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Efficacy and safety of willow bark extract in the treatment of osteoarthritis and rheumatoid arthritis: Results of 2 randomized double-blind controlled trials

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To investigate the efficacy and safety of a standardized willow bark extract in patients with osteoarthritis (OA) and rheumatoid arthritis (RA). We studied 127 outpatients with hip or knee OA and a WOMAC pain score of at least 30 mm and 26 outpatients with active RA in 2 randomized, controlled, double-blind trials with followup for 6 weeks. OA trial: Patients were randomized to receive willow bark extract, corresponding to 240 mg of salicin/day, diclofenac 100 mg/day, or placebo (n = 43, 43, and 41, respectively). Main outcome measure was the pain subscore of the WOMAC OA Index. RA trial: Patients were randomized to receive willow bark extract, corresponding to 240 mg salicin/day (n = 13) or placebo (n = 13). Main outcome measure was the patient's assessment of pain rated on a 100 mm visual analog scale (VAS). OA trial: WOMAC pain scores decreased by 8 mm (17%) in the willow bark group and by 23 mm (47%) in the diclofenac group, compared with 5 mm (10%) in the placebo group. The difference between willow bark extract and placebo was not statistically significant (-2.8 mm; 95% CI -12.1 to 6.4 mm; p = 0.55, ANCOVA), but the difference between diclofenac and placebo was highly significant (-18.0 mm; 95% CI -27.2 to -8.8 mm; p = 0.0002, ANCOVA). RA trial: The mean reduction of pain on the VAS was -8 mm (15%) in the willow bark group compared with -2 mm (4%) in the placebo group. The difference was not statistically significant (estimated difference -0.8 mm; 95% CI -20.9 to 19.3 mm; p = 0.93, ANCOVA). The OA study suggested that the willow bark extract showed no relevant efficacy in patients with OA. Similarly, the RA trial did not indicate efficacy of this extract in patients with RA.
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2121
Biegert, et al: Willow bark in OA and RA
Efficacy and Safety of Willow Bark Extract in the
Treatment of Osteoarthritis and Rheumatoid
Arthritis: Results of 2 Randomized Double-Blind
Controlled Trials
CLAUDIA BIEGERT, IRMELA WAGNER, RAINER LÜDTKE, INA KÖTTER, CLAUDIA LOHMÜLLER,
ILHAN GÜNAYDIN, KATJA TAXIS, and LUTZ HEIDE
ABSTRACT. Objective. To investigate the efficacy and safety of a standardized willow bark extract in patients
with osteoarthritis (OA) and rheumatoid arthritis (RA).
Methods. We studied 127 outpatients with hip or knee OA and a WOMAC pain score of at least 30
mm and 26 outpatients with active RA in 2 randomized, controlled, double-blind trials with followup
for 6 weeks. OA trial: Patients were randomized to receive willow bark extract, corresponding to 240
mg of salicin/day, diclofenac 100 mg/day, or placebo (n = 43, 43, and 41, respectively). Main out-
come measure was the pain subscore of the WOMAC OA Index. RA trial: Patients were randomized
to receive willow bark extract, corresponding to 240 mg salicin/day (n = 13) or placebo (n = 13).
Main outcome measure was the patient’s assessment of pain rated on a 100 mm visual analog scale
(VAS).
Results. OA trial: WOMAC pain scores decreased by 8 mm (17%) in the willow bark group and by
23 mm (47%) in the diclofenac group, compared with 5 mm (10%) in the placebo group. The dif-
ference between willow bark extract and placebo was not statistically significant (–2.8 mm; 95% CI
–12.1 to 6.4 mm; p = 0.55, ANCOVA), but the difference between diclofenac and placebo was high-
ly significant (–18.0 mm; 95% CI –27.2 to –8.8 mm; p = 0.0002, ANCOVA). RA trial: The mean
reduction of pain on the VAS was –8 mm (15%) in the willow bark group compared with –2 mm
(4%) in the placebo group. The difference was not statistically significant (estimated difference –0.8
mm; 95% CI –20.9 to 19.3 mm; p = 0.93, ANCOVA).
Conclusion. The OA study suggested that the willow bark extract showed no relevant efficacy in
patients with OA. Similarly, the RA trial did not indicate efficacy of this extract in patients with RA.
(J Rheumatol 2004;31:2121–30)
Key Indexing Terms:
OSTEOARTHRITIS RHEUMATOID ARTHRITIS
WILLOW BARK DICLOFENAC DRUG THERAPY
From the Pharmaceutical Institute, Eberhard Karls-Universität,
Tübingen; the Department of Internal Medicine II (Haematology,
Oncology, Immunology, and Rheumatology), University Hospital,
Tübingen; and the Karl and Veronica Carstens Foundation, Essen,
Germany.
Supported by Tübingen University and by Robugen GmbH, Esslingen,
Germany. R. Lüdtke was supported by funding from the Karl and
Veronica Carstens Foundation.
C. Biegert, PhD; I. Wagner, PhD; K. Taxis, PhD; L. Heide, PhD,
Pharmaceutical Institute, Eberhard Karls-Universität Tübingen; I. Kötter,
MD; C. Lohmüller, MD; I. Günaydin, MD, Department of Internal
Medicine II, University Hospital, Tübingen; R. Lüdtke, Dipl. Stat., Karl
and Veronica Carstens Foundation.
Dr. Biegert and Dr. Wagner contributed equally to this report.
Address reprint requests to Dr. L. Heide, Pharmaceutical Institute,
University of Tübingen, Auf der Morgenstelle 8, 72076 Tübingen,
Germany. E-mail: heide@uni-tuebingen.de
Submitted March 4, 2004; revision accepted May 21, 2004.
