T. Palynomorphological investigation of the species
Petasites hybridus and Petasites albus. Farmaceuticky Obzor 1981:50:569-
574.

[10.] Blumenthal M, ed. The Complete German Commission E Monographs.
Austin, TX: American Botanical Council; 1998;183:365.

[11.] Brune K, Bickel D, Peskar BA. Gastro-protective effects by
extracts of Petasites hybridus: the role of inhibition of peptido-
leukotriene synthesis. Planta Med 1993;59:494-496.

[12.] Lin H, Chien CH, Lin YL, et al. Inhibition of testosterone
secretion by S-petasin in rat testicular interstitial cells. Chin J
Physiol 2000:43:99-103.

***Supporting BMJ Weblink :
http://bmj.com/cgi/content/full/324/7330/144

Competing interests:
Professor Joseph Chikelue Obi MBBS MD MPH DSc FRIPH FACAM is also the Chairman of the General Wellness Assembly (GWA); an International Professional Body for Independent Wellness Consultants . He humbly invented the 'Omnipill'.

Butturbur and cetirizine for treating seasonal allergic rhinitis: an
example of alleged “evidence based medicine”

The paper by Schapowal et al. (1) postulates that the effects of
butturbur and ceterizine were comparable in patients with hay fever. The
wording of this conclusion is misleading, because an equivalence of
specific therapeutic effects has not been documented by appropriate
biometrical respectively statistical analysis:

- The main outcome variable was the health survey questionnaire SF36
Score. This score is validated for an overall assessment of physical and
mental integrity but has no specificity for seasonal allergic rhinitis
(2).

- Efficacy has to be assessed by the difference between values after
therapy minus baseline as indicated in the paper under statistics. The
results are given as absolute values after two weeks‘ treatment but not as
values for the difference.

- The information about statistical methods and results is sparse and
incomplete. E.g. the analysis included each of out 8 items of the SF-36.
There is no clear information about the correction for multiple testing.

- The study intends to show non-inferiority, which asks for appropriate
design and statistical analysis. E.g. an adequate primary endpoint has to
be selected and justified. The statistical analysis has to be performed in
the PP and not in the ITT-population. Confidence intervals would be more
appropriate for the presentation of the results, but are not given.

The wording of a correct conclusion should be: „After a two week treatment
with butterbur or cetirizine similar effects regarding physical and mental
integrity in patients with hay fever were observed. Butterbur may produce
fewer sedating effects than cetirizine. Both observations are not
demonstrated by appropriate statistical methods“.
Since in addition to statistical errors of this paper (3,4,5), also
concerns about the toxicity of butterbur were raised in some letters
(6,7), a clarifying statement by the BMJ is actually needed and expected.

1. Schapowal A. Randomised controlled trial of butterbur and
cetirizine for treating seasonal allergic rhinitis BMJ 2002;324:144

2. Ware JJ, Sherbourne CD. The MOS 36-item short-form health survey (SF-
36). I. Conceptual framework and item selection. Medical Care 1992; 30:473
-83.

3. Kubba H, Oko M. A knife through butterbur bmj.com, 5 Feb 2002

4. Jacobs A. Lack of evidence of difference is not evidence of lack of
difference bmj.com, 24 Jan 2002

5. McArthur CA, Arnott N. The trial does not show that there is no
difference between butturbur and cetirizine bmj.com, 24 Jan 2002

6. Davis A.M. Cautions regarding butterbur for allergic rhinitis bmj.com,
21 Jan 2002

7. Firenzuoli F., Gori F. Toxicity of pyrrolizidine alkaloids. bmj.com
22 Jan 2002

Benno Schnyder, Juerg Hüsler and Werner J. Pichler, Division of
Allergology, Inselspital,
Univ. of Bern, Switzerland;

e-mail: Werner.Pichler@insel.ch

No competing interests of the three authors

We would like to raise two points regarding the paper by Schapowal et
al. We feel there may be a possibility of bias and we would question the
statistical interpretation of the data.

This is an unusual clinical trial in that it seems to be trying to
prove no difference between the treatment arms. Most trials are trying to
show that one treatment is better than the other. It is this unusual
feature which gives us concern regarding the methodology and the analysis.

In the usual situation, where a trial is investigating a possible
difference between treatments, double blinding is used to prevent bias by
patients or researchers. Without knowing which treatment they are on, they
cannot consistently overestimate one or other of the treatment effects.
However, if the hypothesis is that there is no difference between
treatments, it is possible to bias the result towards supporting the
hypothesis. This happens if one tends to score all patients similarly.
This bias could easily result unconsciously on behalf of patients and
researchers. Given that the trial on Butterbur (a petasite) is conducted
by the Petasites study Group there may well be a strong desire for the
researchers to prove their hypothesis and this makes them vulnerable to
unconsciously biasing the results in this way.

