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Willow Bark

Scientific Name(s): Salix alba L., Salix purpurea L., Salix fragilis L., and several other species. Family: Salicaceae (willow family)

Common Name(s): Willow , weidenrinde , white willow ( S. alba ), purple osier willow/basket willow ( S. purpurea ), crack willow ( S. fragilis )

Uses

Willow bark can be an effective analgesic if the salicylate content is adequate. Anticancer, antioxidant, and anti-inflammatory activity has been documented in limited trials. Clinical trials have shown that willow has moderate efficacy in treating lower back pain but very little efficacy in treating arthritic conditions.

Dosing

Willow is available in several dosage forms, including tablets, capsules, powder, and liquid. Willow bark has been used for analgesia at daily doses of 1 to 3 g of bark, corresponding to salicin 60 to 120 mg. A clinical study of patients with lower back pain used willow bark at a dose of salicin 120 to 240 mg/day. A proprietary extract of willow bark, Assalix , was standardized to contain 15% salicin. The pharmacokinetics of salicylic acid delivered from willow bark have been studied, and plasma half-life is approximately 2.5 hours. Another pharmacokinetic study of salicylic acid from salicin found peak levels within 2 hours after oral administration.

Contraindications

Patients with known hypersensitivity to aspirin should avoid any willow-containing product. This caution also applies to patients with asthma, impaired thrombocyte function, vitamin K antagonistic treatment, diabetes, gout, kidney or liver conditions, peptic ulcer disease, and in any other medical conditions in which aspirin is contraindicated.

Pregnancy/Lactation

Avoid use because of the lack of information regarding safety and efficacy during pregnancy and lactation.

Interactions

In general, drug interactions associated with salicylates may apply to willow-containing products. Therefore, avoid use with alcohol, barbiturates, sedatives, and other salicylate-containing products because of additive irritant effects and adverse reactions on the GI tract and blood platelets. Willow may also interact with oral anticoagulants (eg, warfarin), seizure medications (eg, phenytoin, valproate acid), and other medications (eg, methotrexate).

Adverse Reactions

Reports from clinical trials primarily document GI discomfort, such as nausea and stomachache, as well as dizziness and rash. An anaphylactic reaction to willow bark has been reported.

Toxicology

There is little or no toxicity information on the use of willow bark. However, the same toxicity associated with salicylates applies to willow. Patients should monitor for blood in stools, tinnitus, nausea or vomiting, and stomach or kidney irritation.

Botany

The genus Salix has nearly 450 species. Most willows are found in temperate and arctic zones, but some species can be located in subtropical and tropical zones. They are geographically distributed in all continents except Antarctica and Australia. Willows include small trees, shrubs, and groundcovers, and many species are dioecious with male and female catkins (flowers) on separate plants. The catkins are cylindrical in shape, measuring 6 to 7 cm in length. The male flowers are yellow, and the female flowers are green. Insect pollinated, different species of willow hybridize freely. Willow trees may grow 6 to 18 m in height. Medicinal willow bark is collected in the early spring from young branches (2 to 3 years of age). Other species of Salix have similar chemistry and pharmacology. The plant species has been used in various ecosystem restoration projects, particularly for erosion control, because of its fibrous root system. 1 , 2

History

The medicinal use of willow dates back 6,000 years. Ancient civilizations used willow tree extracts to treat pain, inflammation, and musculoskeletal conditions. Assyrian clay tablets excavated by archaeologists document these uses of willow and also in treating fever. Egyptians used willow to treat joint pain and inflammatory conditions associated with wounds. Chinese civilizations used willow to treat fever, pain, colds, hemorrhages, goiter, and rheumatic fever and applied willow as an antiseptic for wounds and abscesses. Physicians of ancient Greece, including Dioscorides who wrote the precursor to all modern pharmacopeias, prescribed willow for its analgesic and anti-inflammatory properties. 3 , 4 , 5

North American willows have also been used in folk medicine. Most of the European medicinal willows were introduced to the Americas and escaped cultivation. In the late 19th century, salicylic acid was widely used in place of willow bark, and its derivative, aspirin, was discovered to be less irritating to the mouth and stomach. 6 , 7

Chemistry

Salicylate derivatives are the primary medicinal constituents of willow bark. While small amounts of salicylic acid can be detected in most species, the principle salicylates of S. alba are the phenolic ester glycoside salicortin 8 , 9 and glycoside salicin, its acid hydrolysis product. Although salicin is considered the major active constituent, there is research interest in the anticancer activity of polyphenols and flavonoids in willow bark. 10

