Salix – Willow Bark (Salicis cortex)
|Latin name of the genus:||Salix|
|Latin name of herbal substance:||Salicis cortex|
|Botanical name of plant:||Salix [various species including s. purpurea l.; s. daphnoides vill.; s. fragilis l.]|
|English common name of herbal substance:||Willow bark|
Latin name of the genus: Salix
Latin name of herbal substance: Salicis cortex
Botanical name of plant: Salix [various species including S. purpurea L.; S. daphnoides Vill.; S. fragilis L.]
English common name of herbal substance: Willow Bark
- TABLE OF CONTENTS
- II.ASSESSMENT REPORTON WILLOW BARK AND HERBAL PREPARATION(S)
- I.REGULATORY STATUS OVERVIEW1
- II.ASSESSMENT REPORTON
- WILLOW BARK AND HERBAL PREPARATION(S) THEREOF WITH WELL- ESTABLISHED USE (WEU)AND/OR TRADITIONAL USE (TU)
- BASED ON ARTICLE 10A OF DIRECTIVE 2001/83/EC AS AMENDED
- (WELL-ESTABLISHED USE)
- BASED ON ARTICLE 16D(1) AND ARTICLE 16F AND 16H OF DIRECTIVE 2001/83/EC AS
- (TRADITIONAL USE)
- II.1 I
- II.1.1 Description of the herbal substance(s), herbal preparation(s) or combinations thereof
- II.1.2 Information on period of medicinal use in the Community regarding the specified indication
- II.2.1 Pharmacology
- II.2.1.1 Overview of available data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- II.2.1.2 Assessor’s overall conclusions on pharmacology
- II.2.2 Pharmacokinetics
- II.2.2.1 Overview of available data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- II.2.2.2 Assessor’s overall conclusions on pharmacokinetics
- II.2.3 Toxicology
- II.2.3.1 Overview of available data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
- II.2.3.2 Assessor’s overall conclusions on toxicology
- II.3.1 Clinical Pharmacology
- II.3.1.1 Pharmacodynamics
- II.188.8.131.52 Overview of available data regarding the herbal substance(s)/herbal preparation(s) including data on constituents with known therapeutic activity.
- II.184.108.40.206 Assessor’s overall conclusions on pharmacodynamics
- II.3.1.2 Pharmacokinetics
- II.220.127.116.11 Overview of available data regarding the herbal substance(s)/herbal preparation(s) including data on constituents with known therapeutic activity.
- II.18.104.22.168 Assessor’s overall conclusions on pharmacokinetics
- II.3.2 Clinical Efficacy
- II.3.2.1 Dose response studies
- II.3.2.2 Clinical studies (case studies and clinical trials)
- II.3.2.3 Clinical studies in special populations (e.g. elderly and children)
- II.3.2.4 Assessor’s overall conclusions on clinical efficacy
- II.3.3 Clinical Safety/Pharmacovigilance
- II.3.3.1 Patient exposure
- II.3.3.2 Adverse events
- II.3.3.3 Serious adverse events and deaths
- II.3.3.4 Laboratory findings
- II.3.3.5 Safety in special populations and situations
- II.22.214.171.124 Intrinsic (including elderly and children)/extrinsic factors
- II.126.96.36.199 Drug interactions
- II.188.8.131.52 Use in pregnancy and lactation
- II.184.108.40.206 Overdose
- II.220.127.116.11 Drug abuse
- II.18.104.22.168 Withdrawal and rebound
- II.22.214.171.124 Effects on ability to drive or operate machinery or impairment of mental ability
- II.3.3.6 Assessor’s overall conclusions on clinical safety
TABLE OF CONTENTS
II.ASSESSMENT REPORTON WILLOW BARK AND HERBAL PREPARATION(S)
I.REGULATORY STATUS OVERVIEW1
MA: Marketing Authorization;
TRAD: Traditional Use Registration;
Other TRAD: Other national Traditional systems of registration;
Other: If known, it should be specified or otherwise add ’Not Known’
1This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in the MSs concerned.
2Not mandatory field
WILLOW BARK AND HERBAL PREPARATION(S) THEREOF WITH WELL- ESTABLISHED USE (WEU)AND/OR TRADITIONAL USE (TU)
BASED ON ARTICLE 10A OF DIRECTIVE 2001/83/EC AS AMENDED
BASED ON ARTICLE 16D(1) AND ARTICLE 16F AND 16H OF DIRECTIVE 2001/83/EC AS
II.1.1 Description of the herbal substance(s), herbal preparation(s) or combinations thereof
There are about 500 species of Salix species called willow, mainly found in Europe and North America. The species of medical interest include Salix alba, S. nigra and S. purpurea, but S. daphnoides and S. fragilis along with S. purpurea contain the greatest yield of salicylate precursors.
According to the Ph. Eur. (01/2005:1583), the herbal substance is the whole or fragmented dried bark of young branches or whole dried pieces of current year twigs of various species of genus Salix including S. purpurea L., S. daphnoides Vill. and S. fragilis L. The drug contains not less than 1.5 per cent of total salicylic derivatives, expressed as salicin (C13H18O7; Mr 286.3), calculated with reference to the dried drug.
The characteristic constituents are derivatives of salicin, mainly salicortin,
Salicylates, calculated as total salicin (and determined after hydrolysis) vary between species: 0.5% in Salix alba,
The bark of Salix purpurea L. contains
The bark of Salix daphnoides Vill. contains more than 4% of total salicin. Phenol glucosides include salicortin
Willow monographs are included in general reference books on herbal substances such as the American Herbal Pharmacopoeia (1999), British Herbal Compendium (1983), British Herbal Compendium (1992), Commission E monographs (1984) and ESCOP (2002) .