We would also like to question the interpretation of the data. The
authors use a “Mann-Whitney rank sum test (one sided)”. They state that
significant values mean Butterbur is not inferior. The P values for this
test are mostly 0.001. This seems to imply that Butterbur has been shown
to be not inferior to cetirizine with only a 0.1% chance of this result
being wrong.

Our understanding is that in general there are two errors that a
trial can make. Type one error is for the trial to show a difference
between treatments when, in reality there is no true difference. The risk
of this error occurring is quantified by the P value. The P value is
therefore important when assessing the usual type of trial which is
claiming to show a difference. Type two error on the other hand is for the
trial to show no difference between treatments when, in reality there is a
true difference. The risk of this error occurring is quantified by the
power calculation. Therefore it is the power of the study which is crucial
in this trial which claims to have found no difference between treatments.

The authors quote an 80% power for the study. This means that there
is a 20% chance of a type two error occurring. That is a 20% chance that
there is in reality a difference between Butterbur and cetirizine and that
the trial results are wrong, (not a 0.1% chance as implied in the paper.)

To summarise, the trial fails to show evidence of a difference
between the treatments but it also fails to show evidence of no
difference. There is subtle but very important distinction between these
two statements. In effect the trial does not really give any support one
way or another to justify the use of Butturbur.

Many medicinal plants are used as treatment in traditional medicine,
often without any evidence of efficacy and sufficient safety. Butterbur
(Petasites hybridus L. or P. officinalis L.), Coltsfoot (Tussilago farfara
L.) , Common comfrey (Symphytum officinale L.), Borage (Borago
officinalis L.) , Crotalaria (Crotalaria retusa L.) and Common groundsel
(Senecio vulgaris L.) are only few samples of medicinal plants for which
there is a very old tradition of use, few clinical data on their
pharmacological efficacy, while enough data to state they toxic and
cancerogenic , because all these plants contain pyrrizolidine
alkaloids(PA).

In reference to the paper of Dr. A. Schapowal, we think the Author
did not deserve any attention to the main toxicological problematics of
Petasites hybridus. This plant in fact is known to contain PA: in rhizomes
they range from 5 to 90 ppm, whereas leaves contain between 0.02 to 1.50
ppm (1).

PA are usually concentrated in the metabolically active parts of the
complex rhizome which are the thickenings just below the leaves. They are
also present in flower stalks but are almost absent in leaf buds, the
petioles and the leaf blades (2). PA and PA-N-oxides induce tumors via a
genotoxic mechanism, and tumorigenicity is mediated by a set of eight
dehydroretronecine-derived DNA adducts. This mechanism may be general to
other carcinogenic PA and may also be responsible for the other
genotoxicities of PA, including mutagenicity and teratogenicity (3).
Besides the well known hepatotoxicty of PA, they have been associated with
potentially fatal hepatic veno-occlusive disease (Budd-Chiari Syndrome)
and fibrotic lung disease (4).

Papers dealing with herbal extract should report complete extractive
techniques, content of main constituents, presence or absence of toxic
substances, probable or demonstrated toxic effects, drugs interferences
and geographical area of production.

About Petasites hybridus the aim of future research should be the evidence
of clinical activity of preparations without PA content, especially for
chronic treatment and administration in gestational age and childhood.

We think should be improved vigilance of medical authorities on the use,
often as self-therapy, of over-the-counter herbal derivatives from which
toxic constituents have not been removed (5).

Bibliography

1. Wildi E, Langer T, Schaffner W, et al.: Quantitative analysis of
petasin and pyrrolizidine alkaloids in leaves and rhizomes of in situ
grown Petasites hybridus plants. Planta medica 1998;64:264-267.

2. Chizzola R, Ozelsberger B, Langer T.: Variability in chemical
constituents in Petasites hybridus from Austria. Bioch Syst Ecology 2000;
28: 421-432.

3. Fu PP, Chou MW, Xia Q, et al.: Genotoxic pyrrolizidine alkaloid N-
oxides. Mechanism leading to DNA adduct formation and tumorigenicity. J
Environ Sci Health 2001; 19/2: 353-385.

4. Pearson W.: Pyrrolizidine alkaloids in higher plants: Hepatic veno-
occlusive disease associated with chronic consumption. J Nutraceuticals
Funct Med Foods 2000; 3/1: 87-96.

5. Firenzuoli F, Gori L.: Herbal medicine. Minerva Med 2001; 92 (Suppl. 1
al N.3): 1-14.