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Willow bark extract STW 33-I in the long-term treatment of outpatients with rheumatic pain mainly osteoarthritis or back pain.

ARTICLE INFO

Keywords:

Willow bark

Rheumatic pain

Back pain

Osteoarthritis

Long-term-study

ABSTRACT

Study objective: Efficacy and safety of willow bark extract for pain reduction in patients suffering from musculoskeletal disorders (MSD) has been shown in clinical short term trials. Therefore this observational study over 6 months should evaluate patterns of treatments like mono- or combinations therapy, dosage and safety during long-term treatment under pragmatic conditions with the aqueous willow bark extract STW 33-1, (Proaktiv[R]; drug-extract-ratio 16-23:1).

Patients and methods: The patients were treated with STW 33-I; comedication with other NSAIDs and opioids was allowed. An extensive case report form including pain questionnaires and patient diary was used for outcome evaluation.

Results: Four hundred and thirty-six patients with rheumatic pain mainly due to osteoarthritis (56.2%) and back pain (59.9%) were included. During the study the mean reductions from baseline value 58.4 [+ or -] 22.6-31.8 [+ or -] 22.5 after 24 weeks in the pain intensity scale (VAS 0-100 mm) were significant even after 3 weeks with a reduction by 26 mm (45.6% of the baseline value) at the end of the study. The relative reductions of the weekly means of the daily patient self-rated scores of the pain (6-point Likert-scales) were between 33% and 44% of the baseline values during the course of the study. We present results of subgroups according their analgetic/antiphlogistic comedication.

The distribution and specification of the main adverse events and the ratings of the treatment showed a good tolerability. No relevant drug interactions were reported.

Conclusion: These data suggest that STW 33-I can be used as a basic treatment in the long-term therapy of painful musculoskeletal disorders and that it can be combined with NSAIDs and opioids if necessary.

[c] 2013 Elsevier GmbH. All rights reserved.

Introduction

Willow bark (WB) has already been mentioned in ancient and medieval writings as an agent against fever and pain. A characteristic constituent of WB is salicin and its derivates (ESCOP 2003). Salicin was discovered in 1831 and was used then as isolated substance to treat fever and pain. Yet, salicin is a prodrug which is metabolized in the gut and liver via salicylic alcohol into salicylic acid--the active drug. Salicin as well as its chemically modified derivative acetylsalicylic acid (ASA) are known to inhibit the cyclooxygenases (COX) 1 and 2, COX-inhibition has been regarded as the main mechanism of the anti-inflammatory activity of WB, which contains a complex composition of various salicin-derivates. WB has been considered a natural form of ASA (Nahrstedt et al. 2007).

However, the daily recommended dosage of WB corresponding to only 120-240 mg total salicin might rise doubts about this assumption (ESCOP 2003; Gagnier et al. 2006; Nahrstedt et al. 2007). Consequently there should be other active constituents in extracts from WB. Meanwhile it was shown that preparations from WB can also inhibit lipoxygenase (LOX-5), modulate relevant pro- and anti-inflammatory cytokines (Interleukin 1, 6, 8, 10) and nuclear factors (TNF-[alpha], NF-kB). All these effects were attributed to a lesser extent to salicin derivates rather than to polyphenols, flavonoids and proanthocyanidins in WB. In addition polyphenols and flavonoids showed anti-oxidative effects, which also have an anti-inflammatory impact. Moreover in vivo models for acute and chronic inflammation (e.g. paw edema, adjuvant-induced arthritis in rats), and analgesia (e.g. writhing test in mice), showed a dose-dependent effect for aqueous WB extracts corresponding to the same dose of ASA (Bonaterra et al. 2010; Cameron et al. 2009; Fiebich et al. 2005; Fiebich and Chrubasik 2004; Khayyal et al. 2005; Nahrstedt et al. 2007; Ulrich-Merzenich et al. 2008).

