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NATURAL STANDARD REVIEW
Catherine Ulbricht, PharmD, MBA(C), Column Editor
Butterbur:
An Evidence-Based Systematic
Review by the Natural Standard
Research Collaboration
Mary Giles, PharmD
Catherine Ulbricht, PharmD
Karta Purkh Singh Khalsa, CDN, RH
Catherine DeFranco Kirkwood, MPH, CCCJS-MAC
Christine Park, PharmD
Ethan Basch, MD
for the Natural Standard Reseach Collaboration
Mary Giles is affiliated with the University of Rhode Island.
Catherine Ulbricht is affiliated with the Massachusetts General Hospital.
Karta Purkh Singh Khalsa is affiliated with Bastyr University.
Catherine DeFranco Kirkwood is affiliated with the MD Anderson Cancer Center.
Christine Park is affiliated with Northeastern University.
Ethan Basch is affiliated with the Memorial Sloan-Kettering Cancer Center.
Natural Standard (www.naturalstandard.com) Copyright ©2005. Reprinted with
permission.
Journal of Herbal Pharmacotherapy, Vol. 5(3) 2005
Available online at http://www.haworthpress.com/web/JHP
Digital Object Identifier: 10.1300/J157v05n03_12 119
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ABSTRACT. An evidence-based systematic review including written
and statistical analysis of scientific literature, expert opinion, folkloric
precedent, history, pharmacology, kinetics/dynamics, interactions, ad
-
verse effects, toxicology, and dosing.
KEYWORDS. Blatterdock, langwort, petasitidis folium (flower), Petadolor
H, wild rhubarb
SYSTEMATIC AGGREGATION, ANALYSIS,
AND REVIEW OF THE LITERATURE
Search Strategy
To prepare each Natural Standard review, electronic searches are
conducted in nine databases, including AMED, CANCERLIT, CINAHL,
CISCOM, the Cochrane Library, EMBASE, HerbMed, International
Pharmaceutical Abstracts, Medline, and NAPRALERT. Search terms
include the common name(s), scientific name(s), and all listed syn-
onyms for each topic. Hand searches are conducted of 20 additional
journals (not indexed in common databases), and of bibliographies
from 50 selected secondary references. No restrictions are placed on
language or quality of publications. Researchers in the field of comple-
mentary and alternative medicine (CAM) are consulted for access to ad-
ditional references or ongoing research.
Selection Criteria
All literature is collected pertaining to efficacy in humans (regardless
of study design, quality, or language), dosing, precautions, adverse ef
-
fects, use in pregnancy/lactation, interactions, alteration of laboratory as
-
says, and mechanism of action (in vitro, animal research, human data).
Standardized inclusion/exclusion criteria are utilized for selection.
120 JOURNAL OF HERBAL PHARMACOTHERAPY
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Data Analysis
Data extraction and analysis are performed by health care profes
-
sionals conducting clinical work and/or research at academic centers,
using standardized instruments that pertain to each review section (de
-
fining inclusion/exclusion criteria and analytic techniques, including
validated measures of study quality). Data are verified by a second
reviewer.
Review Process
Blinded review of reviews is conducted by multidisciplinary re
-
search-clinical faculty at major academic centers with expertise in
epidemiology and biostatistics, pharmacology, toxicology, complementary
and alternative medicine (CAM) research, and clinical practice. In cases
of editorial disagreement, a three-member panel of the Editorial Board
addresses conflicts, and consults experts when applicable. Authors of
studies are contacted when clarification is required.
Update Process
Natural Standard regularly monitors scientific literature and indus-
try warnings. When clinically relevant new data emerge, best efforts are
made to update content immediately. In addition, regular updates with
renewed searches occur every 3-18 months, variable by topic.
Synonyms/Common Names/Related Substances
•
Blatterdock, bog rhubarb, bogshorns, butcher’s rhubarb, butterbur
coltsfoot, butterburr, butter-dock, butterdock, butterfly dock, cap
-
dockin, coughwort, donnhove, European pestroot, exwort, flap
-
per-bags, flapperdock, fuki, horsehoof, langwort, paddy’s rhubarb,
pestwurz, Petadolex
®
, Petadolor H, Petaforce
®
, petasites, petasites
flower, petasites leaf, petasites rhizome, petasites root, Petasites
hybridus, P. officinalis, P. ovatus, P. vulgaris, Petasitidis folium
(flower), Petasitidis hybridus, Petasitidis rhizoma (rhizome), plague
-
wort, purple butterbur, sweet coltsfoot, Tesalin
®
, Tussilago farfara,
Tussilago hybrida, Tussilago petasites, umbrella leaves, umbrella
plant, western coltsfoot, wild rhubarb, ZE 339.
Natural Standard Review 121
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•
Selected combination products: Alzoon, Butterbur root extract,
Feverfew/dogwood Supreme, Neurochol, Petaforce
®
, Wild Cherry
Supreme.
CLINICAL BOTTOM LINE/EFFECTIVENESS
Brief Background
•
Butterbur is a perennial shrub, found throughout Europe as well as
parts of Asia and North America. It is usually found in wet, marshy
ground, in damp forests, and adjacent to rivers or streams. The
leaves are broad and can attain a diameter up to three feet. Butter
-
bur plant has lilac-pink flowers and can grow up to three feet high.
The leaves of the plant are responsible for its botanical and com-
mon names. The genus name, Petasites, is derived from the Greek
word “petasos,” which is the felt hat worn by shepherds. The com-
mon name is attributed to the large leaves being used to wrap but-
ter during warm weather.
1
•
Extracts from P. hybridus have been in therapeutic use for more
than 2000 years. They have been claimed to improve gastroin-
testinal pain, lung-diseases, and spasms of the uro-genital
tract.
2
Pre-clinical studies report anti-inflammatory and leukotriene
inhibitory properties. There is compelling initial evidence from hu-
man trials to suggest benefits in migraine headache prophylaxis.
