Willow Bark – Salicis cortex (Salix [various species including S. purpurea L.; S. daphnoides Vill.; S. fragilis L.])
|Latin name of the genus:||Salicis cortex|
|Latin name of herbal substance:||Salix [various species including s. purpurea l.; s. daphnoides vill.; s. fragilis l.]|
|Botanical name of plant:||Herbalref.com|
|English common name of herbal substance:||Willow bark|
Latin name of the genus: 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
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% of total salicylic derivatives, expressed as salicin (C13H18O7; MW 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
It is suggested that all components identified play a role in the
There seems to be seasonal variation in the content of salicylates in willow bark. Förster et al. (2009) performed a qualitative analysis on samples of Salix daphnoides, Salix pentandra and Salix purpurea were collected over three years (2006, 2007, 2008) in Germany, Poland, Austria, Switserland and Italy. Salicylate content was analyzed with HPLC. According to their findings the authors make recommendation for optimal periods of harvesting (Förster et al. 2010).
Table 1: Seasonal variation of salicylate content of different Salix species collected over three different years. Different characters mean significant differences between different years for the same species (Föster et al. 2009).
Esatbeyoglu et al. (2010) analysed 57 different samples of white willow bark (Salix alba) with regard to their dimeric and polymeric procyanidin composition. Polymeric procyanidins of white willow bark were found to contain the highest amount of
Kim et al. (2015) isolated two new salicin derivatives, saliglandin and
Wiesneth et al. (2015) isolated and analysed proanthocyanidins (PAs) from an
Figure 1: Structures of the isolated procyanidins (PC)
Willow monographs are included in general reference books on herbal substances such as the American Herbal Pharmacopoeia (1999), British Herbal Pharmacopoeia (1983), British Herbal Compendium (1992), Commission E monographs (1984), ESCOP (2003), Dingerman et al. (2002).
DAB 10 (and DAB 10 Kommentar resp. 1991 and 1995) and Bisset (1994) recommend
Barnes et al. (2007) 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% 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.
During the first assessment in 2008 it was discussed whether preparations in the TU part of the monograph should be quantified or not. The HMPC concluded not to use 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
In Germany, a Marketing Authorisation (MA) was granted for the following
•Combinations of herbal substance(s) and/or herbal preparation(s) including a description of vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products assessed, where applicable.
1.2. Search and assessment methodology
Starting from the references used for the first version additional information was searched in
•Books and book chapters: Barnes et al. (2007), Dingerman et al. (2002), Madaus (1935), McGuffin (1997), Schmid et al. (2002), Williamson et al. 2013.
•Monographs: ESCOP, Kooperation Phytotherapie
Search engines used: keywords Salix OR willow within a timeframe January 2011 to January 2016. Scientific databases: Embase
Medical databases: PubMed
Data from EU and
•Monographs: Kooperation Phytotherapie.
Figure 2: literature selection flowchart
2. Data on medicinal use
2.1. Information about products on the market
2.1.1. Information about products on the market in the EU/EEA Member States
Information on medicinal products marketed in the EU/EEA
This overview is not exhaustive. It is provided for information only and reflects the situation at the time when it was established.
Table 2: Information on medicinal products marketed in Germany
Table 3: Information on medicinal products marketed in Poland
Information on active or analytical marker(s) or constituents with known therapeutic activity
1. 330 mg of powdered Salicis cortex contains not less than 20.0 mg of phenolic glycosides counted as salicin.
2. Quality in line with Eur. Ph. Daily dose corresponds to 240 mg phenolic glycosides counted as salicin.
Countries without information on products on the market (reporting September – October 2015)
Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Malta, the Netherlands, Norway, Portugal, Romania, Slovakia, Slovenia, Spain, UK, Sweden.