Upto date efficacy and safety of WB have mostly been investigated for alcoholic extracts in patients suffering from pain in various musculoskeletal disorders. For low back pain moderate efficacy was found in 2 placebo- and 1 NSAID-controlled RCT (Gagnier et al. 2006). For osteoarthritis (OA), however, one placebo- and one 3-armed RCT with placebo and NSAID-control found inconsistent results (Cameron et al. 2009). For rheumatoid arthritis a systematic review found no significant efficacy in a placebo-controlled RCT. However, the treatment periods have only been relatively short ranging from 2 to 6 weeks and daily dosage equivalent to 120-240 mg salicin was administered with 2-4 tablets (Cameron et al. 2009: Gagnier et al. 2006: Wegener 2009). Additional trials, 4 open and 2 RCTs have been summarized elsewhere (Wegener 2009). Meanwhile a further open study with 877 patients treated with a WB extract equivalent to 60-240 mg salicin daily over a period of 6-8 weeks showed a clinically relevant pain reduction (Sailer et al. 2008).

An aqueous WB extract has been investigated in a NSAID-controlled 3-armed RCT in 60 patients with osteoarthritis (OA) of the hip or knee over 3 weeks with daily dosage equivalent to 90 mg versus 180 mg salicin versus 150 mg diclofenac and resulted in no significant differences between groups (Lardos et al. 2004).

The aim of this observational study was to evaluate efficacy, tolerability and safety of the aqueous WB extract STW 33-I in a long-term treatment for up to 6 months in outpatients suffering from musculoskeletal disorders. Another important aim was to evaluate the role of comedication patterns of the herbal drug with other analgesics like NSAIDs or opioids in daily medical routine.

Patients and methods

Study design

In this observational study ('Anwendungsbeobachtung' according to German regulations) patients of both genders over 18 years were included suffering from musculoskeletal disorders (MD) like OA or back pain. The multi-center study was placed in regional pain centers and in practices of general practitioners (GPs) familiar with pain therapy. Additionally it was planned that the outpatient clinic of the Department of Natural Medicine, Charite University Medicine Berlin would include about 100 outpatients for comparison. Patients were enrolled from 1/2008 to 12/2009.

Study drug

STW 33-I(Proaktiv[R], registered as a herbal OTC drug by German Federal Institute for Drugs and Medical Devices (BfArM), drug-extract-ratio (DER) 16-23:1, 23-26% total salicin) is an aqueous extract of WB which allows the daily administration of the equivalent of 240 mg salicylic alcohol derivates with only 2 tablets. The extract STW 33-1 has been characterized by a HPLC-fingerprint analysis with identification of the main salicylalcohol-derivatives and flavonoids. This analysis with the necessary description of the technique (apparat, column, solvent system) has been published in Phytomedicine by Bonaterra et al. (2010) and Freischmidt et al. (2012).

In agreement with the open character of the study no strict drug regime was prescribed by protocol. It was the aim of this study to evaluate long-term treatment with STW 33-I alone or in combination with other analgesics (e.g. NSARs, opioids). The patients ought to be treated overa period of 24 weeks with clinical visits at baseline and after 3, 6, 12, 18 and 24 weeks.

Outcome measure

Patients' and physicians' ratings

During the visits the global pain intensity was rated by the patient on a visual analogue scale VAS (0-100 mm from "no pain" to "strongest pain"). Additionally, the global efficacy of the treatment was rated by the physician on a 5 point Likert-scale: 0 = very good/nearly complete remission, 1 = moderate/partly remission of symptoms, 2 = mild improvement, 3 = no improvement/worsening, 4 = not assessable. Safety and tolerability were measured from the 2nd to the last visit onward in terms of adverse drug reaktion (ADR), adverse events (AE) and dropouts. For assessment of severity of the ADRs a 5-point Likert-scale was used: 0 = none, 1 = non-significant impairment, 2 = significant impairment, 3 = ADRs outweigh the therapeutic efficacy, 4 = not assessable. For AEs, intensity (mild, moderate, severe) and for SAE (severe AE), whether they were expected/unexpected, their mode (once, intermittent continuously, unknown), the relation to the drug (assured, likely, possible, unlikely, not assessable, cannot be determined, no correlation) the action undertaken, and the course of AE had to be documented. For dropouts, the reasons had to be documented (e.g. improvement, intolerability).