Evidence in support of use for allergic rhinitis prevention is also
promising, although studies in this area have been methodologically
weak. Benefits have not been demonstrated scientifically for any
other condition.
122 JOURNAL OF HERBAL PHARMACOTHERAPY
TABLE 1. Scientific Evidence for Common/Studied Uses
Indication Evidence Grade
Allergic rhinitis prevention B
Migraine prophylaxis B
Allergic skin disease C
Asthma C
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Natural Standard Review 123
TABLE 2. Natural Standard Evidence-Based Validated Grading Rationale™
•
Grades reflect the level of available scientific evidence in support of the efficacy of a
given therapy for a specific indication.
•
Expert opinion and folkloric precedent are not included in this assessment, and are re
-
flected in a separate section of each monograph (“Strength of Expert Opinion and His
-
toric/Folkloric Precedent”).
•
Evidence of harm is considered separately; the below grades apply only to evidence of
benefit.
Level of Evidence Grade Criteria
A (Strong Scientific Evidence)
Statistically significant evidence of benefit from > 2
properly randomized trials (RCTs), OR evidence from
one properly conducted RCT AND one properly
conducted meta-analysis, OR evidence from multiple
RCTs with a clear majority of the properly conducted
trials showing statistically significant evidence of
benefit AND with supporting evidence in basic
science, animal studies, or theory.
B (Good Scientific Evidence)
Statistically significant evidence of benefit from 1-2
properly randomized trials, OR evidence of benefit
from ⱖ1 properly conducted meta-analysis OR
evidence of benefit from > 1 cohort/case-control/
non-randomized trials AND with supporting evidence
in basic science, animal studies, or theory.
C (Unclear or Conflicting Scientific
Evidence)
Evidence of benefit from ⱖ 1 small RCT(s) without
adequate size, power, statistical significance, or
quality of design by objective criteria,* OR conflicting
evidence from multiple RCTs without a clear majority
of the properly conducted trials showing evidence of
benefit or ineffectiveness, OR evidence of benefit
from ⱖ1 cohort/case-control/non-randomized trials
AND without supporting evidence in basic science,
animal studies, or theory, OR evidence of efficacy
only from basic science, animal studies, or theory.
D (Fair Negative Scientific
Evidence)
Statistically significant negative evidence (i.e., lack of
evidence of benefit) from cohort/case-control non-
randomized trials, AND evidence in basic science,
animal studies, or theory suggesting a lack of benefit.
F (Strong Negative Scientific
Evidence)
Statistically significant negative evidence (i.e., lack of
evidence of benefit) from ⱖ 1 properly randomized
adequately powered trial(s) of high-quality design by
objective criteria.*
Lack of Evidence
†
Unable to evaluate efficacy due to lack of adequate
available human data.
*Objective criteria are derived from
validated instruments for evaluating study quality
, including the
5-point scale developed by Jadad et al., in which a score below 4 is considered to indicate lesser
quality methodologically (
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan
DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: Is blinding neces
-
sary? Controlled Clinical Trials 1996; 17[1]:1-12
See Table 4.
† Listed separately in monographs in the “Historical or Theoretical Uses which Lack Sufficient Evi
-
dence” section.
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•
Raw, unprocessed butterbur plant should not be ingested due to
the potential hepatotoxicity of pyrrolizidine alkaloids with long-
term use (specifically, concern of veno-occlusive disease), and
possible carcinogenicity based on animal studies. This includes
any teas, capsules of raw herb, or unprocessed tinctures or ex
-
tracts. Use should be limited to commercially available prod
-
ucts that are free of pyrrolizidine alkaloids, which are generally
believed to be well-tolerated, although long-term safety (be
-
yond 12-16 weeks of use) is not well studied.
Historical or Theoretical Indications Which Lack Sufficient
Evidence
•
Antispasmodic, anxiety, appetite stimulant, cardiovascular condi
-
tions, chills, chronic cough, colds, cramps, diuretic, fever, gastric ul-
cers, headache treatment, indigestion, insomnia, irritable bladder,
ocular allergy, pain, plague, urinary complaints, urinary tract spasm,
whooping cough, wound/skin healing.
Expert Opinion and Folkloric Precedent
•
Butterbur is traditionally considered to possess anti-spasmodic,
anti-inflammatory and antitussive properties. It has been used as an
antispasmodic and analgesic, specifically for conditions af-
flicting the stomach, bile ducts, and duodenum. Butterbur is
believed to help strengthen digestion and improve obstructed
bile flow. Butterbur has also been given for inflammation of
the urinary tract and cramps.
3
•
Butterbur has been used for hundreds of years to treat aches and
pains, including headache.
3
Brief Safety Summary
•
Likely Safe: Studies have reported safety and good tolerability of
commercially available butterbur products (which are free of poten
-
tially carcinogenic pyrrolizidine alkaloid constituents), when used
orally in recommended doses for up to 12-16 weeks.
•
Likely Unsafe: Raw, unprocessed butterbur plant should not be
ingested due to the potential long-term hepatotoxicity of pyrrolizidine
alkaloids, and possible carcinogenicity based on animal studies.
This includes any teas, capsules of raw herb, or unprocessed
tinctures or extracts.
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DOSING/TOXICOLOGY
General
•
Recommended doses are based on those most commonly used in
available trials, or on historical practice. However, with natural
products it is often not clear what the optimal doses are to balance
efficacy and safety. Preparation of products may vary from manu
-
facturer to manufacturer, and even from batch to batch within one
manufacturer. Because it is often not clear what are the active com
-
ponents of a product, standardization may not be possible, and the
clinical effects of different brands may not be comparable.
Standardization
•
Currently there are a few available standardized products of butterbur
root rhizome. Products may be standardized to their specific petasin
and isopetasin contents. Petadolex® and Petaforce® are carbon
dioxide standardized extracts from the rhizome of P. hybridus.
4
Petadolex
®
contains 7.5 mg of petasin and isopetasin per each 50
mg tablet.