Information on relevant combination medicinal products marketed in the EU/EEA
Information on other products marketed in the EU/EEA (where relevant)
2.1.2. Information on products on the market outside the EU/EEA
2.2. Information on documented medicinal use and historical data from literature
Medicinal use of different parts of the willow tree has been mentioned by Pedanius Dioskorides (1st century AD) and Philippus Aureolus Theophrastus Bombastus von Hohenheim or Paracelsus (16th century) (Madaus 1935). 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 anti- inflammatory drugs has increased scientific interest in willow bark (Mayer and Mayer 1949) (McGuffin et al. 1997) (Kaul et al. 1999). Even in
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. 2007; Beer et al. 2008). The use in case of lumbar pain is less supported by scientific data (Beer & Loew 2008).
The British Herbal Pharmacopoeia (1983) and British Herbal Compendium volume 1 (1992) included a liquid extract (1:1 in 25% alcohol):
Wichtl (2002) / Hänsel (1991) / Hagers Handbuch (Blaschek et al. 1998) and ESCOP (2003) 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 (1984) approved internal use for diseases accompanied by fever, rheumatic complaints and headaches. Apart from these indications the use in quite a lot of other conditions have been listed. The following indications can be found in standard sources: amongst others adjuvans in diabetes mellitus, anthelminticum, diaphoreticum, diureticum, dyspepsia, malaria, bronchitis, against neuralgia, sedative and as a tonicum. Traditional external use includes the use as amongst others antisepticum, adstringens, keratolyticum, rubefaciens and in case of ear infection (Benedum et al. 2006).
März and Kemper (2002) made an overview of preclinical and clinical investigations, confirming pharmacodynamic properties and clinical value of willow preparations.
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 favor
•Oral solution (drops) containing an ethanol (60%) extract
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 0.5 l water).
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.
Table 4: Overview of historical data
2.3. Overall conclusions on medicinal use
Table 5: Overview of evidence on period of medicinal use
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
3.1.1. Primary pharmacodynamics
In vitro studies
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
Isolated tremulacin, s.c. injected at 100 mg/kg bw 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 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
It should be noted that after oral ingestion of the extract, these inhibitory effects were no longer demonstrated. Moreover salicin components may not be the only constituents responsible for the activity (Fiebig and Appel 2003).
In another in vitro study with primary human monocytes, the extract 70% ethanol
A third study examined a water extract 33:1 in two inflammation models in rats, the 6day air pouch model and the
contribute to the overall activity as the extract contains considerably lower amounts of salicylates (Khayyal et al. 2005).
The effects of 5 fractions of a standardized willow bark extract from Salix daphnoides, purpurea and fragilis were investigated on human monocytes. Positive controls were diclofenac and acetylsalicylic acid. The willow bark extract, as well as its 5 fractions inhibited the
A pharmacological in vivo and in vitro study on an aqueous willow bark extract
Salicin administered orally to rats at 5 mmol/kg bw 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, hyaluronidase and scavenge free radicals (Kuppsamy et al. 1990;
An aqueous extract of the bark of Salix purpurea (DER
Shakibaei et al. (2012) studied the
Figure 3: Inhibitory effects of willow bark extract on
Dried aerial parts of willow bark (7.5 g) were extracted in 100 ml water at 90°C for 15 min. Different concentrations of this aqueous herbal extract was incubated with THP1 macrophages, and interleukin
Table 6: Overview of the main
Preclinical experimental data in vitro were obtained by using human and canine monocytes, chondrocytes, macrophages and
administered in vivo must also be considered as
3.1.2. Secondary pharmacodynamics
Wuthold et al. (2004) published an analysis of 22 various extracts (aqueous and
The potential of willow bark extracts as anticancer agents has been reported. A study demonstrated the inhibition of anchorage independent growth, motility, migration, and adhesion of colon cancer cell lines
Fiebig et al. (2010) investigated the influence of different fractions of the STW
The influence of salicylalcohol, flavonoids and proanthocyanidins isolated from willow bark extract BNO 1455 on proliferation and apoptosis of human colon and different cancer cells. All compounds showed
The willow bark STW
Willow bark extract (WBE; not specified) prevented
Polyphenols including procyanidins are suggested to contribute to the overall effect of willow bark. Kaufeld et al. (2014) investigated the relaxant response to a highly purified and chemically defined
mediated through the
Kong et al. (2014) investigated the antitumorigenic and antiangiogenic activity of salicin and its underlying mechanism of action. Salicin suppressed the angiogenic activity of endothelial cells, such as migration, tube formation, and sprouting from an aorta. Moreover, salicin reduced reactive oxygen species production and activation of the extracellular
Some compounds isolated by Kim et al. (2015) were evaluated for their nitric oxide (NO) inhibitory efficacy in lipopolysaccharide
More recent interest raised in the antitumoral, cardiovascular and
3.1.3. Safety pharmacology
No data available.
