RHEUMATIC PAIN TREATMENT WITH WILLOW BARK (SALICIS CORTEX)
* From the Department of Family Medicine, Ben-Gurion University of the Negev, POBox 653, Beer-Sheva 84105, Israel
Salicin standardized extracts of Salix species bark are used for the treatment of rheumatic pain. The main active principles (salicylate derivatives) act via the inhibition of the eicosanoid biosynthesis, the cycloxygenase. Preparations from Salix species, the natural NSAID, contain a total of more than 1 % salicylates. Salicylate concentrations in the range causing analgesia are achieved with daily consumption of extract standardized at least on 240 mg Salicilin (ESCOP Monograph). Salicylate side-effects may occur during treatment. However, blood coagulation is less affected than with acetylsalicylate. and the occurrence of allergies is very rare. A randomized double-blind pilot study revealed significant analgesic effectiveness if Salix extract with 240 mg Salicin was consumed compared to placebo. A GCP study is presently running.
Key words: rheumatic pain, phytotherapy, salicis cortex
Standardized extracts of the bark of Salix species have been used to prepare oral medications. The trees grow in the United States, Europe and northern Asia. The drug consists of the dried bark of young branches. It contains not less than 1 % of total salicin. Other characteristic constituents are salicortin and 2-0-acetyl-salicortin and/or tremulacin.
For the treatment of feverish conditions, mild rheumatic complaints, and relief of pain including mild headache, the ESCOP Monograph (1) recommends dried hydroalcoholic or aqueous extracts or preparations equivalent to up to 240 mg of total salicin per day or 3 - 6 g powdered drug as a decoction. In children, the dose has to be adjusted according to body weight and stature to a maximum of extract with 120 mg salicin.
Salicin, the main component of Salix species, is stable under acidic conditions (with or without pepsin) and in human saliva (pH 7.2) (2). Salicortin degraded in artificial gastric juice to salicin, with a half-life of about 4 h (3). Enzymes converted in vitro salicortin (acetyl-) to salicin (acetyl-); salicin and salicortin to saligenin and salicylic acid; and tremulacin to tremuloidin (4, 5, 6, 7). 14C-labeled salicin was rapidly and completely metabolized after oral administration, with salicylic acid as the main metabolite (8). Peak concentrations of salicylic acid were reached three hours after oral administration of bark extract in volunteers (plasma half-life 2.5 h) (9, 10). It seems likely that salicylate concentrations peak later after oral salicin than after oral sodium salicylate. Metabolites other than salicylate were not detectable in the blood after the administration of oral salicin 4 g (2). The urinary metabolite spectrum of oral salicin was similar to that of oral acetylsalicylic acid (2, 11) (Fig. 1).
The hen's egg chorioallantoin membrane test system has been used to study the anti-inflammatory effect of salicin and tremulacin, constituents of willow bark. Onset of the anti-inflammatory effect was delayed in comparison with salicylic alcohol, sodium salicylate and acetylsalicylate, indicating that the active principle may be metabolites of salicin and tremulacin (12).
A randomized placebo-controlled double-blind clinical trial on the analgesic effect of the oral application of a standardized willow bark extract was conducted by the University of Tuebingen, Department of Pharmaceutical Biology and Department of Rheumatology (Schmid, Heide et al., manuscript in preparation). Seventy-eight inpatients of a clinic for rheumatic diseases (Federseeklinik, Bad Buchau, Germany) were included, who suffered from osteoarthritis of the knee and/or hip joint, as verified by the ARA criteria (13). After a wash-out period of four days, patients received daily 1360 mg willow bark extract (in form of coated tablets) or placebo for two weeks. Verum medication corresponded to 240 mg salicin/day. An analgesic effect of the verum medication was observed by monitoring the change of the WOMAC pain index (14) from day 0 to day 14 as the main study criterion. Using 10 cm visual analogue scales, a statistically significant difference (p <0.05) between verum and placebo group was observed both in the intention-to-treat population (n = 78 patients) and in the per-protocol population (n = 68 patients). Daily 10 cm VAS pain scales, and final overall assessments by patient and doctor, were used as secondary criteria and confirmed the positive effect of the verum medication.
In clinical observations of 120 patients with rheumatic arthritis, 70% of the patients experienced both objective and subjective improvement, as evidenced by decreased pain and increased mobility after one and four weeks (15). From a total of 733 patients and volunteers treated with three different Salix bark preparations, mild adverse events were reported in only 27 cases (about 4%). During two weeks of co-treatment with tablets containing willow bark extract 360 mg (standardized for 11% total salicylates), there were five reports of stomach ache, two of nausea, one of dizziness, one of sweating, and one of reversible skin rashes (16). Only one of another 11 patient taking the same medication for 14 days complained of stomach ache, which appeared to be unrelated to taking the preparation (17). Reversible gastrointestinal complaints were reported in 13 patients out of 228 treated for one day with willow bark extract as co-medication (18). Another 12 volunteers who consumed the bark extract of Salix species (167 mg standardized for 11% total salicin per tablet) did not complain of adverse effects during their two-day consumption of up to nine tablets (9, 10). Of another 41 patients with chronic arthritic pain receiving 200 mg of Salix bark extract per dose in a two month double-blind study, three cases of adverse effects were reported (each n =1: dyspeptic symptoms, diarrhea, headache) (19).
According to the European Monograph, the duration of treatment with willow bark extract is not restricted. Special warnings or precautions are not required. The irreversible inhibition of platelet aggregation by acetylsalicylic acid is probably not induced by the structurally different salicin (20). In accordance with general medical practice in the use of salicylic acid derivatives, the extract should not be used during pregnancy and lactation without medical advice. Undesirable effects have not been reported. In cases of sensitivity to salicylates, the use of Salix preparations should be avoided. No toxic effects have been reported. Preclinical safety data are not available.
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