DAB 10 (and DAB 10 Kommentar) and Bisset (1994) recommend
Barnes et al (2002) recommended
The concentration of salicin in the herbal substance varies (see above). The Ph. Eur. stipulates a minimum content of 1.5% total salicin in the herbal substance. It is clear that
The herbal substance as such is however not used; only the bark reduced in size to comminuted or powdered is used (herbal preparations).
According to the Ph. Eur. (04/2008: 2312), willow bark dry extract contains minimum 5.0 per cent of total salicylic derivatives, expressed as salicin (C13H18O7; Mr 286.3) (dried extract). The extract is produced from the herbal drug by a suitable procedure using either water or a
The Ph. Eur. monograph only stipulates a minimum content of total salicylic derivatives, expressed as salicin. Each manufacturer needs to provide a range for the quantified extract used in his finished product. The 15% total salicin, as contained in the extract for which moderate clinical efficacy was demonstrated, represents an average value. The exact range needs to be established for each finished product on the basis of the manufacturer’s specifications.
The MLWP discussed in September 2008 whether preparations in the TU part of the monograph should be quantified or not. Some members were in favour of such quantification because 1) salicin is a source of salicylates and in view of interactions and safety profile, the amount of salicin is an important piece of information to have, 2) for eligibility to TU registration, the pharmacological effect of the preparations should be plausible and the plausibility is linked to the amount of salicin, 3) at the time of assessment of the quality dossier, if the quantification for salicin is not provided, which criteria should be applied to accept or refuse 4) quantification is justified given that it concerns an active substance. On the contrary some members were against the quantification for salicin. The HMPC Chair in particular pointed out that the quantification is irrelevant given the very low posology of the preparations. Whether a product is quantified to 15 mg or to 50 mg has no relevance to the activity and both products should be granted a TU registration. The quantification is relevant if a minimum amount of salicin is established that guarantees the plausibility of the effect. A choice is to be made between relying purely on the traditional use of the preparations or requiring some scientific evidence in which case quantification must be associated with the requirement for a minimum of salicin. The MLWP decided to delete the term “quantified” in the TU part of the monograph.
The Commission E monograph (1984) on willow bark recommends liquid and solid preparations; daily dose corresponding to
The British Herbal Pharmacopoeia (1983) and British Herbal Compendium volume 1 (1992): liquid extract (1:1 in 25% alcohol):
In Germany, a Marketing Authorisation (MA) was granted for the following
Combinations of herbal substance(s) and/or herbal preparation(s)
This AR assesses willow bark as a sole active substance in (traditional) herbal medicinal products (HMPs).
II.1.2 Information on period of medicinal use in the Community regarding the specified indication
Willow bark has had a long tradition as febrifuge dating back to the 18th century. Following the identification of salicin and the subsequent synthesis of salicylic acid and more importantly acetyl salicylic acid (end of 19th century), the interest in willow bark had decreased substantially. However, the demand for phytoanalgetica with better tolerability versus
Willow bark has traditionally been used for muscular and arthroidal rheumatism with inflammation and pain, influenza, respiratory catarrh, gouty arthritis, ankylosing spondylitis, and specifically for rheumatoid arthritis (RA) and other systemic connective tissue disorders characterised by inflammatory changes (Barnes
et al 2002).
Wichtl (2002) / Hänsel (1991) / Hagers Handbuch (Blaschek et al 1998) and ESCOP (2002) state the use as a relief of low back pain; symptomatic relief of mild osteoarthritic and rheumatic complaints.
HagerROM (2001) mentions the traditional use of powdered drug and herbal teas in case of
The German Commission E monograph (1992) approved internal use for diseases accompanied by fever, rheumatic complaints and headaches.
In Germany, MAs were granted for HMPs containing:
Dry extract ethanol 70%
Dry aqueous extracts
Dry aqueous extract
Powdered willow bark: 500 mg per coated tablet or capsule (MAs since 1991 and 1992 respectively).
Cut herb: 1.995 g/teabag,
All preparations for which MA for “TU” had been granted (according to former national regulations) were included in the overview by Germany (some of them not in accordance with the actual provisions of Directive 2004/24/EC). Traditional preparations were authorised in
Willow bark is also ingredient in combination products (3 WEU products and 2 TU products) and a standard MA for combination products with willow bark as a herbal tea exists.
In Spain, 400 mg powdered willow bark is administered every 8 hours.
In France, capsules containing 260 mg willow bark powder are authorised since 1988.
No single ingredient products are authorised / registered in the other Member States: willow bark is included in combination HMPs in Belgium, Malta, Czech Republic, UK, Austria, Latvia and Italy.
In Austria, a MA exists for a combination
No willow bark containing products are authorised in Norway, Finland and Portugal. For information, in Italy food supplements with the following preparations were notified:
Capsules with a combination of 400 mg dry extract of Salix alba (15% salicin) and 460 mg powdered bark (notified in 2004) : claim that it may favour
Oral solution (drops) containing extract ethanol 60%
In central Italy dried willow bark is applied topically to treat warts (Leporatti 1990).
Hagers Handbuch includes external use to help healing of wounds (50 g herbal substance per 0.5L water).