3.1.4. Pharmacodynamic interactions
The number of genes regulated by the three treatments were 1673 (WB), 117
exceeded the threshold in 5 disease clusters (cardiac⇑arteriopathy and stenosis, glomerular injury, pulmonary hypertension, alkaline phosphatase levels ). Imipramine treatment hit 13 disease clusters: amongst others tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, precipitation of congestive heart failure; urinary retention, altered liver functions. Those correspond to known potential adverse events. Glomerular injury and altered liver functions are part of the side effect profile of salicylic acid derivatives in agreement with the findings for the salicin rich
The authors conclude that there is no linear relationship between the number of constituents of a drug (preparation) and the number of different targets hit in a biological system on the gene expression level. Therefore, the number of genetic targets in a biological system does not necessarily increase with the complexity of the treatment corresponding to the
There are no
There seems to be no linear relationship between the number of constituents of willow bark extracts and the number of different targets hit in a biological system on the gene expression level. Interaction studies prove that the number of genetic targets in a biological system does not necessarily increase with the complexity of the treatment. A possible synergism between willow and coffee components. Synergism was observed for ability of inhibition of lipid peroxidation and reducing power.
However both findings have a speculative character, as their clinical relevance remains to be demonstrated.
Willow preparations inhibit
3.2. Overview of available pharmacokinetic 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
Figure 4: Effect of extraction system on
After oral administration of salicin (400 mg/kg bw) or sodium salicylate (29 mg/kg bw) to rats, salicylic acid appeared slowly (salicin, Cmax of 82.4 μg/ml after 5 hours) or rapidly (sodium salicylate, Cmax of 104.2 μg/ml after 1.5 hours). Elimination was slower with sodium salicylate. The relative bio- availability of salicylic acid from salicin was only 3.25% of that from sodium salicylate (Fötsch et al. 1990), which was much lower than postulated after administration of 1 mmol salicin / kg bw = 268 mg/kg bw (Fötsch et al. 1989). Salicin appears to be a
The in vitro and in vivo pharmacokinetics of salicin in rats and its precursors are documented in literature. The data should be read in conjunction with the clinical pharmacology data (pharmacokinetic data).
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
3.3.1. Single dose toxicity
No data are available on single dose toxicity.
3.3.2. Repeat dose toxicity
Salicin did not induce gastric lesions in rats even at a dose of 5 mmol/kg bw. Saligenin and sodium salicylate induced severe gastric lesions in a
An LD 50 of 28 ml/kg is described for a
No data available.
No data available.
3.3.5. Reproductive and developmental toxicity
Only indirect data on reproductive toxicity and teratogenicity are available for willow bark. No data on willow bark as a single ingredient were found. Teratogenicity of salicylates in animal models is described.
3.3.6. Local tolerance
No data available.
3.3.7. Other special studies
No data available.
Very limited data on willow bark are available.
Tests on reproductive toxicity, genotoxicity and carcinogenicity have not been performed.
3.4. Overall conclusions on
Specific preclinical data on interactions with other substances are not available. Nevertheless, a warning in case of concomitant use with anticoagulants is recommended in the monograph.
As there is no information on reproductive and developmental toxicity, the use during pregnancy and lactation cannot be recommended.
Tests on reproductive toxicity, genotoxicity and carcinogenicity have not been performed.
4. Clinical Data
4.1. Clinical pharmacology
4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
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
Willow bark is the
Orally administered willow bark dry extract
AA and adenosine diphosphate
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
In a 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
Schmid et al. (2002) reviewed the metabolism of willow compounds after administering an extract of Salix purpurea and daphnoides to 10 human volunteers (6 men; 4 women; mean 34.6 years of age). They ingested 2 tablets with 340 mg willow extract, corresponding to 120 mg salicin derivatives before taking a standard breakfast (8:30 am) and two other tablets at 11:30 am, corresponding to a total of 240 mg salicin derivatives. Blood collection started one hour after the first intake. The results are given in Figures 5 to 7.