Patients' rating

Additionally, patients had to fill out their dairy with daily self-rating of (a) pain at rest, (b) pain during movement, (c) the duration of pain, (d) overall impairment due to pain, (e) impairment of quality of sleep due to pain (f) and changes in their pain therapy and dosage of STW 33-land other analgesics. The scales for all these measures, except duration of pain and dosage, were 6 point Likert-scales: 0 = none/not at all, 1 = mild, 2 = moderate, 3 = marked, 4 = strong, 5 = very strong. For the assessment of pain duration the 6 point scale was: 0= none, 1 = [less than or equal to]1 h, 2 = 1-2 h, 3 = 2-6 h, 4 = 6-12 h, 5 = permanently. Dosage of analgesics had to be given by number of tablets or in mg.

Statistics

Data were mainly subjected to descriptive statistical evaluation. Statistical analysis was performed with SAS[R] Version 9.1 (Cary, North Carolina, USA). The data are presented as means [+ or -] one standard deviation (SD), additionally medians as well as 95% confidence intervals and numbers of patients were calculated. Categorical data are presented using counts and percentages rounded to one decimal place. All p-values are two-tailed, and p < 0.05 was considered statistically significant.

In this observational study it was planned to evaluate more than 400 patients within 2 years.

Results

Demographic and anamnestic data

A total of 436 patients (n = 327, resp. 75.2% female, n = 108, resp. 24.8% male) were included in 74 study centers; 103 of those patients were recruited at the Department of Natural Medicine. Demographic data are shown in Table 1. Regarding occupation 44.3% of the patients were retired and 24.8% were in full-time jobs.

Table 1

Patients' demographic data.

Gender, n (%)

Male                                                   108 (24.8%)
Female                                                   327 (75%)

Ethnic, n (%)

Caucasian                                              306 (70.2%)
Other                                                   56 (12.8%)

Age, years (SD, median, min.-max.)   59.3 mean (12.1, 59.5, 22-87)
Weight, kg (SD, median)                     76.1 mean (16.2, 75.0)
BMI, kg/[m.sup.2] (SD, median)               26.8 mean (5.1, 26.1)


A majority of patients suffered from OA or back pain. Other diagnoses were less than 18% of patients (Table 2). Co-morbidity of both, OA and back pain was observed in about 1 third of patients.

Table 2 Etiology of musculoskeletal pain.

Musculoskeletal disorder             n (%)

OA                             245 (56.2%)
Back pain                      261 (59.9%)
Soft tissue rheumatism           25 (5.7%)
Rheumatoid arthritis             33 (7.6%)
Fibromyalgia                    67 (15.4%)
Others                          77 (17.7%)
OA & back pain                 149 (34.2%)
OA & back pain & fibromyalgia    40 (9.2%)


The chronic condition is reflected by more than 5 years history of pain in 58% of the patients (Table 3). The majority of the patients had received a multimodal therapy with pharmacological (80.3%) and non-pharmacological treatment (physiotherapy 62.2%, massages 47.5%; multiple nominations possible). Patients had been treated mostly by general practitioners (GPs).

Table 3

Anamnesis of patients pain duration.

Duration                                  n (%)

<1 month                               2 (0.5%)
1 to <6 month                         16 (3.7%)
0.5-1 year                            34 (7.8%)
1 to <2 years                        45 (10.3%)
2 to <5 years                        78 (17.9%)
[greater than or equal to] 5 years  253 (58.0%)


Co-medication patterns and reasons for discontinuation

All patients started treatment with STW 33-1. 61.5% of the patients (n = 268) took no analgesic co-medication. 28.9% (n = 126) took comedications with NSAIDs (mostly diclofenac or ibuprofen) and only 3,9% received a triple therapy (STW 33-I + NSAID + opioid). Only 5.7% (n = 25) used other analgesics like gabapentin.

63.5% of the patients (n = 277) continued treatment over 24 weeks, while 36.5% (n = 159) terminated prematurely. Of these patients 42.8% (n = 68) dropped out due to lack of efficacy (11.2% with monotherapy, 19.0% with dual, therapy, 23.5% with triple therapy, and 40.0% under other co-medications).