In the MLWP September 2007 the conditions associated with “fever” and “pain” in which HMPs containing willow bark are traditionally used were specified as “a) the symptomatic relief of minor articular pain” with a duration restriction to a maximum of 4 weeks, “b) the symptomatic relief of fever associated with common cold” for no longer than 3 days (in common cold, fever is experienced for 3 days), and “c) the symptomatic relief of headache”. If fever exceeds 39°C, persists or is associated with severe headache (meningitis) or if symptoms worsen during the use of the medicinal product, a doctor should be consulted. If headache persists for more than one day or is recurrent, medical advice is sought.
These TU uses are
The posology section covers only the preparations for which posology is documented. A posology for dry bark for herbal tea preparation, dry aqueous extracts, liquid extract and powdered dry bark were specified
II.2.1.1 Overview of available data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Pharmacological actions normally associated with salicylates are also applicable to willow which support most of the herbal uses, although no studies are available for willow covering most uses.
Salicin is probably the most active
The hen’s egg choriollantoic membrane test system has been used to study the anti- inflammatory effect of the willow bark constituents salicin and tremulacin (isolated from Populus spp). Onset of this anti- inflammatory effect is delayed in comparison with saligenin (salicyl alcohol), sodium salicylate and acetylsalicylic acid, indicating that the active principles may be metabolites of salicin and tremulacin (Albrecht et al 1990).
Isolated tremulacin, sc injected at 100mg/kg bwt significantly inhibited
A water extract of Salix caprea bark showed moderate inhibition of prostaglandin synthesis and PAF- induced exocytosis in vitro (Tunón et al 1995).
A water extract of willow bark strongly inhibited oxidation of LDL by copper ions in a number of vitro tests. Copper chelation seemed to be only partially involved in inhibition of
Willow bark extract ethanol 70% (total salicin 15%) demonstrated a
A pharmacological in vivo and in vitro study on an aqueous willow bark extract
Wuthold et al (2004) published an analysis of 22 various extracts (aqueous and
Salicin administered orally to rats at 5 mmol/kg bwt significantly reduced
Other ingredients of the extract may contribute to the overall analgesic effects. These constituents may include naringenin, catechins and eriodictyol, that inhibit lipoxygenase (Wurm 1982), hyaluronidase (Kuppsamy et al 1990) and scavenge free radical
Tannins are known to have astringent properties.
II.2.1.2 Assessor’s overall conclusions on pharmacology
The relatively low number of studies published may be due to the fact that pharmacological actions normally associated with salicylates are also estimated to be applicable to willow bark and salicin.
A number of recent in vitro and in vivo studies were published on the
Recent understandings concur that other ingredients of the extract (such as naringenin, catechins and eriodictyol) may contribute to the overall effects of willow bark.
II.2.2.1 Overview of available data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Salicortin was unchanged after 1 hour of incubation in artificial gastric juice (pH 1.0). After 6 hours of incubation with artificial intestinal juice ph.
Salicin is stable under acidic conditions (0.5% hydrochloric acid with or without pepsin) and produces no saligenin, even after incubation with human saliva at pH 7.2) (Steinegger et al 1972, Fötsch et al 1989 a and b).
Transport of salicin and saligenin into erythrocytes was rapid for saligenin (1 minute to saturation) and delayed for salicin (4 hours to saturation). The process was reversible exhibiting rapid release for saligenin and slower release for salicin. Saligenin and salicin both bind to human serum albumin but saligenin has a significantly higher affinity (Matsumoto et al 1993).
Saligenin was transformed to salicylic acid by homogenised liver, lung and kidney. Gentisic acid was quantitatively detectable in homogenised liver after incubation with saligenin (Fötsch et al 1989 a and b). Salicin was partially metabolised to saligenin and salicic acid after incubation with homogenised kidney from rats (Adamkiewicz et al 1961).
Salicin injected into an isolated
After oral administration of salicin (400 mg/kg bwt) or sodium salicylate (29 mg/kg bwt) to rats, salicylic acid appeared slowly (salicin, Cmax of 82.4 µg/ml after 5 h) or rapidly (sodium salicylate, Cmax of 104.2 µg/ml after 1.5 h). Elimination was slower with sodium salicylate. The relative
II.2.2.2 Assessor’s overall conclusions on pharmacokinetics
The in vitro and in vivo pharmacokinetics of salicin and its precursors are well documented in literature. The data should be read in conjunction with the clinical pharmacology data (pharmacokinetic data).
II.2.3.1 Overview of available data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
Salicin did not induce gastric lesions in rats even at a dose of 5 mmol/kg bwt. Saligenin and sodium salicylate induced severe gastric lesions in a
An LD50 of 28 ml/kg is described for an
Only indirect data on chronic toxicity, reproductive toxicity and theratogenicity are available for willow bark. No data on willow bark as a single ingredient were found. Teratogenicity of salicylates in animal models is described.
II.2.3.2 Assessor’s overall conclusions on toxicology
Very limited data on willow bark are available.
Tests on reproductive toxicity, genotoxicity and carcinogenicity have not been performed.
II.3.1 Clinical Pharmacology
II.126.96.36.199 Overview of available data regarding the herbal substance(s)/herbal preparation(s) including data on constituents with known therapeutic activity.
It is mainly salicin and the salicyl glycosides which form salicin after hydrolysis that represents a
In view of the considerable variation in salicylate concentrations between different Salix species, the salicin content of the products should be quantified and declared.