Figure 5: Main metabolites of salicin derivatives in humans (Schmid et al. 2002).
Figure 6: Mean serum levels of salicylic acid, gentisinic acid and salicyluric acid. Each point represents the mean values for 10 human volunteers, with the 95% confidence intervals. ‘Gesamtsalicylate’ is the result of the sum of the three salicylates (Schmid et al. 2002).
Figure 7: Excretion of salicylic acid derivatives and their sum (= Gesamtsalicylate) for 10 human volunteers. Each point represents the mean with the 95% confidence interval (Schmid et al. 2002).
Knuth et al. (2013) performed kinetic comparative studies in wistar rats and in man. After oral administration of 100 mg/kg b.w. (235.8 μmol/kg) salicortin to Wistar rats, they detected peak serum concentrations of 1.43 mg/L (13.0 μM) catechol after 0.5 hours in addition to salicylic acid by HPLC‑
DAD after serum processing with
Figure 8: Catechol and salicylic acid concentration in glucuronidase- and
± SD (Knuth et al. 2013).
4.2. 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. Wegener (2009) published an overview of 10 clinical studies with more than 1400 patients suffering from low back pain. The clinical studies (all located in the therapeutic area of (minor) articular disorders) are summarized below
4.2.1. Dose response studies
Low back pain (LBP)
Chrubasik 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 standardized willow bark extract
Primary outcome parameter: % of patients
Secondary outcome: 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
4.2.2. Clinical studies (case studies and clinical trials)
126.96.36.199. Low Back Pain
(See also Table 7)
Chrubasik et al. (2000). Treatment of low back pain exacerbations with willow bark extract: a randomized
Details see 4.2.1.
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
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 (4 capsules of Assalix = 1572 mg standardized willow bark extract
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):
•Allergy: 1 possible, 3 likely, 1 clear connection.
•GI (dyspepsia, vomiting, heartburn, diarrhoea): 7 possible, 3 likely, 1 clear connection.
•Dizziness: 1 possible.
•Headache: 1 possible.
•Blood pressure instability: 1 possible. Rofecoxib group (N=114):
27 adverse effects in total; asthma, dyspepsia, nausea, diarrhoea, heartburn, ulcer, GI bleeding, dizziness, headache, oedema.
The open study design may induce bias and jeopardizes results/conclusions regarding equivalence or
Chrubasik 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 = standardized willow bark extract
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:
•18% of the “placebo” group (with conventional treatment) were
Willow bark groups, N=112+115 patients: GI (6), allergic skin reaction (3)
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
Shara and Stohs (2015) grant Salix preparations an efficacy in case of joint pain and osteoarthritis. They state that, although willow bark extracts are generally standardized to salicin, other ingredients in the extracts including other salicylates as well as polyphenols, and flavonoids may also play prominent roles in the therapeutic actions. Furthermore adverse effects appear to be minimal as compared to
Vlachojannis et al. (2009) reviewed 6 clinical trials with ethanolic extracts of Salix. The authors expressed the need for studies with a higher dose equivalents than 240 mg salicin (Vlachojannis et al. 2009).
188.8.131.52. Osteoarthritis and Rheumatoid Arthritis
(See also Table 8)
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.
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 double blind 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 per day (393 mg extract Salix daphnoides ethanol 70%
RA trial: Placebo versus salicin 240 mg per day (393 mg extract
OA trial: pain
RA trial: patient’s assessment of pain rated on a 100 mm 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: 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).
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.
Beer and Wegener 2008. Willow bark extract (Salicis cortex) for gonarthrosis and coxarthrosis
Open, multicentric observational study with reference treatment, 90 patients treated with a standardised willow bark extract preparation, 41 patients with a standard therapy prescribed by a doctor and 8 patients with a combination of the two.