The use of herbal medicines is popular in many industrial-
ized countries. A 1997 survey estimated that 12.1% of
adults in the United States had taken a herbal medicine in
the previous 12 months
1
. In Germany, herbal drugs are used
even more frequently, not only in self-medication but also
in medical prescribing
2
. Despite the widespread use of
herbal medicines there is still a lack of data on their efficacy
and safety derived from well designed randomized con-
trolled clinical trials
3-5
.
For the treatment of chronic pain, German patients fre-
quently use herbal remedies because they fear the risk of
gastrointestinal (GI) side effects associated with non-
steroidal antiinflammatory drug (NSAID) treatment
6,7
.
Preparations containing a standardized, highly dosed wil-
low bark extract are marketed in Germany for the support-
ive treatment of rheumatic diseases
2
, and they have been
officially licensed by the federal health authorities for this
indication. Three recent randomized controlled trials report-
ed evidence for an analgesic efficacy of willow bark extract.
A 4-week placebo controlled trial in patients with low back
pain resulted in a remarkably high efficacy
8
. A later study
by the same group compared willow bark with rofecoxib in
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low back pain
9
, and did not find a difference between effi-
cacies of the 2 medications. Unfortunately, patients with
much lower disease activity were enrolled in the rofecoxib
controlled trial than in the preceding placebo controlled
trial. A placebo controlled 2-week trial in patients with
osteoarthritis (OA) carried out by our group
10
resulted in a
moderate analgesic efficacy that just reached statistical sig-
nificance (p = 0.047).
We conducted a 6-week, 3-arm, randomized controlled
trial comparing the efficacy and safety of a standardized
willow bark extract with diclofenac and placebo in patients
with OA of the hip and the knee. The principal advantage of
such a 3-armed study is that it simultaneously provides evi-
dence of effectiveness (willow bark vs placebo) and of
study sensitivity (diclofenac vs placebo)
11
. The design and
the outcome measures of our study followed the current
recommendations of the European Agency for the
Evaluation of Medicinal Products (EMEA) and the
Osteoarthritis Research Society and included all outcome
measures recommended by the US Food and Drug
Administration
12-14
. In addition, we carried out a small pilot
trial (6 weeks, randomized and placebo controlled) in
patients with rheumatoid arthritis (RA), in order to provide
a first estimate of the efficacy of willow bark in the treat-
ment of inflammatory rheumatic diseases.
MATERIALS AND METHODS
The trials were conducted in accord with the principles of good clinical
practice and the revised Declaration of Helsinki. The study protocols were
approved by the respective ethics committees, and all patients gave their
written informed consent.
Study medication. An extract of the bark of Salix daphnoides cultivated in
Germany (extraction solvent: ethanol 70% v/v, drug-extract ratio: 8–14:1)
was obtained from Finzelberg, Andernach, Germany. The total salicin con-
tent was 15.0% after alkaline hydrolysis
15
. A detailed chemical characteri-
zation of the extract will be reported elsewhere. This extract was used in
the form of coated tablets prepared by Robugen GmbH, Esslingen,
Germany. Each tablet contained 393.24 mg extract (corresponding to 60
mg of salicin). Disintegration testing was carried out according to the
European Pharmacopoeia.
The diclofenac tablets contained 25 mg diclofenac in enteric coated
form. They were produced by Robugen GmbH and tested in accord with
the USP monograph for diclofenac sodium delayed release tablets
16
.
Willow bark extract tablets, diclofenac tablets, and placebo tablets were
of identical appearance, odor, and taste.
Osteoarthritis trial
Patient inclusion criteria. Subjects were required to be outpatients with
OA of the hip or knee, verified according to the clinical, laboratory, and
radiographic classification criteria of the American College of
Rheumatology (ACR)
17,18
, age over 18 years, with a Western Ontario and
McMaster Universities Osteoarthritis Index (WOMAC, VA 3.0) pain
score
19,20
of at least 30 mm on Day 0.
Exclusion criteria. Criteria for exclusion were use of corticosteroids with-
in the past 8 weeks (intraarticular in the target joint or systemic therapy);
surgery of the target joint during the past 8 weeks; inflammatory joint dis-
eases [erythrocyte sedimentation rate (ESR) > 40 mm/h]; known allergy to
salicylates, willow bark extract preparations, or NSAID; abnormal renal or
hepatic function [creatinine clearance < 40 ml/min
21
; AST > 35 U/l or ALT
> 35 U/l or gamma-glutamyl transferase (GGT) > 50 U/l]; unexplained
dyshemopoiesis; chronic obstructive airway diseases requiring prophylac-
tic medication; GI ulcers (bleeding, discolored stool, or occult blood in the
stool during the past 8 weeks); history of alcohol abuse; pregnancy and lac-
tation; current therapy with an anticoagulant; malignant diseases; chronic
heart failure (NYHA III and IV); participation in a clinical trial during the
past 4 weeks; and WOMAC pain score on Day –7 < 23 mm without prior
use of analgesics or NSAID.
No additional analgesics or NSAID or systemic or intraarticular corti-
costeroids were allowed during washout phase and the 6-week study phase.
Aspirin was allowed up to 100 mg daily. Patients were allowed to contin-
ue any physical therapy, but such therapy had to remain unchanged during
the study.
Study design. A double-blind, 3-arm, parallel randomized trial over 6
weeks was performed at 2 study centers in Germany from May 2001 to
September 2002. Randomization was carried out in blocks of 6, using com-
puter generated random numbers (Rancode™, IDV, Munich, Germany).