The analgesic activity of willow bark was studied in
Influence on cyclooxygenase activity and TNFα and
In contrast to acetylsalicylic acid, aggregation of thrombocytes is affected to a far lesser extent by willow bark. Platelet aggregation was followed in patients receiving willow bark extract (corresponding to 240 mg salicin per day), 100 mg acetylsalicylic acid per day or placebo. Willow bark decreased AA- and
Serum salicylate concentrations during treatment suggest that a daily consumption of 240 mg of salicin as extract is
II.188.8.131.52 Assessor’s overall conclusions on pharmacodynamics
Willow bark is the
Orally administered willow bark dry extract
AA and adenosine diphosphate
II.184.108.40.206 Overview of available data regarding the herbal substance(s)/herbal preparation(s) including data on constituents with known therapeutic activity.
In a recent 24 hours pharmacokinetic study in 10 healthy volunteers (Schmid et al 2001a), intake of standardized willow bark extract (1360 mg, equivalent to 240 mg salicin, dose divided into 2 tablets at T0h and another 2 tablets at T3h), resulted in salicylic acid as the major metabolite of salicin detected in the serum (86% of total salicylates), besides salicyluric acid (10%) and gentisic acid (4%). Peak levels were reached within 2 hours after oral administration. Peak serum levels of salicylic acid were on average 1.2 mg/L and the AUC was equivalent to that expected form an intake of 87 mg acetylsalicylic acid. Considerably higher peak levels of salicylic acid are observed after analgesic doses of acetylsalicylic acid.
Renal elimination occurred predominantly in the form of salicyluric acid (71% of total salicylates), followed by salicylic acid (15%) and gentisic acid (14%). No saligenin or salicin could be detected in serum or urine. After 24 hours, on average 15.8% of the orally ingested dose of salicin was detected in the urine as salicylates. Since approximately 5% of the salicylates had not yet been excreted by the kidneys after 24 hours, it could be estimated that at least 16.6% of the ingested salicin had been absorbed and metabolized to salicylates.
Based on the in vivo findings in rats, it was repeatedly suggested that in humans salicin is also hydrolysed by the flora of the lower intestine prior to absorption of the aglycone (salicyl alcohol). This is contradicted by the studies of Schmid et al (2001a), Steinegger et al (1972, 4 g pure salicin) and Pentz et al (1989) combination product of caffeine and willow bark) that found salicylic acid in the serum as early as 1 hour after ingestion, and peak levels recorded after
II.220.127.116.11 Assessor’s overall conclusions on pharmacokinetics
The pharmacokinetics of willow bark extract are well described (Schmid et al 2001a).
II.3.2 Clinical Efficacy
In spite of its long (traditional) use, only a few controlled trials have been conducted with willow bark to support its analgesic and/or antipyretic action.
The clinical studies (all located in the therapeutic area of (minor) articular disorders) are summarized below
Acute Low Back Pain (LBP) is a symptom, heterogeneous and
CPMP (1998 and 2003) issued Points to consider papers on clinical investigation of medicinal products for treatment of OA and RA, respectively.
II.3.2.1 Dose response studies
Low back pain (LBP)
Chrubasik S, Eisenberg E et al (2000). Treatment of low back pain exacerbations with willow bark extract: a randomized
Randomized double blind clinical trial, 3 arms, no report of randomization method, 4 weeks
210 patients, N=70 in each group, 191 completed the trial. Inclusion criteria: >18 years, at least 6 months of intermittent low back pain that could not be attributed to identifiable causes, a current exacerbation of their pain at rest and with movement that caused pain of at least 5 of 10 on a VAS and that was expected to require at least 4 weeks of treatment. The characteristics of the participants were similar in the 3 groups (e.g. radiation into leg(s), neurological signs), except that the
placebo versus daily dose ~ 120 mg salicin (786 mg dry extract) versus daily dose ~ 240 mg salicin (1572 mg dry standardized willow bark extract, 15 % salicin, Plantina manufacturer, Assalix, 70% ethanol, DER
Primary outcome parameter:
% of patients
Change from baseline in modified Arhus score; % of patients requiring tramadol
Primary outcome: 6% responders in the placebo group, 21% in the low dose group and 39% in the high dose group (P< 0.001). Similar results were obtained when
A significant increase in proportion of patients without rescue medication in the high dose group was apparent after 1 week of treatment and became progressively greater during the 4 weeks of treatment. The smaller effect seen in the 120 mg group was significantly different from placebo by the second week of treatment.
significantly more patients in the placebo group required tramadol during each week of the study
declines in the modified Arhus score (overall and its individual components) were significant. Change in overall Arhus score and its pain component was significantly greater in the 240 mg than in the 120 mg group.
Willow bark groups: N=140 patients): 1 patient suffered a severe allergic reaction (exanthema, pruritis, swollen eyes; 120 mg group, could be attributed); other adverse effects (N=2) attributed to tramadol).
Placebo group : N=70 : 3 cases of mild abdominal pain in placebo group (with or without diarrhoea)
Assessor’s comment: The study is of good quality. The results indicate a
II.3.2.2 Clinical studies (case studies and clinical trials)
Low Back Pain
Chrubasik S, Eisenberg E et al (2000). Treatment of low back pain exacerbations with willow bark extract: a randomized
Details see II.3.2.2
Chrubasik S, Kunzel O et al (2001a). Treatment of low back pain with a herbal or synthetic anti- rheumatic: a randomized controlled study. Willow bark extract for low back pain. Rheumatology 40:1388- 93.
228 patients, N=114 with per group. 183 patients completed the trial. Inclusion criteria: >18 years, at least 6 months of
Daily dose ~ 240 mg salicin (1572 mg standardized willow bark extract, 4 capsules of Assalix, ethanol 70%,
pain on a VAS, modified Arhus index, its pain component and the total pain index (TPI), physician and
After 4 weeks of treatment, the Arhus index had improved by 20% (both groups) and its pain component by 30%, and the TPI by 35%.