3
Tesalin
®
(or ZE 339) is a carbon dioxide extract stan-
dardized to 8.0 mg of total petasin per tablet.
5
•
Petasites hybridus exists in two chemo-varieties. The petasin chemo-
variety has been suggested as being superior to the furano-petasin
chemo-variety with regard to safety and efficacy.
5
•
Raw, unprocessed butterbur plant should not be ingested due to the
potential long-term hepatotoxicity of pyrrolizidine alkaloids. This
includes any teas, capsules of raw herb, or unprocessed tinctures or
extracts. Therefore, use should be limited to commercially avail
-
able products that are free of pyrrolizidine alkaloids.
Adult Dosing (18 Years and Older)
Oral
•
Allergic rhinitis: 50 mg of standardized butterbur (Petadolex
®
,
standardized to contain 7.5 mg of petasin and isopetasin per each
50 mg tablet) has been used twice daily.
6-8
A large study used one
tablet of carbon dioxide extract standardized to 8.0 mg of total
petasin per tablet (Tesalin
®
), taken 4 times daily,
9
while a smaller
study reported that 2 standardized tablets taken 3 times daily was
effective.
10
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•
Asthma: Dosing for asthma is undefined due to a lack of evidence. One
small study used 50 mg of standardized butterbur (Petaforce
®
), admin
-
istered in 2 divided daily doses, in patients maintained on inhaled
corticosteroids.
7
A larger trial used 150 mg of standardized butterbur
daily in 3 divided daily doses (Petadolex
®
), for 2-4 months.
11
•
Migraine prophylaxis: When used prophylactically, a pyrrolizidine-
free butterbur rhizome extract standardized to 7.5 mg of petasin and
isopetasin per each 50 mg tablet (Petadolex
®
), dosed at 50-75 mg
twice daily for up to 4 months has been studied.
4,12,13
One study
suggested that the 75 mg dose but not the 50 mg dose is effective.
13
•
Other/General: Butterbur comes in various forms and is an ingre
-
dient in many products. For making a tea, 1 teaspoonful of the root
in 1 cup of boiling water, 3 times a day has been used. In a tincture,
1-2 mL has been used 3 times daily. Adult dosage may range from
50-100 mg twice daily with meals. However, raw, unprocessed
butterbur plant should not be ingested due to the potential long-
term hepatotoxicity of pyrrolizidine alkaloids. This includes any
teas, capsules of raw herb, or unprocessed tinctures or extracts.
Therefore, use should be limited to commercially available prod-
ucts that are free of pyrrolizidine alkaloids.
Pediatric Dosing (Younger Than 18 Years)
Oral
•
Asthma: One study reported that 50-150 mg daily (depending on
age) of a pyrrolizidine-free butterbur rhizome extract standardized
to 7.5 mg of petasin and isopetasin per each 50 mg tablet (Petadolex®)
may be effective.
11
However, due to lack of safety and efficacy
data, butterbur cannot be recommended for this or any other use in
children at this time.
Toxicology
•
There are no reports of butterbur overdose in the available pub
-
lished literature.
•
The plant’s pyrrolizidine alkaloids are thought to be hepatotoxic in hu
-
mans with long-term use (specifically, concern of veno-occlusive dis
-
ease), and may be carcinogenic based on animal studies. Due to these
concerns, commercially available extracts have the pyrrolizidine alka
-
loids removed, and therefore are presumed to be free of the related po
-
tential mutagenicity, carcinogenicity, or hepatotoxicity.
1
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PRECAUTIONS/CONTRAINDICATIONS
Allergy
•
Caution should be exercised in patients with known allergy/hyper
-
sensitivity to Petasites hybridus or other plants from the Asteraceae/
Compositae family such as ragweed, marigolds, daisies, and chry
-
santhemums.
Adverse Effects
•
General: Standardized butterbur extract products which are free of
pyrrolizidine alkaloids are generally believed to be well-tolerated
when taken as directed, although long-term safety (beyond 12-16
weeks of use) is not well studied.
•
Neurologic: When taken orally, butterbur may cause headache,
drowsiness, or fatigue.
•
Ophthalmologic: When taken orally, butterbur may cause itchy
eyes or eye discoloration.
•
Gastrointestinal: When taken orally, butterbur may cause sus-
tained constipation, discoloration of stool, dysphagia, severe nau-
sea, vomiting, diarrhea, or stomach upset. Butterbur may increase
liver enzyme levels.
9
Raw, unprocessed butterbur plant should not
be ingested due to the potential hepatotoxicity of pyrrolizidine al-
kaloids with long-term use (specifically, concern of veno-occlu-
sive disease). This includes any teas, capsules of raw herb, or
unprocessed tinctures or extracts. Use should be limited to commer
-
cially available products that are free of pyrrolizidine alkaloids.
•
Pulmonary: When taken orally, butterbur may cause difficulty breathing.
•
Dermatologic: When taken orally, butterbur may cause skin dis
-
coloration or pruritis.
•
Oncologic: Long-term use of raw, unprocessed butterbur plant
should be avoided due to the potential carcinogenicity of pyrrolizidine
alkaloids based on animal studies.
Precautions/Warnings/Contraindications
•
The plant’s pyrrolizidine alkaloids are thought to be hepatotoxic,
carcinogenic, mutagenic, and nephrotoxic. However, commer
-
cially available extracts have the pyrrolizidine alkaloids removed.
•
Safety in children is unknown.
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Pregnancy and Lactation
•
The use of Petasites hybridus during pregnancy and lactation
should be avoided due to a lack of safety studies.