Adults aged between 50 and 75 with degenerative complaints of the major and minor joints. The inclusion criteria were coxarthrosis with hip pain diagnosed by a specialist or gonarthrosis with knee pain according to the statement of a specialist.
The study medication used was a standardised dry extract of willow bark (DER
Evaluation was performed after 3 and 6 weeks.
Effectiveness and tolerance were determined by the doctor (clinical findings, recording of adverse events, global tolerance) and by the patients (WOMAC questions concerning pain and stiffness, questions on general state of health).
Undesirable effects of treatment.
A total of 88 patients in the willow bark group and 40 patients in the reference group completed the study. The doctors’ and patients’ judged effectiveness in both groups to be comparable. After 6 weeks the effectiveness of the willow bark extract was better than conventional therapy. Also in de subgroup of chronically ill sick patients (43 months), after 6 weeks the effectiveness of both forms of treatment was comparable. However, the effect was slower to set in the willow bark group than in de reference group.
There were no side effects in the willow bark group, whereas one case of reflux occurred in the reference group and in the combination group.
The results of the study suggest that willow bark extract is as effective as conventional reference therapy in the treatment of degenerative complaints of the major and minor joints. However, the result of this study cannot be seen as conclusive because the trail was an open study with a limited number of patients.
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 per day; N=22 aqueous extract equivalent to 90 mg salicin per day; N=21 aqueous extract equivalent to 180 mg salicin per day). Inclusion and exclusion criteria are described. A 3 week
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 dose- dependency in effect could be observed.
An unpublished trial was provided by Poland. Samochowiec (2001) studied the efficacy of willow bark extract (in patients with arthrosis (knee or hip) in a
The willow bark preparation is insufficiently characterized. It is not possible to evaluate 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.
Werner, 2004. In a
Full details of the
Saller et al. 2008. In an observational study with duration
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.
Mills et al. 1996. A
willow bark formulation (containing 100 mg Salix alba extract, guaiacum, black cohosh, sarsaparilla and poplar bark) compared to placebo.
Müller et al. 2010. 350 patients suffering from low back pain and pain due to osteoarthritis were observed during 6 months. They were using a water extract of Salix (DER
The same authors reported about an observational study of 333 patients with osteoarthritis, rheumatoid arthritis or low back pain. The patients were treated with a water extract of Salix (DER 16- 23:1) during a mean period of 3.3 (+ 0.9) weeks, 85% of the patients receiving a daily dose of 480 mg. Satisfaction rate (good/very good) was reached in 80% of the patients. According to the physicians the results were comparable to NSAIDs and paracetamol. More than 90% of the patients reported a good to very good tolerability
Stange et al. (2014) followed 436 patients with musculoskeletal pain of different ethology during 24 weeks. The patients were taking a water extract of Salix
An overview of 15 systematic reviews of herbal medicines used in the treatment of osteoarthritic complaints and chronic low back pain was 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 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).
The clinical studies are
184.108.40.206. Migraine prophylaxis
Tanacetum parthenium and Salix alba either alone or in combination were shown to strongly inhibit binding to
oxetorone, cyproheptadine) while only Salix alba (and the combination) recognized
(targets of triptans), leading to the hypothesis that the combination would provide superior migraine prophylactic activity compared with Tanacetum alone (randomized
Shrivastava et al. (2006) performed a prospective
Salix alba 300 mg (salicin content ≥ 1.5%) twice daily was administered to determine the effects on
migraine attack frequency (primary outcome parameter), intensity and duration (secondary outcome parameters). Attack frequency was reduced by 57.2% after 6 weeks (P=0.029) and 62.6% at 12 weeks (P=0.025) in 9 out of 10 patients (no significant improvement between 6 and 12 weeks) with 70% of patients having a reduction of at least 50%. Attack intensity was reduced by 38.7% after 6 weeks and 62.6% after 12 weeks in 10 out of 10 patients (both significant), with 70% having a reduction of at least 50%. Attack duration decreased by 67.2% after 6 weeks and 76.2% after 12 weeks in 10 out of 10 patients (both significant). Two patients were excluded for reasons unrelated to treatment. No adverse events occurred. In patients with more than 2 migraine attacks per month, current prophylaxis reduces the number of attacks by up to 50% but in only half the patients. A
Table 7: Clinical studies in humans, indication low back pain
4.3. Clinical studies in special populations (e.g. elderly and children)
No studies performed.