Patients that resorted to NSAIDs and/or tramadol: 9 in willow bark group (average of 120 mg diclofenac equivalents and 5 mg tramadol) versus 12 in rofecoxib group (average of 42 mg diclofenac equivalents and 17 mg tramadol).
Patients that resorted to other treatments: 13 in willow bark group versus 17 in rofecoxib group.
Patients’ and physicians’ judgments of effectiveness were largely concordant.
The multivariate analyses of changes in Arhus score and TPI did not identify significant differences related to willow bark versus rofecoxib
Willow bark group, N=114:
o allergy: 1 possible, 3 likely, 1 clear connection
oGI (dyspepsia, vomiting, heartburn, diarrhoea): 7 possible, 3 likely, 1 clear connection
o Dizziness: 1 possible o Headache: 1 possible
oblood pressure instability: 1 possible
Rofecoxib: 27 adverse effects in total; asthma, dyspepsia, nausea, diarrhoea, heartburn, ulcer, GI bleeding, dizziness, headache, oedema
Assessor’s comment: the open study design may induce bias and jeopardizes results/conclusions regarding equivalence or
Chrubasik S., Kunzel 0 et al (2001b). Potential economic impact using a proprietary willow bark extract in outpatient treatment of low back pain: an open
451 patients > 18 years (N=115 in 120 mg salicin group, N=112 in 240 mg salicin group, N=224 in “placebo” group) with acute exacerbations of chronic (at least 6 months) nonspecific LBP. The baseline characteristics of the 3 groups were slightly different: the “placebo” group had a shorter duration of exacerbation but their pain tended to be more severe as judged by the Arhus index and TPI.
Daily dose of 120 mg salicin + conventional treatment, versus 240 mg salicin + conventional treatment versus conventional treatment alone. Salicin groups received standardized willow bark extract, (Assalix, ethanol 70%;
Study of safety and economic impact of including a regular intake of willow bark extract in the conventional treatment scheme. Outcome parameters:
The study design does not allow conclusions on efficacy of willow bark because conventional treatment that was resorted to was variable between groups.
When limiting to the patients included in this study that only used willow bark (no conventional treatment), pain relief of 240 mg dose seems to be superior to 120 mg and control group: 41%
18% of the “placebo” group (with conventional treatment) were
Willow bark groups, N=112+115 patients: GI (6), allergic skin reaction (3)
Assessor’s comment: Important flaws in the study design make conclusions on the efficacy of willow bark based on the results impossible. The open study design may induce bias and jeopardizes results/conclusions regarding equivalence or
The adverse effects are taken into account for evaluation of clinical safety.
Gagnier et al (2007) published a systematic Cochrane review of the randomized clinical trials to determine the effectiveness of herbal medicine compared with placebo, no intervention or standard/accepted/conventional treatments for nonspecific LBP. A total of 10 studies met the criteria, among those the
Schnitzer et al (2004) reviewed clinical trials
chronic LBP, of muscle relaxants in acute LBP and of antidepressants in chronic LBP. Data on the other therapeutic approaches were considered inadequate to allow conclusions. Standardized approaches to evaluate therapies in LBP are needed, as well as rigorous clinical trial methodology, standardized outcome measures to evaluate many current and future therapeutic interventions.
Osteoarthritis and Rheumatoid Arthritis
Schmid, Ludtke et al (2001b). Efficacy and tolerability of a standardized willow bark extract in patients with osteoarthritis: randomized
78 patients, N=39 per group. Inclusion criteria: >18 years, OA of hip or knee, verified according to the clinical, laboratory and radiographic criteria of the American College of Rheumatology (ACR). Baseline characteristics are similar between both groups except that the baseline WOMAC pain score was lower for the willow bark group. Exclusion criteria are described. 5 patients withdrew during the study and 10 were excluded from the
placebo versus daily dose ~ 240 mg salicin (340 mg standardized willow bark extract Salix daphnoides and S. purpurea, 17.6% total salicin, ~ 60 mg salicin per coated tablet). Daily dose was divided into 2 tablets twice daily. No additional analgesics, NSAIDs or systemic corticoids were allowed during wash- out and study phases.
Difference in pain dimension WOMAC OA Index between day 0 and day 14.
Differences in the stiffness and physical function dimensions of the WOMAC, daily VAS on pain and physical function and final overall assessments by patients and investigators.
A (borderline) significant superiority of willow bark over placebo with regard to WOMAC pain dimension after 2 weeks
No significant differences between the 2 groups with regard to the secondary parameters, except for patients’ and investigators’ assessment (willow bark significantly superior).
Willow bark group, N=38 patients: allergic skin reactions (6), GI (3). No evaluation presented on causality.
1 patient in the willow bark group withdrew due to allergic symptoms.
Assessor’s conclusion: A moderate analgesic effect was observed in the willow bark group; a difference in pain dimension in the treated group compared to the placebo group just reached statistical significance. There are deficiencies in the quality of the methodology of the study that may affect the outcome/conclusions: namely the relatively low number of patients, the shortness of the duration (the maximum treatment effect was probably not yet reached after 2 weeks) and the differences in baseline WOMAC pain dimension scores between the 2 groups. The extraction solvent and DER of the used willow bark extract is not given. Additional studies, with NSAID (diclofenac) control group were stated to be in preparation.