Patients' and physicians ratings

There is a continuous and significant pain reduction during the whole treatment period (Fig. 1).

The mean reductions in the pain intensity scale (from baseline value 58.4 [+ or -] 22.6 to 31.8 [+ or -] 22.5 after 24 weeks) were significant (p < 0.01) already after 3 weeks and clinically relevant with a reduction of 26 mm (45.6% of the baseline value) at the end of the study.

This was in line with the physicians' global rating of efficacy of the treatment from the second until last visit (Table 4). Of the patients available for the last rating after 24 weeks 60% had a nearly complete or partly remission (rating 0-1) of their symptoms compared to 27.1% after 3 weeks.

Table 4 Physician's global rating of efficacy, weeks 3-24 (n, %).

Week                Physician's global rating of efficacy            n
                                                                  Total

             0            1            2            3          4

3    23 (5.6%)   89 (21.6%)  143 (34.6%)  136 (32.9%)  22 (5.3%)    413

6   44 (12.0%)  117 (32.0%)  105 (28.7%)   97 (26.5%)   3 (0.8%)    366

12  55 (16.7%)  117 (35.5%)   89 (27.0%)   68 (20.6%)   1 (0.3%)    330

18  63 (22.1%)   92 (32.3%)   68 (23.9%)   56 (19.6%)   6 (2.1%)    285

24  84 (31.1%)   78 (28.9%)   63 (23.3%)   42 (15.6%)   3 (1.1%)    270

Global rating cf efficacy, weeks 3-24 (n, %); 5 point Likert-scale:
0 = very good/nearly complete remission, 1 = moderate/partly remission
of symptoms. 2 = mild improvement. 3 = no improvement/worsening, 4 =
not assessable.


Patients daily rating--the diary

In the patients' diary the different aspects concerning pain were measured. All scores show significant reductions of pain during treatment (Table 5 and Fig. 2 as an example). The absolute reductions of the weekly means of the daily scores of the pain variables are in the range of 0.87 (impairment of quality of sleep by pain)-1.31 (impairment by pain),--relative reductions between 33% and 44% of the baseline values.

Table 5 Patients' diary.

Week    Pain in motion       Impairment by pain

      Mean (SD) median    n    Mean (SD) median    n

1      3.36 (1.30) 3.5  237     3.03 (1.1) 3.14  238

6        2.78 (1.34) 3  232     2.46 (1.27) 2.5  234

12     2.4 (1.34) 2.33  209     2.13 (1.26) 2.0  212

24    2.13 (1.35) 2.14  149    1.72 (1.26) 1.57  151

Likert-scales from 0 to 5. For readability only
values of weeks 1, 6, 12 and 24 are shown.


Safety and tolerability

During the study a total of 176 AEs (adverse events) were reported in 106 patients. SAEs (severe adverse events) were reported in 7 of these. All of these were regarded as unrelated to STW 33-1. Sixty-three AEs (35.8%) were reported under STW 33-1 monotherapy, 96 (54.5%) under STW 33-1 + NSAIDs and 17 (9.7%) under triple analgesic therapy.

The distribution and specification of the main AEs (n [greater than or equal to] 10) by system organ class shows gastrointestinal disorders (n = 45, like upper abdominal pain, nausea, gastric disorder, dyspepsia) to be the most frequent ones. They are followed by general disorders (n = 17, like influenza like illness, pain, fatigue), infections and infestations (n = 17, like gastrointestinal infection, viral infection) and musculoskeletal and connective tissue disorders (n = 13, like arthralgia, sciatica).

Physicians' rating of patient's treatment tolerability indicates an overall good tolerability and can be seen in Table 6, with the majority of the patients (99.3%) having no or no significant ADR after 24 weeks compared to 95.8% after 3 weeks. The difference could be explained by the dropouts.

Table 6 Treatment tolerability.