4.4. Overall conclusions on clinical pharmacology and 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 Gagnier 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.
When revising the assessment report in 2016, no new clinical trials could be found. However meta- analysis of the existing studies seem to confirm the daily dose equivalent with 240 mg salicin as an effective dose in reducing pain and equivalent to 12.5 mg rofecoxib (Oltean et al. 2014).
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
See chapter 5.3
5.2. 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 2734 patients and healthy volunteers treated with various
reported in 95 cases (3.5%), predominantly GI and allergic reactions (including 2 severe). Data obtained with combination products are not included in this overview of adverse events.
Full details of the
5.3. Adverse events, serious adverse events and deaths
The following undesirable effects were reported in randomized clinical trials.
Chrubasik et al. (2000): Willow bark groups: N= 70+70 patients
•1 patient suffered a severe allergic reaction (exanthema, pruritis, swollen eyes; 120mg group, could be attributed).
•Note that the other adverse effects (N=2) were attributed to tramadol (rescue medication). Chrubasik et al. (2001a): Willow bark group, N= 114 patients
•Allergy : (1 possible, 3 likely, 1 clear connection)
•GI (dyspepsia, vomiting, heartburn, diarrhoea) (7 possible, 3 likely, 1 clear connection)
•Dizziness: (1 possible)
•Headache: (1 possible)
•Blood pressure instability (1 possible)
Chrubasik et al. (2001b) Willow bark groups, N=112+115 patients
•Allergic skin reaction (3)
•No evaluation of causality presented
•Schmid et al. (2001b) Willow bark group, N=38 patients:
•Allergic skin reactions (6) No evaluation of causality presented.
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)
•Allergy (exanthema, 1) (mild itching, 1)
No evaluation of causality presented.
Schmid et al. (2001a): willow bark group N=10 volunteers
Adverse events not recorded / reported
Krivoy et al. (2001): willow bark group N=35 patients
Adverse events not recorded / reported.
Literature reports a case of anaphylaxis resulting from the use of a
Plants that contain more than 10% tannins (willow bark:
Vlachojannis et al. (2011) reported that Salix extracts are not interfering with platelet aggregation, which proves a mechanism of action different from the NSAIDs and acetylsalicylic acid.
Undesirable effects are reflected in section 4.8 of the monograph.
5.4. Laboratory findings
No data available.
5.5. Safety in special populations and situations
Intrinsic as well as extrinsic factors are considered.
5.5.1. Use in children and adolescents
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.
Moro et al. (2011) reported about a hypovolemic shock due to severe gastrointestinal bleeding in a 4- year old boy taking a herbal syrup with Filipendula ulmaria and Salix spp. The preparation was marketed as food and prescribed by his paediatrician to treat a mild cold accompanied by fever. Quali- quantitative analysis confirmed the presence of salicylates in the syrup. Naranjo algorithm showed a probable correlation between the onset of symptoms and the consumption of the herbal remedy. The child recovered after receiving intensive care. This adds to the justification of restricting Salix– containing products to adults and elderly (Moroa et al. 2011).
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 2006).
Concurrent administration of willow bark with other
Hypersensitivity to salicylates or other NSAIDS
There is a considerable
Asthma Patients with existing asthma and nasal polyps or chronic urticaria have a greater frequency of hypersensitivity. Because of the relatively high incidence of
Children 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 (Rotblatt 2002). Because of the clinical importance of the syndrome and the avoidable risk, use of salicylates in patients below 16 years is questioned.
The approach to the
In the Salix monograph of 2009 a special warning on Reye‘s syndrome for patients under 18 years was included: “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“. Although, – up to now – no occurrence of Reye’s syndrome after intake of Salix preparations has been reported, the HMPC decided, as a precautionary measure, to include in the revised monograph a contraindication for children and adolescents because of the lethal outcome of this syndrome. There are no pharmacovigilance reports on serious undesirable effects in children and adolescents.