Biegert C et al. (2004). Efficacy and safety of willow bark extract in the treatment of OA and RA: results of 2 randomised db controlled trials. J Rheumatol 31,
OA trial: 127 patients; N=43 in willow bark group, N=43 in control group, N=41 in placebo group. Inclusion criteria: > 18 years, OA of hip or knee, verified according to the clinical, laboratory and radiographic criteria of the American College of Rheumatology (ACR) with WOMAC pain score of at least 30mm. Baseline characteristics are similar between the groups. Exclusion criteria are described. 106 patients completed the study and were included in the efficacy and safety analysis. The willow bark group received significantly less physical therapy.
RA trial: 26 patients, N=13 in each group. Inclusion criteria: diagnosis of RA according to ACR: RA functional class I, II or III, evidence of at least moderate disease activity (criteria given). The willow bark group showed a more active disease in all baseline arthritis assessments. Exclusion criteria are described.
OA trial: Placebo versus salicin 240 mg/day (393 mg extract Salix daphnoides ethanol 70%
RA trial: Placebo versus salicin 240 mg/day (393 mg extract
OA trial: pain
RA trial: patient’s assessment of pain rated on a 100mm VAS.
OA trial: WOMAC stiffness and function
RA trial: included number of tender/swollen joints, physical function (HAQ), disability index, patients’ assessment of severity of morning stiffness (100 mm VAS), patients’ and assessors’ assessment of overall efficacy, Quality of life
Primary: WOMAC scores decreased for willow bark (but not significantly) and diclofenac (P=0.0002)
Secondary: willow bark only significantly improved the physical function
Primary: RA trial: pain on the VAS decreased for willow bark but not significantly. A power estimate of the study showed that that a true difference in pain reduction between willow bark and placebo of 15 mm (suggested as the minimum clinically relevant difference) or more can be excluded with a probability of 93%.
Secondary: no significant changes between willow bark and placebo.
Willow bark group in OA trial (N=43): GI (7), plus allergy (exanthema, 1). Significantly lower adverse events in willow bark versus diclofenac
Willow bark group in RA trial (N=13): allergy (mild itching, 1)
Assessors comment: The studies are in general of high quality but numbers of patients are small.
With regard to the OA trial, the study did not confirm efficacy of willow bark in OA as willow bark only significantly improved the physical function
With regard to the RA trial, again no efficacy was demonstrated for willow bark in RA, the most common inflammatory rheumatic disease. The number of patients included in the RA trial is very small and is therefore considered as a pilot study.
Lardos et al (2004) carried out a randomised double blind clinical trial with 60 patients (intention to treat) with hip or knee arthrosis. The study included 3 arms (N=17 diclofenac 150 mg/day; N=22 aqueous extract equivalent to 90 mg salicin/day; N=21 aqueous extract equivalent to 180 mg salicin/day). Inclusion and exclusion criteria are described. A 3 week
Assessor’s comment: The study indicates analgesic effects of an aqueous extract of willow bark in patients with arthrosis. The sample size is however small; the study is considered as a pilot study. The herbal preparation is not fully characterised (DER). Comparability of the 3 arms at baseline is difficult to interpret. No
An unpublished trial was provided by Poland. Samochowiec (2001) studied the efficacy of willow bark extract (Salix ®) in patients with arthrosis (knee or hip) in a
Assessor’s comment: The willow bark preparation is insufficiently characterized. It is not possible to situate the results in relation to the other clinical trials with willow bark. Patient numbers are rather small, and end points should be more clearly defined.
Assessor’s comment: Full details of the
In an observational study with duration
Assessor’s comment: This concerns an observational study, no control group is included. Records of dose administered (1572 mg or 786 mg dry extract) are not presented. Baseline characteristics are not given (per grouped diagnosis). No conclusions can be drawn with regard to efficacy.
Tanacetum parthenium and Salix alba either alone or in combination were shown to strongly inhibit binding to
Shrivastava et al (2006) performed a prospective
An overview of 15 systematic reviews of herbal medicines used in the treatment of osteoarthritic complaints and chronic low back pain was recently published by Chrubasik et al (2007). The evidence was found as conflicting for willow bark due to the confirmatory study of Biegert et al (2004) in OA and RA with negative result (no statistically significant results).
Setty et al (2005) reviewed herbal preparations commonly used in the treatment of rheumatic indications. The resurgent interest in willow bark as a treatment for chronic pain syndromes was illustrated by a
summary of the clinical trials. The authors concluded that trials longer than 4 weeks must be performed before declaring salicin’s safety and efficacy as the conditions are chronic (OA).
Willow bark is safer than aspirin, but effective dosing may be difficult to obtain. Several controlled trials have demonstrated benefits for extract products in the treatment of rheumatic and musculoskeletal pain. A pure historic interest may be a premature judgement (Rottblatt 2002).
The clinical studies are
II.3.2.3 Clinical studies in special populations (e.g. elderly and children)
No clinical studies were performed in patients below 18 years..
II.3.2.4 Assessor’s overall conclusions on clinical efficacy
Under WEU: General conclusion on the clinical studies on analgesic effects of willow bark:
The disease studied, the design and quality of the published trials was variable (see assessors comments per study, see also Garnier et al 2007). Shortcomings in some of the controlled clinical trials are: small numbers of patients and/or short duration of the study, slightly different baseline characteristics which hamper conclusions on changes towards baseline, open study design, and access to rescue analgesics/NSAIDs/corticoids again hampering conclusions on efficacy of willow bark. The willow bark preparations are not always carefully characterized and described (extraction solvent, DER). The quantity of salicin should be stated although other constituents may contribute to the activity. The composition with regard to salicylates and other constituents varies among extracts (Kammerer et al 2005). Results for a particular extract cannot be extrapolated to other extracts.