Assessors and patients were blinded to the allocation.
Outpatients were recruited by orthopedists, internists, and general prac-
titioners and by public advertisement. After a placebo washout phase of
4–10 days, depending on the half-life of the analgesic or NSAID (at least
7 days for long-acting NSAID, e.g., piroxicam), patients who were eligible
for the study were randomly assigned to one of the following treatments:
willow bark extract, 2 tablets twice daily, corresponding to a dose of 240
mg of salicin/day; or diclofenac, enteric coated tablets, 2 tablets twice
daily, corresponding to 100 mg/day; or placebo, 2 tablets twice daily. Each
medication was taken for 6 weeks in the mornings and evenings, half an
hour before mealtimes.
Patients were assessed by a physician on Days –7, 0, 14, and 42. On
Day 28, patients completed several questionnaires at home.
Outcome measures. The primary outcome measure was change in the pain
subscore of the WOMAC OA Index from Day 0 to Day 42 [visual analog
scale, VAS, ranging from 0 (best) to 100 mm (worst)]
19,20
. We followed the
translation of Stucki, et al
22
for the German phrasing of the questionnaire.
Secondary outcome measures were as follows: (1) WOMAC stiffness sub-
score; (2) WOMAC function subscore; (3) WOMAC total index (the total
index was calculated as pain 42%, stiffness 21%, and physical function
37%); (4) patient’s and physician’s assessment of overall efficacy meas-
ured by a 100 mm VAS; (5) quality of life assessment using the Short
Form-36 (SF-36), which referred to patient’s condition during the previous
week, using the validated German translation
23
; (6) patient’s assessment of
tolerability measured by a 100 mm VAS; and (7) safety of the study drug.
On Day –7, medical history, physical examination, and laboratory tests
(blood and urine samples) were conducted. The more painful hip or knee
joint was identified as the target joint, i.e., this joint was used for future
assessment in the study. Patients were given a diary to document the num-
ber of tablets taken each day, to record any adverse events, and to score
their pain on a 100 mm VAS each evening.
Efficacy was assessed by the WOMAC on Day –7, 0, 14, and 42. On
Day 28, an additional WOMAC questionnaire was filled in by patients
independently at home. Quality of life was measured on Day 0 and Day 42.
Patient’s assessment of efficacy was evaluated on Day 14 and 42 as well as
on Day 28 (take-home questionnaire); physician’s assessment of efficacy
was evaluated on Day 42. Safety evaluation was based on laboratory test-
ing (blood and urine samples on Day 0 and 42) and reports of adverse
events. Data on adverse events were collected by interviewing patients on
each visit and by records in the patients’ diaries. Onset, duration, end, and
intensity (mild, moderate, or severe) of each adverse event, as well as the
action taken and outcome, were recorded. The relationship between event
and study medication was judged by the physician as none, unlikely, pos-
sible, probable, or certain. Adverse events were classified according to the
World Health Organization terminology
24
. Patients assessed the tolerabili-
ty of the study drug on the final visit on a 100 mm VAS.
Statistical analysis. Sample size calculation was based on a subset of the
2122 The Journal of Rheumatology 2004; 31:11
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results of a previous clinical trial
10
(WOMAC pain score, = 9.4 mm, SD
15.4 mm). A sample size of 126 patients (42 per group) was calculated to
give 80% power with a type I error rate of 5% (2-tailed).
The primary analysis of efficacy was based on the intention-to-treat
population. The intention-to-treat population included all patients who
were randomized on Day 0 and took at least one dose of study medication.
The per-protocol population excluded patients with protocol violations,
patients who withdrew from the study due to reasons other than pain before
Day 14, and patients who were noncompliant. Patients were judged to be
noncompliant if they had taken less than 80% of the study medication,
according to pill counts at each followup visit.
Missing values were imputed by carrying forward the last observed
value for patients who discontinued for reasons other than arthritic pain.
Missing values for patients who withdrew due to pain (treatment failures)
were replaced by the mean of the 5 worst values of patients in the respec-
tive treatment group.
The primary endpoint was analyzed by analysis of covariance (ANCO-
VA) with baseline values, center, and the use of physical therapy (yes/no;
see Results) as covariates. Secondary endpoints were analyzed in the same
way.
The principal comparison was between the willow bark and placebo
groups; 95% confidence intervals (CI) were calculated for mean changes
from Day 0 to Day 42. In terms of a priori ordered hypotheses, the willow
bark and placebo groups were compared first, and the diclofenac and place-
bo groups subsequently.
Demographic variables were compared using the chi-square test for
categorical data and Kruskal-Wallis test for continuous data. Numbers and
rates of adverse events (AE) were tabulated for each treatment group and
analyzed using the Cochrane-Mantel-Haenszel test (numbers of AE) and
Friedman test (rates of AE). In all statistical tests, the level of type I error
(2-tailed) was set at 0.05. Reported p values for secondary outcome meas-
ures and AE were considered descriptive only. All analyses were performed
with SAS version 8.02 software (SAS Institute Inc., Cary, NC, USA).
Rheumatoid arthritis trial
Patient inclusion criteria. Subjects were required to be outpatients with a
diagnosis of RA defined by ACR criteria
25
; RA functional class I, II, or III
26
;
age over 18 years; evidence of at least moderate disease activity at the ran-
domization visit, i.e., at least 2 of the following signs and symptoms: 6 ten-
der joints, 3 swollen joints, morning stiffness 45 min, ESR 28 mm/h.