As a precautionary measure, the HMPC decided to include in the revised monograph a contraindication for children and adolescents (see above). Furthermore, considering the SmPC of authorized acetylsalicylic acid containing products, the following contraindications are also included:
•Hypersensitivity to the active substance.
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.
•Hypersensitivity to salicylates or to other NSAIDs (e.g. history of angioedema, bronchial spasm, or chronic urticaria in response to salicylates or to other NSAIDs).
•Asthma due to sensitivity to salicylates.
•Active peptic ulcer disease.
•Third trimester of pregnancy.
There is a case report of a woman with G6PD who developed massive haemolysis after taking an herbal preparation containing salicin (Baker et al. 1987). In Sardinia there is a high incidence of G6PdH deficiency. Salicylates have been contraindicated by all the experts for these patients. Therefore, the use of willow bark in case of G6PD deficiency is
•Children and adolescents under 18 years of age due to the risk of Reye’s syndrome.
•Severe liver or renal dysfunction.
Precautions associated with salicylate therapy are also applicable to willow bark. In case of severe liver or renal dysfunction, coagulation disorders (risk of haemorrhagia), gastric/duodenal ulcer, willow bark should be
5.5.3. Special Warnings and precautions for use
Regulatory action for salicylates:
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.
Other precautions with regard to intake of salicylates
As a matter of precaution special warnings and precautions for use are included in the monograph.
•The product is not intended to be used in case of acute arthritis as this condition requires medical advice.
•If fever exceeds 39°C, persists or is associated with severe headache or if symptoms worsen during the use of the medicinal product, a doctor should be consulted.
•For tinctures, extracts, containing ethanol, the appropriate labelling for ethanol, taken from the ‘Guideline on excipients in the label and package leaflet of medicinal products for human use’, must be included.
•Concomitant use with salicylates and other NSAIDs is not recommended without medical advice.
•If the symptoms worsen during the use of the medicinal product, a doctor or a pharmacist should be consulted.
5.5.4. Drug interactions and other forms of interaction
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
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.
According to Williamson et al. (2013) no
5.5.5. Fertility, 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, it was agreed not to include the symptoms of overdose with acetylsalicylic acid.
5.5.7. Effects on ability to drive or operate machinery or impairment of mental ability
No data available.
5.5.8. Safety in other special situations
Chrubasik (2002) stated that willow bark does not enhance menstrual bleeding. The author supported this statement referring to observations with a commercial product equivalent to a daily dose of 240 mg.
5.6. Overall conclusions on clinical safety
Clinical data, from a total of nearly 600 patients and healthy volunteers treated with various single- ingredient preparations containing willow bark, adverse events were predominantly mild.
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
6. Overall conclusions
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 low back pain, osteoarthritis and rheumatoid arthritis. 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). Based on data in text books and information provided by interested parties, the following are included in the monograph: powdered and comminuted herbal substance, dry extract (DER
In view of the lack of adequate toxicity data on willow bark, the usual precautions for use associated with salicylate therapy are also applicable to willow. Appropriate
Allergic reactions (rash, pruritis, urticaria, asthma, exanthema) and gastrointestinal symptoms (nausea, vomiting, abdominal pain, diarrhoea, dyspepsia, heartburn), may occur. The frequency cannot be estimated accurately due to the limited number of patients in controlled clinical trials. Nevertheless, atopic patients should be warned against the use of willow bark preparations. Due to the mechanism of action warnings should be included with regard of
The use during the first and second trimester of pregnancy and during lactation is not recommended as salicylates cross the placenta. Willow bark preparations are also contraindicated in the third trimester
of pregnancy. They should not be used during breast feeding as small amounts of salicylated also appear in breast milk. No fertility data available.
On the basis of the available information salicin and its metabolites are considered by the HMPC as contributing to the activity of the herbal substance and herbal preparation(s) and therefore are classified as active markers.
Tests on reproductive toxicity, genotoxicity and carcinogenicity have not been performed. Therefore, a list entry is not proposed.