3
INTERACTIONS
Butterbur/Drug Interactions:
•
Anticholinergic agents: Administration of butterbur with anticholi
-
nergics may not be advisable. Numerous drugs and drug classes may
interact with anticholinergic agents. Examples include: acetophene
-
nazine, amantadine, amitriptyline, atropine, benztropine, bethanechol,
biperiden, brompheniramine, carbinoxamine, chlorpromazine, clema
-
stine, clindinium, clozapine, cyclopentolate, cyproheptadine, dicy
-
clomine, diphenhydramine, dixyrazine, ethopropazine, fenotherol,
fluphenazine, haloperidol, homatropine, hyosciamine, ipratropium,
loxapine, mesoridazine, methdilazine, methotrimeprazine, olanzapine,
oxybutynin, perazine, periciazine, perphenazine, pimozide, pipo-
tiazine, prochlorperazine, procyclidine, promazine, promethazine,
propiomazine, quinidine, scopolamine, thiethylperazine, thiori-
dazine, thiothixene, trifluoperazine, triflupromazine, trihexyphenidyl,
trimeprazine, triprolidine.
Butterbur/Herb/Supplement Interactions
•
Pyrrolizidine alkaloid-containing herbs: Raw, unprocessed butterbur
may contain toxic pyrrolizidine alkaloids, although commercially
available products should be free of pyrrolizidine alkaloids. None
-
theless, concomitant use of other agents containing pyrrolizidine
alkaloids should be avoided due to the potential for additive toxic
-
ity. The following herbs may contain unsaturated pyrrolizidine al
-
kaloids: alkanna, borage, gravel root, hemp agrimony, hound’s
tongue, comfrey, coltsfoot, and the Senecio species plants; dusty
miller, alpine ragwort, groundsel, golden ragwort, and tansy ragwort.
•
Anticholinergic Herbs and Supplements: Combination use with
anticholinergic agents may potentiate therapeutic and adverse effects.
Examples of anticholinergic herbs include belladonna, bittersweet
(Solanum dulcamara), henbane (Hyoscyamus niger), and Jimson
weed (Datura stramonium).
Butterbur/Laboratory Interactions
•
Liver function tests (LFTs): Butterbur may increase liver enzyme
levels.
9
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MECHANISM OF ACTION
Pharmacology
•
Constituents: Extracts of butterbur have been made from the rhi
-
zomes, roots and leaves. The sesquiterpenes, isopetasin, oxopetasin,
and petasin, are believed to be the active constituents responsible
for pharmacologic activity.
1
Some research suggests that petasin
may be the most active component.
•
Smooth muscle relaxant/vasodilation properties: The active
constituents of Petasites hybridus have been reported to pos
-
sess smooth muscle relaxant activity on vascular walls with a
particular affinity for cerebral blood vessels. Some authors
have suggested that Petasites’ ability to reduce smooth muscle
spasm may make it a useful therapy for some urinary disor
-
ders, menstrual cramps, migraine headache, kidney stones, ob-
struction of bile flow, and other gastrointestinal disorders
associated with smooth muscle spasm.
1,2,14
•
Anti-inflammatory properties: Potential anti-inflammatory prop-
erties of butterbur extracts have been attributed to the petasin con-
tent, which has been reported to cause inhibition of lipoxygenase
activity and down-regulation of leukotriene synthesis.
1
Isopetasin
and oxopetasin esters in P. hybridus have also been reported to in-
hibit synthesis of leukotrienes.
14
Inhibition of COX-2 and PGE2
has also been reported in animal research.
15
Pharmacodynamics/Kinetics
•
There is limited scientific data available. Petasins have been re
-
ported to be bioavailable and have a half-life of 4-6 hours.
HISTORY
•
Butterbur has been used medicinally for many centuries. In the Mid
-
dle Ages, butterbur was used to treat plague and fever, and in the
17th century it was used in the treatment of cough, asthma, and skin
wounds.
3
Historical sources suggest that P. hybridus was used ther
-
apeutically as a spasmolytic agent for the gastrointestinal tract, and
for asthma exacerbations in early Greek history and during the late
Middle Ages.
14
•
P. hybridus first became popular in the 20th century in 1951, when
Karl Bucher reported spasmolytic effects of a crude plant extract
during experimentation.
14
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130 JOURNAL OF HERBAL PHARMACOTHERAPY
EVIDENCE TABLE
TABLE 3
Condition Study
Design
Author,
Year
N Statistically
Significant?
Quality of
Study
0-2 = poor
3-4 = good
5 = excellent
Magnitude
of Benefit
ARR NNT Comments
Allergic
rhinitis
Randomized,
placebo
controlled,
double-blind,
crossover
Gray, 2004 43 No 5 None NA NA
Petaforce
®
100 mg vs.
placebo
daily for 2
weeks then
crossover
with
washout
period.
Allergic
rhinitis
Randomized,
placebo
controlled,
double-blind,
crossover
Lee, 2004 16 Yes 5 Large NA NA Petaforce®
100 mg vs.
fexofenadine
180 mg vs.
placebo
daily for 1
week then
crossover
with
washout
period.
Allergic
rhinitis
Randomized,
placebo
controlled,
double-blind,
crossover
Lee, 2003 20 Yes 5 Large NA NA Petaforce®
100 mg vs.
placebo
daily for 2
weeks then
crossover
with
washout
period.
Allergic
rhinitis
Randomized,
controlled,
double-blind,
parallel
Schapowal,
2002
125 Yes 2 Small NA NA One
standardized
ZE 339
tablet, 4
times daily
vs. cetirizine
(Zyrtec
®
)
10mg for 2
weeks. Both
produced
similar ef
-
fects, with
butterbur
having less
sedative
effects. No
placebo arm.
Allergic
rhinitis
Open study Thomet,
2002
6 Yes NA NA NA NA Two
standardized
ZE 339
tablets, 3
times daily
for 5 days.
Migraine
prophylaxis
Randomized,
placebo
controlled,
double-blind,
three arm,
parallel
Lipton,
2004
245 Yes (150 mg)
No (100 mg)
5 Medium
(150 mg)
None (100
mg)
19%
(150
mg)
5
(150
mg)
150 mg
standardized
Petasites
extract vs.
100 mg
standardized
Petasites
extract vs.
placebo for
4 months.