Week            Rating of tolerability of the treatment        n

              0          1          2         3         4  Total

3   362 (88.5%)  30 (7.3%)  10 (2.4%)  0 (0.0%)  7 (1.7%)    409

6   330 (91.2%)  19 (5.2%)  10 (2.8%)  1 (0.3%)  2 (0.6%)    362

12  301 (92.6%)  19 (5.8%)   2 (0.6%)  2 (0.6%)  1 (0.3%)    325

18  276 (96.8%)   8 (2.8%)     0 (0%)  0 (0.0%)  1 (0.4%)    285

24  262 (96.7%)   7 (2.6%)     0 (0%)  1 (0.4%)  1 (0.4%)    271

Rating of treatment tolerability, weeks 3-24 (n, %): 0 = one
(=very good tolerability, no ADR), 1 = non-significant impairment
by ADR, 2 = significant impairment, 3 = ADRs outweigh the therapeutic
efficacy, 4 = not assessable.


Discussion

In this pragmatic surveillance study (official term by EU-authorities: non-interventional trial) over 24 weeks a total of 436 patients (n = 327%, 75%, female and n = 108%, 24.8% male) were included in 74 study centers. One hundred and three of these patients were included in the department of Natural Medicine of the Charite University Medicine Berlin, the others in practices specialized in pain therapy. All 436 patients were treated with the Willow bark extract STW 33-I; due to the ("real life") character of the study it was the decision of the doctors to treat their patients with additional medication. The largest part of the patients (61.5%) were treated with STW 33-1 alone. 28.9% of the patients received additionally NSAIDs (mainly diclofenac and ibuprofen), 3.9% additionally NSAIDs and opioids and 5.7% additionally other medication. Overall, 36.5% terminated the study prematurely, mainly due to lack of efficacy. Of these patients the proportions were different between the co-medication groups: It was 11.2% in the STW 33-1 mono group, 19% in STW 33-1 + NSAIDs, 23.5% in STW 33-1 + NSAIDs + opioids and 40% in the group receiving other medication. Patients treated with willow bark mono-therapy had the lowest rate of dropouts. These data of patients using combination therapies need a further evaluation to clarify, whether the higher drop-out rate is triggered clue to lack of analgesia in more severe pain conditions. The latter would imply that patients with mild and chronic pain conditions could be treated with WB alone.

Our results concerning efficacy are limited regarding efficacy due to the limitations due to the open design of the study. Yet, there is a significant (p < 0.01) change in the pain intensity rated by the patients with a clinically relevant reduction of 26 mm on the VAS at the end of the study (45.6% of the baseline value). So it may be concluded that this is moderate effect as an analgesic.

The absolute reductions of the weekly means of the daily patient self-rated scores of the pain variables (6-point Likert-scales) are in the range of 0.87-1.31, the relative reductions are between 33% and 44% of the baseline values. It has been shown in osteoarthritis studies that mean VAS scores and its relative changes from baseline are generally highly correlated with corresponding Likert-scales (Bolognese et al. 2003). A 5- or 7-point scale is likely to produce slightly higher mean scores relative to the highest possible attainable score, compared to that produced from a 10-point scale (Dawes 2008). But it should be mentioned that in this study there was a double average calculation from diary data: means over patients as usual and means over days to get the weekly means which may lead to a smaller range of the values. Therefore the percentage of reduction seems more important.

Concerning the comparison of the ITT and the PP collectives (Fig. 1, VAS and Fig. 2, pain at rest, patients diary) it is worth to mention that the two groups have comparable baseline values and both run very closely. So the drop-outs are not those which would have perceived no benefit. Therefore and because of the overall good tolerability of the treatment it seems inconclusive that 36.5% of the patients terminated the study prematurely due to "lack of efficacy". Other factors like that patients had to pay for their herbal medication (WB extract) out of their pocket might have implied a higher dropout rate, too.

The findings of the present open study indicate that the WB extract examined has a good tolerability and shows, in regard to the limitation inherent to the study design, the therapeutic usefulness of WB extract in the long-term treatment of up to 24 weeks in patients suffering from back pain and OA.