Salicin is hydrolyzed in the intestine to saligenin (o-hydroxybenzyl alcohol), which is absorbed and then oxidized to salicylic acid. 11 Salicortin and other related salicylates are chemically unstable (ie, to boiling water for teas) 12 and to avoid the loss of these compounds, careful drying of the bark is required. 12 , 13 , 14 Extraction protocols, used to avoid decomposition of the native glycosides, have been developed. Most standards for medicinal willow bark require salicylates to be present in more than 1% of dry weight, but are difficult to achieve with many species. This has stimulated surveys of the salicylate content of many other species of Salix 15 , 16 as well as aspen ( Populus ), which also contains salicylates. 17 While the leaves generally contain lower concentrations of salicylates than the bark, several species contain medicinally useful quantities of salicylates in their leaves. 18

A number of analytical approaches have been used to quantify salicylates in willows, including spectrophotometry, 19 thin-layer chromatography (TLC), 20 high-performance liquid chromatography (HPLC) after enzymatic deglycosylation, 21 capillary electrophoresis, 22 and an electrochemical method known as square wave voltammetry. 23 A method using gas chromatography of silyl derivatives of salicylates gave results comparable to those of HPLC. 24 An HPLC method was used to compare the salicylate content of different cultivated clones of Salix myrsinifolia grown in a single location. 25 An HPLC method led to the identification of 13 compounds in 2 pharmaceutical preparations used in clinical trials containing willow bark extract. 26 Nuclear magnetic resonance spectra of the principle salicylates of willows have been reported and assigned. 27

The ecological role of salicylates has also been investigated. 28 Naringenin glycosides, 29 oligomeric procyanidins, 30 and condensed tannins, presumably derived from the simpler flavonols, have been obtained from commercial willow barks. The chemical variation among northern willow species has also been studied. 31

Uses and Pharmacology

The ester glycosides salicortin, tremulacin, and fragilin can be considered to be prodrugs of salicylic acid, which deliver this compound into the systemic circulation without irritating the GI tract. 32 Salicylic acid inhibits cyclooxygenase enzymes, which are involved in prostaglandin synthesis. The anti-inflammatory efficacy of tremulacin, a derivative of salicin, has been studied. 33 , 34

Anticancer activity

Willow bark and leaf extracts have documented anticancer activity. Mechanism of action may be associated with tumor inhibition leading to apoptosis, DNA damage, an affect on cell membranes, and/or denaturation of proteins. 35 , 36

In vitro data

The leaves of S. safsaf inhibited growth of acute myeloid leukemia cells. 37 Another report found that willow extract killed 75% to 80% of abnormal cells harvested from 7 patients with acute lymphoblastic leukemia and 13 patients with acute myeloid leukemia. 35 Willow bark extract inhibited tumor cell growth and induced apoptosis in human colon and lung cancer cell lines. The inhibitory effects were dose dependent. 36

Anti-inflammatory and antioxidant activity
Animal data

An animal model in rats was used to demonstrate that a standardized willow bark extract, on a milligram per kilogram basis, was as effective as acetylsalicylic acid (ASA) in reducing various inflammatory mediators. 38

In vitro data

The phenolic compounds are responsible for the antioxidant and free radical scavenging properties of the plant species. 38 , 39

Arthritis
Clinical data

Eighty-two patients with chronic arthritic pain were randomly assigned to receive a willow bark preparation or placebo for 2 months. Mild efficacy for improvement in pain symptoms with few adverse reactions were reported. 40 Analysis of blood samples from a small study of 3 patients receiving a single dose of willow bark extract equivalent to salicin 240 mg found only moderate inhibition of cyclooxygenase. 41

Two 6-week, randomized, double-blind, clinical trials examined the efficacy of willow bark in treating 127 outpatients with hip or knee osteoarthritis and 26 outpatients with active rheumatoid arthritis. Patients with osteoarthritis received either salicin 240 mg/day, diclofenac 100 mg/day, or placebo. Patients with rheumatoid arthritis received salicin 240 mg/day or placebo. No efficacy was demonstrated in either disease state with willow bark. 42

Lower back pain
Clinical data

A 4-week, double-blind, clinical trial tested 2 oral doses of willow bark extract containing salicin 120 mg or 240 mg against placebo in 191 patients. Primary outcome measure was the number of patients requiring relief medication (tramadol) 5 out of 7 days during the final week of the study. Pain index measures showed reduction in relief medication with both doses of salicin. Patients receiving the 240 mg dose had more improvement in pain index measures. Moderate efficacy was demonstrated with both doses of salicin for short-term treatment of acute episodes of chronic nonspecific lower back pain. 43 Postmarketing surveillance of a proprietary willow bark extract product reported no serious adverse reactions. 44

Another 4-week, randomized, controlled study tested oral willow bark extract (salicin) 240 mg against rofecoxib 12.5 mg/day in 183 patients. Rofecoxib is no longer available, however both the salicin and rofecoxib group improved by 44% on pain index measures. There was no difference in efficacy between the 2 treatment groups. 45

Other pharmacological activity
Platelet aggregation

A 4-week trial involving 51 patients treated with Salicis cortex extract salicin 240 mg/day found that the plant had little effect on platelet aggregation when compared with a daily cardioprotective dose of acetylsalicylate 100 mg. 46 The total serum salicylate concentration of salicin was bioequivalent to acetylsalicylate 50 mg.