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Natural Standard Review 131
Migraine
prophylaxis
Randomized,
placebo
controlled,
double-blind,
parallel
Grossman,
2001;
Grossman,
2000
60 Yes 5 Large NA NA
Petadolex
®
100 mg vs.
placebo
daily for 12
weeks.
Grossman
2001 and
Grossman
2000 are
the same
trial
published
twice
(duplicate
publication).
Migraine
prophylaxis
Randomized,
placebo
controlled,
double-blind
Degenring,
1995
60 Unclear 3 Large NA NA
Petaforce
®
2 capsules
twice daily
halved the
number of
migraines in
70% of
patients over
16 weeks.
Migraine
prophylaxis
Review Diener,
2004
60 Yes NA Large 30% 3
Re-analysis
of efficacy
criteria of
the
Grossman
et al. 2000/
2001 study
(4;12).
Allergic skin
disease
Randomized,
placebo
controlled,
double-blind,
crossover
Jackson,
2004
20 No 5 None NA NA
Petaforce
®
100 mg vs.
fexofenadine
180 mg vs.
montelukast
10 mg vs.
placebo
daily for 1
week then
crossover
with washout
period.
Asthma Randomized,
placebo
controlled,
double-blind,
crossover
Lee, 2004
16 No 4 NA NA NA
Petaforce
®
50 mg vs.
placebo
daily for 1
week then
crossover
with washout
period in
patients
maintained
on inhaled
corticosteroids.
Asthma Non-
randomized,
prospective,
open study
Danesch,
2004
80 Yes 1 Large NA NA
Petadolex
®
150 mg for
adults and
50-150 mg
daily in
children
(dose given
is age-
dependent)
for 2-4
months.
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Condition
Refers to the medical condition or disease targeted by a therapy.
Study Design
Common types include:
•
Randomized controlled trial (RCT): An experimental trial in which
participants are assigned randomly to receive either an interven-
tion being tested or placebo. Note that Natural Standard defines
RCTs as being placebo-controlled, while studies using active con-
trols are classified as equivalence trials (see below). In RCTs, par-
ticipants and researchers are often blinded (i.e., unaware of group
assignments), although unblinded and quasi-blinded RCTs are
also often performed. True random allocation to trial arms, proper
blinding, and sufficient sample size are the basis for an adequate
RCT.
•
Equivalence trial: An RCT which compares two active agents.
Equivalence trials often compare new treatments to usual (stan
-
dard) care, and may not include a placebo arm.
•
Before and after comparison: A study that reports only the change
in outcome in each group of a study, and does not report be
-
tween-group comparisons. This is a common error in studies that
claim to be RCTs.
•
Case series: A description of a group of patients with a condition,
treatment, or outcome (e.g., 20 patients with migraine headache
underwent acupuncture and 17 reported feeling better afterwards).
Case series are considered weak evidence of efficacy.
•
Case-control study: A study in which patients with a certain out
-
come are selected and compared to similar patients (without the
outcome) to see if certain risk factors/predictors are more common
132 JOURNAL OF HERBAL PHARMACOTHERAPY
TABLE 4. Explanation of Columns in Natural Standard Evidence Table
12345 6 7 8 910
Condition Study
Design
Author,
Year
N Statistically
Significant?
Quality of
study
0-2=poor
3-4=good
5=excellent
Magnitude
of Benefit
Absolute
Risk
Reduction
Number
Needed to
Treat
Comments
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in patients with that outcome. This study design is not common in
the complementary and alternative medicine literature.
•
Cohort study: A study which assembles a group of patients with cer
-
tain baseline characteristics (for example, use of a drug), and fol
-
lows them forward in time for outcomes. This study design is not
common in the complementary and alternative medicine literature.
•
Meta-analysis: A pooling of multiple trials to increase statistical
power (often used to pool data from a number of RCTs with small
sample sizes, none which demonstrates significance alone but in
aggregate can achieve significance). Multiple difficulties are en
-
countered when designing/reviewing these analyses; in particular,
outcomes measures or therapies may differ from study to study,
hindering direct comparison.
•
Review: An author’s description of his or her opinion based on per
-
sonal, non-systematic review of the evidence.
•
Systematic review: A review conducted according to pre-specified
criteria in an attempt to limit bias from the investigators. Systematic re-
views often include a meta-analysis of data from the included studies.
Author, Year
Identifies the study being described in a row of the table.
N
The total number of subjects included in a study (treatment group
plus placebo group). Some studies recruit a larger number of subjects
initially, but do not use them all because they do not meet the study’s en
-
try criteria. In this case, it is the second, smaller number that qualifies as
N. N includes all subjects that are part of a study at the start date, even if
they drop out, are lost to follow-up, or are deemed unsuitable for analy
-
sis by the authors. Trials with a large number of drop-outs that are not
included in the analysis are considered to be weaker evidence for effi
-
cacy. (For systematic reviews the number of studies included is re
-
ported. For meta-analyses, the number of total subjects included in the
analysis or the number of studies may be reported.)
Statistically Significant?
Results are noted as being statistically significant if a study’s authors
report statistical significance, or if quantitative evidence of significance
is present (such as p values).
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Quality of Study
A numerical score between 0-5 is assigned as a rough measure of
study design/reporting quality (0 being weakest and 5 being strongest).
This number is based on a well-established, validated scale developed
by Jadad et al. (Jadad AR, Moore RA, Carroll D, et al. Assessing the
quality of reports of randomized clinical trials: Is blinding necessary?
Controlled Clinical Trials 1996;17[1]:1-12). This calculation does not
account for all study elements that may be used to assess quality (other
aspects of study design/reporting are addressed in the “Evidence Dis
-
cussion” sections of reviews).
•
A Jadad score is calculated using the seven items in the Table be
-
low. The first five items are indications of good quality, and each
counts as one point towards an overall quality score. The final two
items indicate poor quality, and a point is subtracted for each if its
criteria are met. The range of possible scores is 0 to 5.