Taking into account the body of available published trials and their respective trial quality and outcomes, the controlled clinical trials published so far provide moderate evidence for the analgesic activity of a daily dose of willow bark extract ethanol 70%
Based on the available clinical studies, daily intake of willow bark dry extract ethanol 70% (total salicin content 15%), equivalent to 240 mg total salicin is advised. The daily dose should be divided into 2 doses. The patient is referred to the physician in case of worsening or no improvement after the first week of use. This limitation of duration of use is based/in accordance with the clinical studies, where improvement is observed after 1 week of treatment with willow bark (Chrubasik et al 2000). The use is not recommended under 18 years of age.
During discussion in the MLWP in September 2007 some members indicated that they would not support a “WEU” indication of “symptomatic treatment of minor articular pain” as they considered that the efficacy of willow bark in treating this condition as not proven. Some clinical studies are indeed of pilot- scale size. However, the human pharmacological data would be sufficient to support an indication in “articular pain” and the body of clinical evidence is more expanded than for e.g. nettle herb. Some members advised caution in defining the indications for willow bark in the knowledge that effective pain relief medicinal products are available. As the evidence for low back pain was stronger than the evidence available for OA, the WEU indication was consequently revised to “HMP used for the
II.3.3 Clinical Safety/Pharmacovigilance
II.3.3.1 Patient exposure
Minor adverse effects have been reported in a relatively small number of patients. Based on the published clinical data, from a total of 620 patients and healthy volunteers treated with various
Assessor’s comment: Full details of the
II.3.3.2 Adverse events
Chrubasik et al (2000): Willow bark groups : N= 70+70 patients:
o1 patient suffered a severe allergic reaction (exanthema, pruritis, swollen eyes; 120mg group, could be attributed);
onote that the other adverse effects (N=2) were attributed to tramadol (rescue medication).
Chrubasik et al (2001): Willow bark group, N= 114 patients:
oallergy : (1 possible, 3 likely, 1 clear connection)
oGI (dyspepsia, vomiting, heartburn, diarrhoea) (7 possible, 3 likely, 1 clear connection)
oDizziness: (1 possible)
oHeadache: (1 possible)
oblood pressure instability (1 possible)
Chrubasik et al (2001b) Willow bark groups, N=112+115 patients:
o allergic skin reaction (3)
o no evaluation of causality presented
Schmid et al (2001b) Willow bark group, N=38 patients: o allergic skin reactions (6)
o GI (3)
o No evaluation of causality presented.
o Note that 1 patient in the willow bark group withdrew due to allergic symptoms.
Biegert et al (2004): Willow bark group in OA trial (N=43) and in RA trial (N=13) : o GI (7)
o allergy (exanthema, 1) (mild itching, 1) o no evaluation of causality presented.
Schmid et al (2001a): willow bark group N=10 volunteers
oadverse events not recorded / reported
Krivoy et al (2001): willow bark group N=35 patients
oadverse events not recorded / reported
Plants that contain more than 10% tannins (willow bark:
The undesirable effects are reflected in section 4.8 of the monograph.
II.3.3.3 Serious adverse events and deaths
One patient suffered a severe allergic reaction (exanthema, pruritis, swollen eyes; 120 mg group, could be attributed (Chrubasik et al 2000).
Literature reports a case of anaphylaxis resulting from the use of a
II.3.3.4 Laboratory findings
II.3.3.5 Safety in special populations and situations
II.18.104.22.168 Intrinsic (including elderly and children)/extrinsic factors
Adverse effects and signs of toxicity normally associated with salicylates (such as gastric and renal irritation, hypersensitivity, blood in stools, tinnitus, nausea and vomiting) may occur. Salicin is documented to cause skin rashes.
In view of the lack of more toxicity data on willow bark, the usual precautions associated with salicylate therapy are also applicable to willow bark. Therefore, in individuals with known hypersensitivity to aspirin, asthma, active peptic ulceration, haemophilia and other bleeding disorders, gout should be aware of the possible risks associated with the intake of willow bark (Clauson et al 2005; Aronson).
Concurrent administration of willow bark with other
Hypersensitivity to salicylates or other NSAIDS
There is a considerable
Patients with existing asthma and nasal polyps or chronic urticaria have a greater frequency of hypersensitivity. Because of the relatively high incidence of
Reye’s syndrome was previously regarded as a
Despite the lack of understanding of the syndrome and the fact that a clear, conclusive link between the syndrome and aspirin (salicylates) is not yet established, the decision has been taken in many countries to advice against the use of salicylates in children (Meylers, Rotblatt 2002). Because of the clinical importance of the syndrome and the avoidable risk, use of salicylates in patients below 16 years should in
general be avoided. Therapeutic alternatives are available (paracetamol, ibuprofen) except for juvenile arthritis.
Examples of regulatory action are:
The UK authorities position paper (2002): not to be used below 16 years as from October 2003.
PhVWP did not issue a
The Belgian authorities issued an advice against use in children below 12 years in case of suspicion of viral infection. A class labelling in the section 4.4 (not 4.3) was imposed for acetylsalicylic acid containing medicinal products : only to be used for these patients in case
other products lack efficacy; information on symptoms of Reye’s syndrome is given; a statement is included that relationship between syndrome and acetylsalicylic acid is not yet established with certainty.