Dosage

Willow is available in several dosage forms including tablets, capsules, powder, and liquid. Willow bark has been used for analgesia at daily doses of 1 to 3 g of bark, corresponding to salicin 60 to 120 mg. A clinical study of lower back pain used willow bark at a daily dose of salicin 120 to 240 mg. 43 A proprietary extract of willow bark, Assalix , was standardized to contain 15% salicin. The pharmacokinetics of salicylic acid delivered from willow bark have been studied, and the plasma half-life is approximately 2.5 hours. 47 Another pharmacokinetic study of salicylic acid from salicin found peak levels within 2 hours after oral administration. 48

Pregnancy/Lactation

Avoid use because of the lack of information regarding safety and efficacy during pregnancy and lactation.

Interactions

In general, drug interactions associated with salicylates may apply to willow-containing products. Therefore, avoid use with alcohol, barbiturates, sedatives, and other salicylate-containing products because of additive irritant effects and adverse reactions on the GI tract and blood platelets. Willow may also interact with oral anticoagulants (eg, warfarin), 49 seizure medications (eg, phenytoin, valproate acid), and other medications (eg, methotrexate).

Adverse Reactions

Reports from clinical trials primarily document GI discomfort such as nausea, stomachache, dizziness, and rash. One review article reported an anaphylactic reaction to willow bark in a 25-year-old patient. 50 Life-threatening intestinal bleeding was reported in a dog after eating food containing willow. 51

Toxicology

Research reveals little or no toxicity information on the use of willow bark. However, the same toxicity associated with salicylates also applies to willow. Patients should monitor for blood in stools, tinnitus, nausea or vomiting, and any stomach or kidney irritation.