Magnitude of Benefit
This summarizes how strong a benefit is: small, medium, large, or
none. If results are not statistically significant “NA” for “not applica
-
ble” is entered. In order to be consistent in defining small, medium, and
large benefits across different studies and reviews, Natural Standard de
-
fines the magnitude of benefit in terms of the standard deviation (SD) of
the outcome measure. Specifically, the benefit is considered:
134 JOURNAL OF HERBAL PHARMACOTHERAPY
Jadad Score Calculation
Item Score
Was the study described as randomized (this includes words such as randomly, random, and
randomization)?
0/1
Was the method used to generate the sequence of randomization described and appropriate (table of
random numbers, computer-generated, etc.)?
0/1
Was the study described as double blind? 0/1
Was the method of double blinding described and appropriate (identical placebo, active placebo,
dummy, etc.)?
0/1
Was there a description of withdrawals and dropouts? 0/1
Deduct one point if the method used to generate the sequence of randomization was described and it
was inappropriate (patients were allocated alternately, or according to date of birth, hospital number,
etc.).
0/⫺1
Deduct one point if the study was described as double blind but the method of blinding was
inappropriate (e.g., comparison of tablet vs. injection with no double dummy).
0/⫺1
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•
Large: if > 1 SD
•
Medium: if 0.5 to 0.9 SD
•
Small: if 0.2 to 0.4 SD
In many cases, studies do not report the standard deviation of change
of the outcome measure. However, the change in the standard deviation
of the outcome measure (also known as effect size) can be calculated,
and is derived by subtracting the mean (or mean difference) in the pla
-
cebo/control group from the mean (or mean difference) in the treatment
group, and dividing that quantity by the pooled standard deviation (Ef
-
fect size = [Mean Treatment – Mean Placebo]/SDp).
Absolute Risk Reduction
This describes the difference between the percent of people in the
control/placebo group experiencing a specific outcome (control event
rate), and the percent of people in the experimental/therapy group expe-
riencing that same outcome (experimental event rate). Mathematically,
Absolute Risk Reduction (ARR) equals experimental event rate minus
control event rate. ARR is better able to discriminate between large and
small treatment effects than relative risk reduction (RRR), a calculation
that is often cited in studies ([control event rate – experimental event
rate]/control event rate). Many studies do not include adequate data to
calculate the ARR, in which cases “NA” is entered into this column.
Number Needed to Treat
This is the number of patients who would need to use the therapy un
-
der investigation, for the period of time described in the study, in order
for one person to experience the specified benefit. It is calculated by di
-
viding the Absolute Risk Reduction into 1 (1/ARR).
Comments
When appropriate, this brief section may comment on design flaws (in
-
adequately described subjects, lack of blinding, brief follow-up, not inten
-
tion to treat, etc.), notable study design elements (crossover, etc.), dosing,
and/or specifics of study group/sub-groups (age, gender, etc.). More de
-
tailed description of studies is found in the “Evidence Discussion” section
that follows the “Evidence Table” in Natural Standard reviews.
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EVIDENCE DISCUSSION
Allergic Rhinitis Prevention
•
Summary: Pre-clinical studies report anti-inflammatory and leuko
-
triene inhibitory properties of butterbur extract, suggesting a possi
-
ble mechanism of action in the prevention of allergic rhinitis exac
-
erbations in susceptible individuals. There are several published
human studies in this area, which overall have been methodologi
-
cally weak. Comparisons of butterbur to prescription drugs such as
fexofenadine (Allegra
®
) and cetirizine (Zyrtec
®
) have reported
similar efficacy. However, due to small sample sizes, short study
durations, and variable outcome measures, these studies can only
be considered exploratory in nature, and not definitive. Nonethe
-
less, their results do suggest benefits of butterbur for this indica-
tion. Better-designed clinical trials are warranted before a firm
conclusion can be reached. The long-term safety of butterbur use
beyond 12-16 weeks is not well studied.
•
Comparison trials: Lee et al. conducted a small randomized, pla-
cebo controlled, double-blind, crossover study in 16 patients with
perennial allergic rhinitis and house dust mite sensitization, com-
paring Petaforce
®
50 mg twice daily, fexofenadine (Allegra
®
) 180
mg once daily, placebo once daily, or placebo twice daily.
7
The
pre-challenge values (L/min) were not significantly different be-
tween groups. The primary outcome measures included PNIF re-
sponse to adenosine monophosphate (AMP) challenge, and total
nasal symptom score. The maximum percent PNIF fall of both
Petaforce® (34 + 3) and fexofenadine (39 + 3) was significant (p <
0.05) compared to placebo (46 + 3). There was no significant dif
-
ference between Petaforce
®
and fexofenadine. Total nasal symp
-
tom score was also reduced significantly (p < 0.05) with Petaforce
®
and fexofenadine compared to placebo. The authors concluded that
butterbur has a potential role in the treatment of allergic rhinitis
due to its apparent superiority to placebo and possible equivalence
to fexofenadine. However, due to the small sample size of this
study, its results can only be considered exploratory.
•
Schapowal et al. conducted a randomized, controlled, double-
blind, parallel group study to compare the efficacy and tolerability
of butterbur to cetirizine (Zyrtec
®
) in patients with seasonal aller
-
gic rhinitis.
9
All patients enrolled in the study were from one of
four outpatient general medicine and allergy clinics in Switzerland
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and Germany. A total of 131 patients were initially screened with
no description of six patients who withdrew prior to randomiza
-
tion. One hundred and twenty-five patients were randomized: 61
to receive butterbur (1 tablet petasites carbon dioxide extract ZE
339 standardized to 8.0 mg of total petasin per tablet; one tablet,
four times daily) and 64 to cetirizine (one 10 mg tablet daily), for 2
consecutive weeks. Main outcome measures included patients’
scores on the SF-36 questionnaire and clinical global impression
scale. The authors reported that improvements in SF-36 scores
were similar in both treatment groups. Similar global improve
-
ment scores on the clinical global impression scale were also seen
between groups. Both groups tolerated treatment well, with the
only difference being the report of sedation in the cetirizine (Zyrtec
®
)
group more commonly than in the butterbur group. Although this
study is suggestive, due to the lack of placebo arm and an unclear
power calculation, the results cannot be considered conclusive. In
addition, SF-36 and global impression scale scores are not consid-
ered direct measures of allergic symptoms, and similar changes in
both groups could be due to other factors unrelated to allergic
symptoms of drug efficacy. The design of this study is weak and its
results cannot be considered definitive.