Exclusion criteria. Criteria for exclusion were intraarticular, intramuscular,
or intravenous injections of corticosteroids within one month before the
study and during the study; chemical, radiologic, or surgical synovectomy
in any large joint within 3 months before the study and during the study;
known hypersensitivity to salicylates or willow bark extract; concomitant
therapy with anticoagulants; concomitant severe cardiac, hepatic, renal, or
hematologic disease; cancer; bronchial asthma; gastrointestinal ulcers; his-
tory of alcohol abuse; pregnancy and lactation; and participation in a clin-
ical trial within the past 30 days.
Disease modifying antirheumatic drugs (except tumor necrosis factor
inhibitors) were allowed as concomitant therapy, but they had to be taken
since at least 6 months before, and their dosage had to be stable for 3
months before and during the study. Treatment with corticosteroids could
not exceed prednisolone 7.5 mg/day or equivalent and had to be stable for
one month before and during the study. NSAID and analgesics had to be
discontinued before entering the trial. Patients were permitted to take low
dose aspirin (up to 100 mg/day).
Study design. A double-blind, 2-arm, parallel randomized trial over 6
weeks was conducted at 4 centers in Germany from June 2001 to
November 2002. Patients were randomly allocated to one of the following
treatment groups: willow bark extract, 2 tablets twice daily, corresponding
to 240 mg salicin per day; or placebo, 2 tablets twice daily. Each medica-
tion was taken for 6 weeks, as described for the OA trial.
A washout period of 4–10 days’ duration was required, depending on
the elimination half-life of the NSAID taken before the study. Patients were
assessed by the investigator on Day –7, 0, 14, 28, and 42.
Outcome measures. Efficacy assessments included all components of the
ACR core set of outcome measures
27
: the primary outcome measure was
the change in patient’s assessment of pain from Day 0 to Day 42 as record-
ed on a 100 mm VAS. Secondary outcome measures were the number of
tender/painful and swollen joints (28 joint count)
28
, physical function
assessed with the Health Assessment Questionnaire (HAQ) Disability
Index
29
(validated German translation
30
), patient’s assessment of the sever-
ity of morning stiffness (100 mm VAS), patient’s and physician’s assess-
ment of overall efficacy (100 mm VAS), quality of life assessed with the
SF-36 index (validated German translation
23
), ESR, plasma concentrations
of C-reactive protein (CRP), and the number of patients who met the ACR-
20 criteria for improvement
31
.
Assessment of tolerability and safety and statistical evaluation were
carried out as described for the OA trial. Analysis was based on ANCOVA
with baseline values and center as covariates.
RESULTS
Osteoarthritis trial
Patient characteristics. As shown in Figure 1, 298 patients
were screened for inclusion in the trial; 68 patients did not
meet entry criteria on Day –7; 6 dropouts occurred during
the washout phase; and 97 patients did not fulfil entry crite-
ria on Day 0. Therefore 127 patients were randomized and
allocated to one of the 3 treatment groups. The treatment
groups were comparable in all relevant demographic and
clinical characteristics (Table 1). However, during the study
only 12% of the patients in the willow bark group reported
to receive physical therapy, in contrast to 40% in the
diclofenac group and 27% in the placebo group. This dif-
ference was statistically significant (p = 0.01). Therefore,
physical therapy was used as a covariate in the ANCOVA
analysis of the outcome variables, as specified in the study
protocol.
Overall, 106 patients (83%) completed the study. Lack of
efficacy was the most common reason for withdrawal (5
willow bark group, 3 diclofenac, and 9 placebo); 2 patients
in the diclofenac group withdrew due to adverse events and
2 patients in the placebo group withdrew since they decided
to take a holiday abroad.
Important protocol violations were committed by 17
patients: 10 (4 willow bark, 2 diclofenac, 4 placebo) had
taken additional NSAID or analgesics (because of reasons
other than OA); 2 patients (both placebo) were considered
noncompliant because they had taken less than 80% of the
study medication. One patient (placebo) reported that his
physical therapy was changed significantly during the study
phase, and his final assessment (Day 42) was carried out
outside the predefined visit window (± 3 days). Four
patients were randomized although they did not fulfil the
entry criteria (2 diclofenac patients and one placebo patient
had taken NSAID during washout phase and one diclofenac
patient had a WOMAC pain score less than the required
minimum of 30 mm on Day 0). All these patients were
therefore excluded from the per-protocol analysis.
2123
Biegert, et al: Willow bark in OA and RA
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Efficacy results. Table 2 shows the mean values for the out-
come measures. Baseline values for each efficacy variable
were similar for all treatment groups and deteriorated only
slightly during the washout phase. At the end of the treat-
ment phase, all groups had improved in nearly all indica-
tors.
Primary outcome measure — WOMAC pain score. Over 6
weeks, WOMAC pain scores decreased by 8 mm in the wil-
low bark group, by 5 mm in the placebo group, and by 23
mm in the diclofenac group. The ANCOVA using baseline
values, center, and physical therapy as covariates showed no
statistically significant difference in the reduction of
WOMAC pain scores between willow bark and placebo
group (intention-to-treat population: –2.8 mm; 95% CI
–12.1 to 6.4 mm; p = 0.55). This was confirmed by the
results of the per-protocol population (difference –1.0 mm;
95% CI –11.2 to 9.2 mm; p = 0.85, ANCOVA).
2124 The Journal of Rheumatology 2004; 31:11
Figure 1. OA trial: Disposition of the study patients.
Table 1. Osteoarthritis trial: baseline demographic and clinical character-
istics of patients. Data are expressed as number for nominal data and as
mean (SD) for continuous data.