Due to different settings in other open studies, as e.g. the use of different extracts of WB and other indications, it is difficult to compare them with the findings of the present study. The best comparability from design and parameters is given in an open study with an alcoholic WB extract equivalent to 60-240 mg salicin daily. Eight hundred and seventy-seven patients suffering from various musculoskeletal disorders (mainly arthrosis and dorsopathies) were treated for 6-8 weeks (Sailer et al. 2008). The pain reduction from 5.32 [+ or -] 1.62 to 2.51 [+ or -] 2.04, 53% on a VAS, 0-9 cm (p < 0.001) is comparable with our findings. For another open, randomized study, which did not show a difference in pain reduction between an alcoholic WB extract equivalent to 240 mg salicin and 12.5 mg rofecoxib over 4 weeks in patients suffering from acute back pain, VAS values have not been published (Gagnier et al. 2006).

In a placebo controlled double blind pilot study with 22 patients suffering from degenerative spinal syndroms the patients were treated with a combination of passion flower and WB extract (equivalent to 240 mg salicin daily) for 2 weeks (Schaffner 1997). In the verum group a reduction of pain (VAS, 0-10 cm) of 40% was observed in contrast to 18% in the placebo group, exact values not reported.

In a 3-arm 6 week double blind study 127 patients suffering from osteoarthritis were treated with ethanolic WB extract (equivalent to 240 mg salicin daily), 100 mg diclofenac or placebo. WB extract and placebo showed only a small pain reduction (pain subscore, VAS, 0-100 mm) (48 [+ or -] 12 baseline, 17% reduction vs. 50 [+ or -] 17, 10%) compared to diclofenac (49 [+ or -] 14 baseline, 47% reduction) (Biegert et al. 2004).

In a randomized double blind study with an aqueous WB extract (Lardos et al. 2004) 60 OA patients were treated with WB extract (equivalent to 90 mg or 180 mg Salicin daily) or diclofenac (150 mg daily) for 3 weeks. All 3 groups showed significant improvements of a pain (VAS, 0-10 cm) by 48% and 31 %, resp., with no significant differences between the groups (Diclo: 6.9 [+ or -] 2.02-3.59 [+ or -] 1.92; WB 90 mg: 6.51 [+ or -] 1.72-3.94 [+ or -] 1.88; WB 180 mg: 5.87 [+ or -] 1.87-4.03 [+ or -] 1.69).

Regarding the heterogeneous design, the number of patients and the rather short treatment periods of the randomized controlled studies a pragmatic study with focus to long treatment time seems appropriate for chronic diseases like OA. The presented data within the pragmatic and real world design of a non-interventional observational study support the safety of a long-term therapy with willow bark extract over 6 months as a mono-therapy or in combination with other conventional analgesics. Therefore the practitioner might start pain therapy with the willow bark extract as a "basic" treatment and add other conventional analgesics according to the individual needs of the patient.

Acknowledgement

This study was in part supported by a grant from Steigerwald Arzneimittelwerk GmbH, Germany.

* Corresponding author at: University of Health and Sports, Vulkanstrasse 1, 10367 Berlin, Germany. Tel.: +49 30 5779737601.

E-mail address: bernhard.uehleke@my-campus-berlin.com (B. Uehleke).

0944-7113/$--see front matter 2013 Elsevier GmbH. All rights reserved.

http://dx.doi.org/10.1016/j.phymed.2013.03.023

B. Uehleke (a), (b), (d), *, J. Muller (e), R. Stange (a), O. Kelber (e), J. Melzer (b), (c)

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(a) Department of Natural Medicine, Charite University Medicine Berlin, Immanuel Krankenhaus, Konigstra[ss]se 63, 14109 Berlin, Germany

(b) Institute for Complementary Medicine, University Hospital Zurich, Ramistrasse 100, 8091 Zurich, Switzerland

(c) Clinic for Psychiatry and Psychotherapy, University Hospital Zurich, Ramistrasse 100, 8091 Zurich, Switzerland

(d) University of Health and Sports, Vulkanstrasse 1, 10367 Berlin, Germany

(e) Clinical Research, Steigerwald Arzneimittelwerk GmbH, Havelstrasse 5, 64295 Darmstadt, Germany
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Author:Uehleke, B.; Muller, J.; Stange, R.; Kelber, O.; Melzer, J.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:4EUGE
Date:Aug 15, 2013
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