•
Placebo controlled trials: Lee et al. conducted an earlier random-
ized, placebo controlled, double-blind, crossover trial in 20 pa-
tients with grass-pollen-sensitized seasonal allergic rhinitis (SAR).
8
Twenty patients were randomized to receive either Petaforce
®
50
mg twice daily or placebo twice daily for 2 weeks during the
grass pollen season. Nasal AMP challenge was administered as a
single 400 mg/mL dose as the primary outcome. In the butterbur
(584 + 289) group, there was significant spontaneous recovery
following AMP challenge (p = 0.028) compared to placebo (1438 +
240). These findings were felt to suggest butterbur’s clinical effi
-
cacy in patients with SAR. Due to the small sample size of this
study, its results can only be considered exploratory.
•
Gray et al. conducted a randomized, placebo controlled, double-
blind, crossover study during the grass pollen season in Tayside,
Scotland.
6
Of the 43 patients with intermittent allergic rhinitis and
who were initially enrolled, 35 completed the study. These 35 pa
-
tients were randomized to receive either Petaforce
®
50 mg twice
daily or placebo twice daily for 2 weeks. After a washout period of
1 week, the 2 groups switched. Measurements were taken in the
morning and evening for peak nasal inspiratory flow (PNIF) as the
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primary outcome variable, as well as nasal symptoms, eye symp
-
toms, and rhinoconjunctivitis-specific quality-of-life score. While
no p-values were given, butterbur was reported to yield no signifi
-
cant effect on PNIF or any of the secondary outcomes when com
-
pared to placebo. These results cannot be considered definitive due
to the small sample size and short duration which may not have
yielded sufficient statistical power to detect between-group differ
-
ences.
Migraine Prophylaxis
•
Summary: Pain relief and headache prevention are traditional uses
of butterbur. Recent pre-clinical studies suggest anti-inflamma
-
tory and vasodilitary properties of butterbur, thereby supporting a
possible mechanism of action. A small number of human trials re-
port efficacy of butterbur for migraine prevention when taken reg-
ularly for up to 4 months. This evidence is compelling enough to
suggest benefits of butterbur for migraine prevention, although ad-
ditional evidence from larger, well-designed studies is necessary
before a strong recommendation can be made. Comparisons to
other agents used for this purpose such as beta-blockers or feverfew
have not been conducted.
•
Controlled trials: Lipton et al. conducted a randomized, placebo
controlled, double-blind, three arm, parallel group study compar-
ing the effects of P. hybridus 75 mg twice daily, 50 mg twice daily,
and placebo twice daily in 245 patients with migraine over a
4-month treatment period.
13
Patients met the International Head
-
ache Society’s criteria for migraine and were 18-65 years old. The
main outcome measure was calculated as a percentage change
from baseline of the decrease in migraine attack frequency per
month. Migraine attack frequency was reduced by 48% for 75 mg
twice daily (p = 0.00012), 36% for 50 mg twice daily (p = 0.127),
and 26% for the placebo group. Only the higher dose of the
Petasites extract was superior to placebo in reducing migraine at
-
tack frequency. The authors concluded that Petasites extract 75 mg
twice daily is well-tolerated and more effective than placebo for
migraine prophylaxis while Petasites extract 50 mg twice daily is
not significantly more effective than placebo.
•
Grossman et al. conducted a randomized, placebo controlled, dou
-
ble-blind, parallel group study that compared Petadolex
®
to pla
-
cebo.
4,12
All individuals enrolled in the study were outpatients at
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the Department of Neurology of the Municipal Hospital, Mu
-
nich-Harlaching. Enrolled patients met the International Headache
Society’s criteria for migraine and were 18-60 years old. A total of
60 patients (28 males and 32 females) met the inclusion criteria.
After a four-week run-in phase, the study participants received ei
-
ther 2 capsules of Petadolex
®
containing 25 mg per capsule, or 2
capsules of placebo over 12 weeks. The primary outcome variable
was defined as the frequency of migraine attacks per four weeks.
Secondary outcomes included number of migraine days and dura
-
tion and intensity of migraine attacks. The authors reported that the
frequency of migraine attacks decreased by a maximum of 60%
compared to baseline. This reduction was statistically significant
(p < 0.05) compared to placebo.
•
Diener et al. performed an independent reanalysis
16
of the above
Petadolex
®
study by Grossman et al.
4,12
to confirm its findings for
regulatory purposes. After a four-week baseline phase, 33 patients
were randomized to treatment with 2 capsules of Petadolex
®
25
mg twice daily and 27 to placebo for 12 weeks. The analysis con-
cluded that the mean attack frequency per month decreased from
3.4 at baseline to 1.8 after 3 months (p = 0.0054) in the Petadolex
®
group and from 2.9 to 2.6 in the placebo group. Forty-five percent
of the patients in the Petadolex
®
group experienced an improve-
ment of migraine frequency > 50% vs. only 15% in the placebo
group. The authors concluded that this confirmed the effectiveness
of butterbur as migraine prophylaxis.
•
Degenring and Bommer conducted a placebo controlled trial in 60
patients with migraine headache.
17
Patients were administered ei
-
ther Petaforce
®
(2 capsules, twice daily) or placebo over a 16 week
period. The authors reported a 50% reduction in the frequency of
migraine headaches among 70% of butterbur-treated patients. In
addition, headache duration was reduced by 55% and pain inten
-
sity was diminished in 57% of butterbur recipients. However,
methods and results were not clearly reported, diminishing the
conclusions.