A special warning on Reye‘s syndrome for patients under 18 is included in the monograph: “In children and adolescents under 18 [product name] should only be used on medical advice and only in cases when other therapies failed to succeed. In a child or adolescent who has become very unwell with severe vomiting, drowsiness or loss of consciousness following a viral infection, a serious disease may be suspected. Reye’s syndrome is an extremely rare but life threatening condition which requires immediate medical attention“. Taking into account the age limit for OTC products, willow bark should only be used in children and adolescents below 18 years under medical supervision. Traditional HMPs containing willow bark are therefore
Other precautions with regard to intake of salicylates
When willow bark preparations are taken according to the normal dosage recommendations, they will produce relatively low salicylate serum levels. Still, reactions in sensitive individuals cannot be ruled out.
Precautions associated with salicylate therapy are also applicable to willow bark. In case of severe liver or renal dysfunction, coagulation disorders (risk of hemorrhagia), gastric/duodenal ulcer, willow bark should be used with caution and under medical supervision. Traditional HMPs containing willow bark are therefore
In patients with
The use of willow bark in patients with active peptic ulcer disease is
II.22.214.171.124 Drug interactions
Only the interactions documented with willow bark are included. A number of theoretical interactions listed for acetylsalicylic acid
Interaction (pharmacokinetic and pharmacodynamic) with oral anticoagulants (heparin, coumarine derivatives) is plausible and of therapeutic importance and therefore included: Krivoy et al (2001) investigated whether treatment with willow bark during treatment of LBP affected platelet aggregation. 35 patients having acute exacerbations of LBP were enrolled in a
aggregation but to a significantly lesser extent than acetylsalicylate did. The mean percentages of maximal
Salicylates are extensively bound to plasma proteins. A recent study on the pharmacokinetics of salicin after oral administration of a standardized willow bark extract (Schmid et al 2001a) demonstrates that the AUC of salicylate after ingestion of a dose corresponding to 240 mg salicin was equivalent to that expected from an intake of 87 mg acetylsalicylic acid;
Shalansky et al (2007) carried out a prospective longitudinal study (171 adults) to determine the risk of bleeding and supratherapeutic international normalised ratios (INR) associated with use of complementary and alternative medicine (CAM) in patients receiving warfarin. Statistically significant associations between the use of willow bark and bleeding events were identified. The risk of a supratherapeutic INR was not increased. After adjustment for the identified
The combined use of willow bark with acetylsalicylic acid/other NSAIDS is not recommended even though an increased risk of gastric irritation has never been described (Rotblatt 2002). The MLWP decided in September 2007 to add a warning that concomitant use with salicylates and other NSAIDs is not recommended without medical advice.
The very high concentration of tannins present may interfere with absorption of other products.
II.126.96.36.199 Use in pregnancy and lactation
Salicylates cross the placenta. Acetylsalicylic acid is teratogenic in rodents, but till now there is no clear evidence of teratogenesis when used in human pregnancy. Increased PG production during pregnancy and/or placental metabolism may have protective roles.
Due to increased bleeding risk, delay of parturition and induction of early closure of the ductus arteriosis, use of acetylsalicyl acid/NSAIDs is
Conflicting reports have been documented concerning the safety of acetylsalicylic acid taken during the first and second trimester of pregnancy. The safety of willow bark has not been established. Occasional ingestion of salicylates does not seem to be a problem (no
Salicylates appear in breast milk and have been reported to cause macular rashes in babies. The two major pathways of salicylate degradation (formation of salicyluric acid and salicyl phenol glucuronide) become saturated at relatively low body levels of the drug. The drug is slowly eliminated by the newborn infant.
Because data on the use during lactation are not available, the use is not recommended as a general precaution.
No toxic effects reported.
Taking into account the relatively low serum levels after oral intake of willow bark and the high content of tannins in willow bark (GI disturbances) which makes intake of large amounts less likely, the MLWP agreed in September 2007 not to include the symptoms of overdose with acetylsalicylic acid.
II.188.8.131.52 Drug abuse
No data available.
II.184.108.40.206 Withdrawal and rebound
No data available.
II.220.127.116.11 Effects on ability to drive or operate machinery or impairment of mental ability
The MLWP decided in September 2007 to mention that no studies on the effect on the ability to drive and use machinery had been performed.
II.3.3.6 Assessor’s overall conclusions on clinical safety
Minor adverse effects have been reported in a relatively small number of patients. Based on the published clinical data, from a total of 620 patients and healthy volunteers treated with various
Adverse effects and signs of toxicity normally associated with salicylates may occur. In view of the lack of more toxicity data on willow, the usual precautions associated with salicylate therapy are also applicable to willow. Therefore individuals with known hypersensitivity to aspirin, asthma, active peptic ulceration, haemophilia and other bleeding disorders, gout should be aware of the possible risks associated with the intake of willow bark. Appropriate
In spite of its long (traditional) use, only a few controlled trials have been conducted with willow bark to support its analgesic and/or antipyretic action. Recent renewed interest in willow bark resulted in a number of clinical trials studying the efficacy in acute exacerbations of LBP, in OA and RA. The design and quality of the published trials was variable.
Taking into account the body of available published trials and their respective trial quality and outcomes, the controlled clinical trials published so far provide moderate evidence for the analgesic activity of a daily dose of willow bark extract
For the symptomatic treatment of fever and pain, only general evidence is available (TU).
In view of the lack of more toxicity data on willow, the usual precautions for use associated with salicylate therapy are also applicable to willow. Appropriate