Characteristics Willow Bark, Diclofenac, Placebo,
n = 43 n = 43 n = 41
Age, yrs 62.9 (7.2) 61.2 (6.6) 62.4 (8.9)
Sex, M/F 22/21 15/28 16/25
Body weight, kg 81.7 (15.4) 79.9 (14.1) 79.6 (12.9)
Height, cm 171.5 (8.4) 167.9 (7.3) 168.1 (7.1)
OA of the hip/knee 8/35 15/28 14/27
OA unilateral/bilateral 9/34 11/32 13/28
Duration of OA, yrs 8.8 (6.4) 8.5 (6.2) 10.9 (8.6)
Prior use of analgesics/ 24/19 28/15 26/15
NSAID, yes/no
Physical therapy during 5/38 17/26 11/30
the study, yes/no*
* Difference statistically significant (p = 0.01, chi-square test).
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However, there was a large and statistically significant
difference in the reduction of WOMAC pain scores between
diclofenac and placebo groups (intention-to-treat popula-
tion: –18.0 mm; 95% CI –27.2 to –8.8 mm; p = 0.0002. Per-
protocol population: –16.2 mm; 95% CI –26.6 to –5.8 mm;
p = 0.003). As shown in Figure 2, most of the improvement
was already achieved after 2 weeks of treatment.
Secondary outcome measures. The WOMAC stiffness
scores and the WOMAC physical function scores showed
strong improvement in the diclofenac group that was signif-
icantly superior to placebo (Table 2). In contrast, the
improvements under willow bark treatment were similar to
those under placebo.
In the SF-36 quality of life index, the diclofenac group
showed a statistically significant improvement in compari-
son to placebo in the subscales of body pain, vitality, phys-
ical functioning, and physical role (all p values < 0.02, data
not shown). The subscales for general health, social func-
tioning, emotional role, and mental health showed smaller
and nonsignificant improvements. In total, this resulted in a
significant superiority of diclofenac over placebo in the
physical component summary (Table 2). As may be expect-
ed, diclofenac did not result in a significant improvement of
the mental component summary of the SF-36.
The willow bark group experienced a statistically signif-
icant improvement in the physical functioning subscale in
comparison to placebo (difference 9.32; 95% CI 0.29 to
18.35; p = 0.04, ANCOVA). Three other subscales of the
SF-36 showed nonsignificant improvement, and 4 subscales
nonsignificant deterioration under willow bark treatment in
comparison to placebo. Correspondingly, neither the physi-
cal nor the mental component summary showed an efficacy
for the willow bark preparation.
In the assessments of overall efficacy (Table 2), both
patients and physicians reported strong improvements with
diclofenac treatment, but only minimal improvements with
willow bark and with placebo. Patient’s assessment showed
a highly significant superiority of diclofenac over placebo,
2125
Biegert, et al: Willow bark in OA and RA
Table 2. Efficacy of willow bark and diclofenac in the treatment of OA. Data are mean values for the intention-to-treat population.
Variable Group* Baseline Final Difference Difference Difference
Assessment Assessment Baseline Willow Bark Diclofenac
(± SD) (± SD) vs Final vs Placebo
2
vs Placebo
3
Assessment
1
(ANCOVA) (ANCOVA)
Day (–7) Day 0 Day 14 Day 28 Day 42 (± SD)
WOMAC (100 mm VAS; best value: 0 mm)
Pain W 44 48 (12) 42 39 41 (22) –8 (21) –2.8 –18.0
P 48 50 (17) 44 45 45 (27) –5 (23) (p = 0.55) (p = 0.0002)
D 47 49 (14) 26 26 26 (21) –23 (20)
Stiffness W 47 50 (21) 48 45 46 (24) –4 (24) 1.1 –18.4
P 52 51 (17) 43 46 46 (25) –5 (26) (p = 0.82) (p = 0.0004)
D 54 53 (21) 31 30 28 (23) –24 (25)
Physical Function W 44 48 (15) 43 43 40 (22) –8 (18) –2.5 –16.4
P 48 50 (14) 45 46 45 (23) –5 (20) (p = 0.54) (p = 0.0001)
D 50 49 (17) 28 28 28 (22) –21 (19)
Total Score W 45 49 (13) 43 41 42 (21) –7 (19) –1.7 –17.6
P 49 50 (13) 44 45 45 (24) –5 (21) (p = 0.69) (p < 0.0001)
D 50 50 (15) 28 28 27 (21) –23 (19)
SF-36 (0 to 100 score; best value: 100)
Physical Component W 31.4 (9.1) 33.1 (10.3) 1.2 (9.1) 2.36 7.94
Summary P 31.9 (8.2) 30.7 (10.3) –1.2 (9.6) (p = 0.24) (p = 0.0001)
D 30.9 (7.9) 37.7 (9.2) 6.8 (8.1)
Mental Component W 56.7 (9.9) 53.7 (11.6) –2.3 (7.6) –1.81 –0.64
Summary P 53.7 (14.0) 53.2 (12.0) –0.5 (10.9) (p = 0.41) (p = 0.77)
D 54.5 (11.1) 53.3 (12.5) –1.1 (10.6)
Overall assessment of efficacy (100 mm VAS; best value: 0 mm)
Patient W 50
4
50 48 46 (24) –4 1.0 –18.4
P50
4
47 47 45 (23) –5 (p = 0.84) (p = 0.0002)
D50
4
27 27 26 (19) –24
Physician W 50
4
45 (20) –5 4.1 –7.6
P50
4
41 (15) –9 (p = 0.30) (p = 0.05)
D50
4
33 (16) –17
1
Within-group baseline vs final assessment, difference of means.