•
Review: Danesch et al. reviewed the safety of butterbur for use in
migraine prevention.
18
Two placebo-controlled clinical trials were
found in support of the use of butterbur, including patients with
acute and subchronic headaches. Chronic animal toxicity studies
and mutagenicity research were reported. Safety data gained from
clinical trials, postmarketing surveillance studies and pharmacovi
-
gilance were evaluated and discussed. The authors concluded that
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patented standardized butterbur root extract is safe as directed for
this use in humans.
Allergic Skin Disease
•
Summary: Pre-clinical studies report anti-inflammatory and leuko
-
triene inhibitory properties of butterbur extract, suggesting a pos
-
sible mechanism of action in the management of atopic skin disorders.
There is limited human evidence in this area, although preliminary re
-
search suggests that butterbur does not effectively suppress exper
-
imentally-induced allergic skin reactions when compared to the
prescription drug fexofenadine (Allegra
®
) which does suppress
these reactions.
•
Evidence: Jackson et al. conducted a randomized, placebo con
-
trolled, double-blind, crossover study in 20 atopic patients, to re-
ceive 1 week of Petaforce
®
50 mg twice daily; fexofenadine
(Allegra
®
) 180 mg once daily and placebo once daily; montelukast
(Singulair
®
, a leukotriene inhibitor) 10 mg once daily and placebo
once daily; or placebo twice daily.
19
All 20 patients completed the
study and underwent measurements of cutaneous wheal and flare
responses to histamine, allergen, and saline control at 10-minute
intervals for 60 minutes. While the mean histamine wheal and flare
response was significantly attenuated by fexofenadine compared
with placebo (p < 0.05), neither butterbur nor montelukast pro-
duced such responses. In addition, while the mean allergen wheal
and flare response was significantly attenuated by fexofenadine com-
pared with placebo (p < 0.05), neither butterbur nor montelukast
produced such responses. This study suggests that butterbur may
not be effective in the management of allergic skin disease.
Asthma
•
Summary: Butterbur was used historically to treat asthma, includ
-
ing in ancient Greece. Pre-clinical studies report anti-inflamma
-
tory and leukotriene inhibitory properties which may lead to clinical
effects. Initial human research suggests possible benefits. How
-
ever, controlled trials with adequate sample sizes are necessary in
order to clarify whether there are true benefits in humans.
•
Controlled trial: Lee et al. reported a small study in 16 atopic asth
-
matic patients with a forced expiratory volume in 1 second (FEV1)
of 4 (78% of the age-matched predicted value), who received
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butterbur as add-on therapy to inhaled corticosteroids.
20
In this
randomized, placebo controlled, double-blind, crossover study,
patients were randomized to receive twice daily either Petaforce
®
25 mg or placebo for 1 week with a washout period prior to cross
-
over. Adenosine monophosphate bronchoprovocation was assessed
as the primary outcome of the study with additional measurements
of exhaled nitric oxide, serum eosinophil cationic protein, and pe
-
ripheral blood eosinophil count. All primary and secondary out
-
comes were reported as significantly superior in the butterbur
group (p < 0.05).
•
Case series: Danesch et al. conducted a prospective, non-random
-
ized, open trial to analyze the efficacy and tolerability of a butterbur
root extract for the treatment of asthma.
11
The study included 80
subjects (64 adults; 16 children) who presented with active asthma
symptoms such as coughing, difficulty breathing, chest tightness,
difficulty exhaling, wheezing and expectoration. All subjects were
given an extract of Petasites hybridus (Petadolex
®
). The adults
were given 50 mg Petadolex
®
three times daily, while the children
were given 50-150 mg daily based on age. No placebo arm was in-
cluded. Outcomes included number, duration, and severity of
asthma attacks; asthma symptoms; peak flow results; asthma med-
ication usage; and evaluation by patient and physician. The au-
thors reported that the mean number, duration, and severity of
asthma attacks decreased, while peak flow, FEV1, and all mea-
sured symptoms improved during butterbur therapy. During the
study, 21.3% of patients reported experiencing an asthma attack.
After two months of treatment, the mean number of asthma attacks
in each group was reduced by 50%. Because no placebo arm was
included, it is not clear to what extent the improvements in both
groups were due to a “placebo effect” or to the natural history of
this condition to improve. Also, the concurrent use of asthma med
-
ications being allowed by the subjects may have affected the re
-
sults. Therefore, these results cannot be considered conclusive.
PRODUCTS STUDIED
Brands Used in Statistically Significant Clinical Trials
•
Petadolex
®
25 mg, standardized (Weber & Weber GmbH & Co.,
KG, Germany).
4,11,12
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•
Petaforce
®
50 mg, standardized to 7.5 mg of petasin and isopetasin
per each 50 mg tablet (Bioforce Ltd, Irvine, UK).
7,8,20
•
Tesalin
®
(or ZE 339), standardized to 8.0 mg of total petasin per
tablet.
9
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adenosine monophosphate induced nasal responsiveness in seasonal allergic rhinitis.
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-
phylaxis of migraine. Int J Clin Pharmacol Ther 2000;38(9):430-435.
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ive preventive treatment for migraine. Neurology 2004;63(12):2240-2244.
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-
hibitors of peptido-leukotriene-synthesis from Petasites hybridus. Planta Med 1994;
60(4):318-322.
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COX-2 and PGE2 release by direct interaction with the enzyme and by preventing p42/
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(Petaforce
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). Schweiz Zschr GanzheitsMedizin 1995;7(7/8):365-370.
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allergen cutaneous response. Ann Allergy Asthma Immunol 2004;92(2):250-254.
20. Lee DK, Haggart K, Robb FM, et al. Butterbur, a herbal remedy, confers
complementary anti-inflammatory activity in asthmatic patients receiving inhaled corti
-
costeroids. Clin Exp Allergy 2004;34(1):110-114.
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