Bibliography

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4. Jones R . Nonsteroidal anti-inflammatory drug prescribing: past, present, and future . Am J Med . 2001 ; 110 ( 1A ): 4S-7S .
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9. Pearl IA , Darling SF . The structures of salicortin and tremulacin . Phytochemistry . 1971 ; 10 : 3161-3166 .
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11. Meier B , Sticher O , Julkunen-Tiitto R . Pharmaceutical aspects of the use of willows in herbal remedies . Planta Med . 1988 ; 54 ( 6 ): 559-560 .
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16. Meier B , Shao Y , Julkunen-Tiitto R , Bettschart A , Sticher O . A chemotaxonomic survey of phenolic compounds in Swiss willow species . Planta Med . 1992 ; 58 : A698 .
17. Clausen TP , Evans TP , Reichardt PB . A simple method for the isolation of salicortin, tremulacin, and tremuloiden from quaking aspen ( Populus tremuloides ) . J Nat Prod . 1989 ; 52 ( 1 ): 207-209 .
18. Julkunen-Tiitto R . A chemotaxonomic survey of phenolics in leaves of northern Salicaceae species . Phytochemistry . 1986 ; 25 ( 3 ): 663-667 .
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24. Meier B , Julkunen-Tiitto R , Tahvanainen J , Sticher O . Comparative high-performance liquid and gas-liquid chromatographic determination of phenolic glucosides in Salicaceae species . J Chromatogr . 1988 ; 442 : 175-186 .
25. Julkunen-Tiitto R , Meier B . Variation in growth and secondary phenolics among field-cultivated clones of Salix myrsinifolia . Planta Med . 1992 ; 58 ( 1 ): 77-80 .
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28. Roininen H , Price PW , Julkunen-Tiitto R , Tahvanainen J , Ikonen A . Oviposition stimulant for a gall-inducing sawfly, Euura lasiolepis , on willow is a phenolic glucoside . J Chem Ecol . 1999 ; 25 ( 4 ): 943-953 .
29. Pearl IA , Darling SF . Phenolic extractives of Salix purpurea bark . Phytochemistry . 1970 ; 9 : 1277-1281 .
30. Kolodziej H . Olimeric flavan-3-ols from medicinal willow bark . Phytochemistry . 1990 ; 29 ( 3 ): 955-960 .
31. Nyman T , Julkunen-Tiitto R . Chemical variation within and among six northern willow species . Phytochemistry . 2005 ; 66 ( 24 ): 2836-2843 .
32. Kaul R , et al. Willow bark. Renaissance of a phyto-analgesic . Dtsch Apoth Ztg . 1999 ; 139 : 3439 .
33. Yang DX , He KQ , Cheng GF . Effect of tremulacin on actions of SRS-A and histamine [in Chinese]. Yao Xue Xue Bao . 1995 ; 30 ( 4 ): 254-257 .
34. Cheng G , et al. Anti-inflammatory effects of tremulacin, a salicin-related substance isolated from Populus tomentosum Carr leaves . Phytomedicine . 1994 ; 1 : 209 .
35. El-Shemy HA , Aboul-Enein AM , Aboul-Enein MI , Issa SI , Fujita K . The effect of willow leaf extracts on human leukemic cells in vitro . J Biochem Mol Biol . 2003 ; 36 ( 4 ): 387-389 .
36. El-Shemy HA , Aboul-Enein AM , Aboul-Enein KM , Fujita K . Willow leaves' extracts contain anti-tumor agents effective against three cell types . PLoS ONE . 2007 ; 2 ( 1 ): e178 .
37. Hostanska K , Jurgenliemk G , Abel G , Nahrstedt A , Saller R . Willow bark extract (BNO1455) and its fractions suppress growth and induce apoptosis in human colon and lung cancer cells . Cancer Detect Prev . 2007 ; 31 ( 2 ): 129-139 .
38. Kahkonen MP , Hopia AI , Vuorela HJ , Rauha JP , Pihlaja K , Kujala TS , Heinonen M . Antioxidant activity of plant extracts containing phenolic compounds . J Agric Food Chem . 1999 ; 47 ( 10 ): 3954-3962 .
39. Khayyal MT , El-Ghazaly MA , Abdallah DM , Okpanyi SN , Kelber O , Weiser D . Mechanisms involved in the anti-inflammatory effect of a standardized willow bark extract . Arzneimittelforschung . 2005 ; 55 ( 11 ): 677-687 .
40. Mills SY , Jacoby RK , Chacksfield M , Willoughby M . Effect of a proprietary herbal medicine on the relief of chronic arthritis pain: a double-blind study . Br J Rheumatol . 1996 ; 35 ( 9 ): 874-878 .
41. Wagner I , Greim C , Laufer S , Heide L , Gleiter CH . Influence of willow bark extract on cyclooxygenase activity and on tumor necrosis factor alpha or interleukin 1 beta release in vitro and ex vivo . Clin Pharmacol Ther . 2003 ; 73 ( 3 ): 272-274 .
42. Biegert C , Wagner I , Ludtke R , et al. Efficacy and safety of willow bark extract in the treatment of osteoarthritis and rheumatoid arthritis: results of 2 randomized double-blind controlled trials . J Rheumatol . 2004 ; 31 ( 11 ): 2121-2130 .
43. Chrubasik S , Eisenberg E , Balan E , Weinberger T , Luzzati R , Conradt C . Treatment of low back pain exacerbations with willow bark extract: a randomized double-blind study . Am J Med . 2000 ; 109 ( 1 ): 9-14 .
44. Chrubasik S , Kunzel O , Black A , Conradt C , Kerschbaumer F . Potential economic impact of using a proprietary willow bark extract in outpatient treatment of low back pain: an open non-randomized study . Phytomedicine . 2001 ; 8 ( 4 ): 241-251 .
45. Chrubasik S , Kunzel O , Model A , Conradt C , Black A . Treatment of low back pain with a herbal or synthetic anti-rheumatic: a randomized controlled study. Willow bark extract for low back pain . Rheumatology . 2001 ; 40 ( 12 ): 1388-1393 .
46. Krivoy N , Pavlotzky E , Chrubasik S , Eisenberg E , Brook G . Effect of salicis cortex extract on human platelet aggregation . Planta Medica . 2001 ; 67 ( 3 ): 209-212 .
47. Pentz R . Bioverfügbarkeit von salicylsäure und coffein aus einem phytoanalgetischen kominationspräparat . Dtsch Apoth Ztg . 1989 ; 92 .
48. Schmid B , Kotter I , Heide L . Pharmacokinetics of salicin after oral administration of a standardised willow bark extract . Eur J Clin Pharmacol . 2001 ; 57 ( 5 ): 387-391 .
49. Shalansky S , Lynd L , Richardson K , Ingaszewski A , Kerr C . Risk of warfarin-related bleeding events and supratherapeutic international normalized ratios associated with complementary and alternative medicine: a longitudinal analysis . Pharmacotherapy . 2007 ; 27 ( 9 ): 1237-1247 .
50. Boullata JI , McDonnell PJ , Oliva CD . Anaphylactic reaction to a dietary supplement containing willow bark . Ann Pharmacother . 2003 ; 37 ( 6 ): 832-835 .
51. Rohner Machler M , Glaus TM , Reusch CE . Life threatening intestinal bleeding in a Bearded Collie associated with a food supplement for horses [in German]. Schweiz Arch Tierheilkd . 2004 ; 146 ( 10 ): 479-482 .

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