2
Between-group baseline vs final assessment, difference willow bark–placebo, estimated
by ANCOVA.
3
Between-group baseline vs final assessment, difference diclofenac–placebo, estimated by ANCOVA.
4
Baseline value corresponding to an
unchanged state. Negative within-group differences are consistent with improvement, except for the SF-36 scores. Negative between-group differences are
consistent with a tendency in favor of willow bark or diclofenac, respectively, except for the SF-36 scores. * W: willow bark extract group, P: placebo,
D: diclofenac.
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while in the physician’s assessment this superiority just
missed statistical significance. This may indicate the well
known fact that patient’s assessment is a more valid and
sensitive outcome indicator than physician’s assessment.
At the end of the study the patients were asked which
type of medication they believed they had received in the
preceding 6 weeks (willow bark, diclofenac, or placebo). In
the willow bark group, 8 patients guessed their medication
correctly, versus 5 patients in the diclofenac group and 14 in
the placebo group. Thus, blinding was apparently successful
during the study.
A power analysis of the results showed that a true differ-
ence for WOMAC pain reduction between willow bark and
placebo of 15 mm or more can be excluded with a proba-
bility of more than 99%. For a difference of 10 mm or more,
the probability is 94%.
Rheumatoid arthritis trial
The trial described above failed to show an efficacy of wil-
low bark extract in OA, the most common form of degener-
ative joint disease. It may be argued that willow bark extract
could be more efficacious in inflammatory rather than in
degenerative diseases, as possibly indicated by a study with
a nonstandardized willow bark preparation
32
.
To test this hypothesis, we decided to carry out a first
pilot trial in patients with RA, the most common inflamma-
tory rheumatic disease. In order to maximize the power of
this small study, a 2-arm rather than a 3-arm design was used
(randomized, placebo controlled, 6-week, double-blind
trial). The outcome variables followed the recommendation
of the ACR
27
, and included measurements of swollen joints,
ESR, and CRP as indicators for inflammatory processes.
Patient characteristics. As shown in Figure 3, 89 patients
were screened and 26 met eligibility criteria and were ran-
domized. Patients were excluded mainly because they did
not meet the ACR criteria for diagnosis of RA or the disease
activity criteria; 6 patients withdrew before completion of
the study due to lack of efficacy (3 willow bark extract, 3
placebo), and one patient in the willow bark group withdrew
due to an adverse event (disc prolapse).
All 26 patients were included in the intention-to-treat effi-
cacy and safety analysis; 18 patients (11 placebo, 7 willow
bark extract) were included in the per-protocol analysis.
Patients were excluded from the per-protocol population
mainly because they had study visits outside the predefined
visit window of ± 3 days of the visits on Days 14, 28, and 42.
Treatment groups were comparable with respect to
patient demographics and medical history (Table 3).
However, patients in the willow bark group showed a more
active disease in all baseline arthritis assessments (Table 4).
Mean baseline pain values in the willow bark group were 10
mm higher than in the placebo group (55 mm vs 45 mm; p
= 0.22, Kruskal-Wallis test).
Efficacy results. Efficacy results are summarized in Table 4.
The mean reduction of pain VAS values was 8 mm (15%) in
the willow bark group compared with 2 mm (4%) in the
placebo group. However, statistical analysis with adjust-
ment for baseline values and study center (ANCOVA), as
predefined in the study protocol, resulted in an estimated
difference of only –0.8 mm (95% CI –20.9 to 19.3 mm; p =
0.93). Similar results were obtained in the per-protocol
analysis (estimated difference of 0.5 mm; 95% CI –25.0 to
26.1 mm; p = 0.97). Similarly, no secondary outcome meas-
ure revealed statistically significant differences between
willow bark extract and placebo groups. While some out-
come measures (HAQ, morning stiffness, SF-36, ESR, and
CRP) showed a slight tendency in favor of willow bark
extract, others showed a tendency in favor of placebo (ten-
2126 The Journal of Rheumatology 2004; 31:11
Figure 2. Influence of willow bark extract and diclofenac on the WOMAC pain score. Difference
between treatment group and placebo group by ANCOVA with 95% CI. Intention-to-treat analy-
sis (n = 127).
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der and swollen joints, patient and physician overall assess-
ment of efficacy). Therefore, the observed between-group
differences may be attributed to chance. Only 2 patients in
the willow bark extract group and one in the placebo group
were classified as ACR-20 responders
31
. At the final visit,
patients were asked which type of medication (placebo or wil-
low bark extract) they believed they had received during the
preceding weeks. Only 4 out of 26 patients believed they had
taken willow bark extract (one correctly, 3 mistakenly).
Apparently, most patients did not feel a clear treatment benefit.
A power estimate of the study showed that a true differ-
ence in pain reduction between willow bark extract and
placebo of 15 mm (suggested as the minimum clinically rel-
evant difference
33
) or more can be excluded with a proba-
bility of 93%. A difference of 10 mm or more can be exclud-
ed with a probability of 83%.
Safety and tolerability. There were 173 adverse events
reported in the OA trial (Table 5), most in the diclofenac
group. Seven GI adverse events were reported in the willow
bark group, 19 in the placebo group, and 35 in the
diclofenac group. The difference between willow bark and
diclofenac was statistically significant (p = 0.001, Friedman
test).
One patient in the willow bark group developed an itch-
ing exanthema after exposure to the sun on Day 30, which
improved until study termination.
Two patients in the diclofenac group withdrew from the
study because of adverse events, one because of indigestion
and another due to typical symptoms of diclofenac intolera-
bility (heartburn, exertional dyspnea, blood in urine and
stool). The latter patient also experienced 2 serious adverse
events 12 days after withdrawal from the study when he was
2127
Biegert, et al: Willow bark in OA and RA
Figure 3. RA trial: Disposition of the study patients.
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hospitalized for suspected gastritis and deep vein thrombo-
sis of the legs.
Changes in hematology and clinical chemistry showed
statistically significant reductions of red blood cell count,
hematocrit, and hemoglobin in the diclofenac group
(p 0.01, Kruskal-Wallis test). The liver enzymes ALT,
AST, and GGT increased significantly under diclofenac
therapy (p 0.001). In the placebo group, there was a sta-
tistically significant increase in serum glucose (p = 0.02). In
the willow bark group, no statistically significant changes in
laboratory values were observed.
Patient’s assessment of tolerability was rated on a 100
mm VAS, 0 mm being the best value. Mean values record-
ed in the OA trial were 13 mm for willow bark, 15 mm for
placebo, and 16 mm for diclofenac.
In the RA trial, there were 7 adverse events reported in
each group (data not shown), none of which was classified
as “serious.” Causality was assessed as “possible” for 2
adverse events in the placebo group and one adverse event
in the willow bark extract group. The latter was mild itching
on the arms, which resolved completely without discontin-
uation of the study drug and without additional treatment.
No patient experienced clinically significant changes in lab-
oratory indicators. Patients rated the tolerability of the study
drug with 14 mm (willow bark extract) and 9 mm (placebo)
on the 100 mm VAS described above.
DISCUSSION
We found no evidence for a relevant analgesic or antiin-
flammatory efficacy of the investigated willow bark extract
in patients with OA and RA.
The sensitivity of the OA study was clearly demonstrat-
ed by the superiority of diclofenac over placebo observed in
all outcome measures. The study confirmed the well known
efficacy as well as the known side effects of diclofenac.
Despite the small sample size (diclofenac, n = 43; placebo,
n = 41), superiority of diclofenac over placebo could be
shown with very high significance (total WOMAC score: p
< 0.0001). This shows the excellent sensitivity of the
WOMAC index for the evaluation of OA treatments.
Our results are in conflict with the positive outcomes of
earlier trials with willow bark extract using identical doses.
Two of these trials were carried out in patients with low
back pain
8,9
. The strong effect reported especially from the
first of these studies
8
is in striking contrast with our find-
ings, although a direct comparison is difficult due to the dif-
ferent diseases investigated. A confirmation of the efficacy
2128 The Journal of Rheumatology 2004; 31:11
Table 3. Rheumatoid arthritis trial: Baseline demographic and clinical
characteristics of patients. Data are presented as number for nominal data
and as mean (SD) for continuous data.
Characteristics Willow Bark, Placebo,
n = 13 n = 13
Age, yrs 56.5 (8.9) 60.1 (11.0)
Sex, M/F 3/10 1/12
Body weight, kg 70.9 (11.7) 68.5 (11.3)
Height, cm 166.5 (6.9) 165.1 (8.3)
Duration of RA, yrs 9.4 (5.3) 13.8 (11.5)
Functional class
I12
II 9 8
III 3 3
Rheumatoid factor positive/negative 10/3 9/4
Radiologic evidence of RA, yes/no 10/3 12/0*
DMARD treatment, yes/no 8/5 10/3
Corticosteroid treatment, yes/no 5/8 6/7
Physical therapy during the study, 7/6 6/7
yes/no
Prior use of analgesics/NSAID, 9/4 8/5
yes/no
* Value missing for one patient. DMARD: disease modifying antirheumat-
ic drug.
Table 5. Adverse events reported under treatment with willow bark, diclofenac, and placebo in the OA trial.
Adverse events are summarized according to the WHO terminology
24
. The same patient may be listed under
different adverse events.
Organ System Willow Bark, Placebo, Diclofenac, Total,
n = 43 n = 41 n = 43 n = 127
GI system 7 19 35 61
Central and peripheral nervous system 7 15 16 38
Body as a whole—general disorders 7 4 11 22
Respiratory system 5 4 3 12
Musculoskeletal system 4 3 3 10
Skin and appendages 3 2 3 8
Psychiatric 1 0 4 5
Cardiovascular disorders, general 1 1 3 5
Urinary system 1 2 2 5
Vision disorders 1 0 2 3
Platelet, bleeding, and clotting disorders 1 0 1 2
Vascular (extracardiac) disorders 0 1 1 2
Total no. of adverse events 38 51 84 173
Total no. of patients experiencing adverse events 19 20 30 69
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of willow bark extract in low back pain by a 3-arm trial, in
comparison to placebo and a standard analgesic drug, may
be desirable in this situation. Our own previous trial, carried
out in OA patients in a hospital setting for 2 weeks, had
shown moderate superiority of willow bark extract over
placebo in the WOMAC pain score (–6.5 mm; p = 0.047),
but no significant improvement in the WOMAC stiffness
and physical function scores
10
. Our present study again
showed a slight tendency in favor of willow bark in the
WOMAC pain score, but the observed difference compared
to placebo was neither statistically significant nor clinically
relevant. The absolute reduction of the WOMAC pain score
from baseline to Day 14 in the previous trial
10
was similar
to that observed in the present study. However, the lower
placebo response in the previous trial was part of the reason
this moderate effect reached statistical significance in com-
parison to placebo.
In our previous study, we used an extract of a Salix pur-
purea x daphnoides hybrid. In the present study, we used the
extract from Salix daphnoides, which is currently contained
in the most widely used commercial willow bark prepara-
tions in Germany. Although both extracts were standardized
for the same total salicin content, we found clear differences
in regard to other constituents (unpublished data).
Willow bark contains salicin derivatives that are meta-
bolized in vivo to salicylic acid. In a recent pharmacokinet-
ic trial
34
, we observed that serum salicylate concentrations
in human volunteers after oral administration of current
therapeutic doses of willow bark extract were too low to
explain a relevant analgesic effect. Willow bark extract has
recently been reported to inhibit the COX-2-mediated
release of prostaglandin E
2
in vitro as well as the release of
tumor necrosis factor-α (TNF-α) and interleukin 1ß (IL-
1ß)
35
. However, we have shown that these effects are only
2129
Biegert, et al: Willow bark in OA and RA
Table 4. Efficacy of willow bark extract in the treatment of RA. Data are mean values for the intention-to-treat population.
Variable Group* Baseline Final Difference Difference
Assessment Assessment Baseline Willow Bark
(± SD) SD) vs Final vs Placebo
2
Assessment
1
(ANCOVA)
Day (–7) Day 0 Day 14 Day 28 Day 42 (± SD)
Primary endpoint
Patient’s assessment W 51 55 (20) 49 52 47 (24) –8 (24) –0.8
of pain
(100 mm VAS; best value: P 44 45 (25) 47 48 43 (30) –2 (27) (p = 0.93)
0 mm)
Secondary endpoints
Tender joint count (total W 9.9 11.0 (6.8) 8.6 9.2 10.0 (7.0) –1.0 (6.7) 2.30
28 joints) P 6.8 7.9 (5.9) 7.2 6.5 5.8 (4.7) –2.1 (2.8) (p = 0.25)
Swollen joint count (total W 8.3 8.2 (7.6) 7.7 7.4 7.5 (7.9) –0.7 (7.4) 0.82
28 joints) P 5.3 6.2 (5.4) 5.8 5.2 5.0 (4.4) –1.2 (3.2) (p = 0.69)
HAQ Disability Index W 1.2 (0.6) 1.2 1.2 1.2 (0.6) 0.0 (0.3) –0.05
(0–3 score; best value: 0) P 0.9 (0.6) 0.9 0.8 0.9 (0.6) 0.1 (0.2) (p = 0.60)
Morning stiffness (100 W 42 50 (29) 42 47 39 (2.6) –11 (26) –4.4
mm VAS; best value: 0 mm) P 45 45 (32) 45 39 42 (31) –3 (36) (p = 0.69)
Patient’s assessment of W 50
4
46 46 53 (17) 3 (17) 1.3
efficacy (100 mm VAS; P 50
4
56 54 52 (25) 2 (25) (p = 0.89)
best value: 0 mm)
Physician’s assessment W 50
4
58 (23) 8 (23) 9.5
of efficacy (100 mm P 50
4
48 (16) –2 (16) (p = 0.26)
VAS; best value: 0 mm)
ESR, mm/h W 25.6 27.8 (19.4) 26.5 (19.9) –1.3 (5.0) –5.95
P 21.5 21.0 (10.2) 25.8 (14.3) 4.0 (12.3) (p = 0.14)
CRP, mg/dl W 2.4 1.9 (1.4) 1.7 (1.6) –0.2 (1.4) –0.74
P 1.8 2.0 (1.7) 2.5 (1.9) 0.5 (1.7) (p = 0.24)
ACR-20 responders, n W 2
P 1 p = 0.55
3
SF-36 (0 to 100 score; best value: 100)
Physical Component W 30.8 (7.4) 33.1 (6.8) 2.6 (5.4) 3.0
Summary P 41.5 (9.2) 39.7 (10.2) –1.3 (5.8) (p = 0.38)
Mental Component W 52.2 (11.1) 51.5 (9.2) 0.6 (9.0) 5.4
Summary P 54.4 (8.5) 50.0 (9.0) –3.3 (4.7) (p = 0.16)
1
Within-group baseline vs. final assessment, difference of means.
2
Between-group baseline vs. final assessment, difference willow bark–placebo, estimated
by ANCOVA.
3
Cochrane-Mantel-Haenszel test.
4
Baseline value corresponding to an unchanged state. Negative within-group differences are consistent with
improvement, except for the SF-36 scores. Negative between-group differences are consistent with a tendency in favor of willow bark, except for the SF-36
scores. * W: willow bark extract, P: placebo.
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observed in vitro and not after oral ingestion of the same
extract by human volunteers, indicating that the active sub-
stances do not reach effective serum concentrations
36
.
The pharmacokinetic, pharmacological, and clinical data
we obtained do not support the hypothesis of a relevant effi-
cacy of currently used doses of willow bark extract in the
treatment of rheumatic diseases.
ACKNOWLEDGMENT
We thank Doctors Bernhard Heilig, Doris Lassak-Siedl, Markus Müller,
Hartmut Rapp, Michaela Geiger, and Constanze Richter for their coopera-
tion. We thank Robugen GmbH, Esslingen, Germany, for preparation of the
study medication and for their constructive cooperation.
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... The willow bark has been used to treat pain, inflammation, osteoarthritis, aches and to reduce fevers [129]. In fact, short period of willow bark supplement (240 mg salicin/day for 2-week) decreases joint pain in patients with osteoarthritis [130], while longer period (6-week) does not seem to improve this symptom [131]. In addition, oral administration of 120 mg or 240 mg salicin for 4-week reduces back pain in patient with low back pain [132]. ...
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