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'Aspirin-like' Botanicals: Are They a Clinically Adequate Substitute?
By David Kiefer, MD. Dr. Kiefer is Clinical Instructor, Family Medicine, University of Washington, Seattle; Clinical Assistant Professor of Medicine, University of Arizona, Tucson; and Adjunct Faculty, Bastyr University, Seattle; he reports no financial relationships relevant to this field of study.
The story behind acetylsalicylic acid (ASA), also known as aspirin, is a fascinating one, both from its botanical origins and its modern recommendations. A classic pain-killer and antipyretic, ASA also is being recommended as primary and secondary prevention for people with diabetes, hypertension, stroke, and coronary artery disease, and is relatively innocuous, barring the small increased risk of gastrointestinal and other bleeding events. Nonetheless, patients still ask for "natural" blood thinning or pain-relieving alternatives. Presumably, many of you in clinic have heard, "Can I take herb X instead of aspirin, please?" or "Will you help me to wean off of warfarin or aspirin?" Below is a discussion of the botanical underpinnings of ASA, that is, plants with related compounds and relevant clinical evidence (referred to below as "aspirin-like" botanicals, or ALB), as well as a brief review of the current recommendations for ASA itself. Essentially, in what situations should clinicians be prescribing ASA or, alternatively, one of its botanical counterparts?
The history of ASA as a purified medicinal compound is relatively recent, hailing from the 19th century. However, the medicinal use of its botanical precursors predates the pharmaceutical by hundreds of years. There is some mention of willow (Genus Salix), perhaps the most well-known ALB, in the Ebers papyrus from 1534 B.C.1 Various species of willow commonly grew in the ancient world, and descriptions in the Ebers papyrus document the use of willow for aches and pains and, interestingly, as a general tonic.
The modern history of ASA probably can be said to begin with the purification of the active compound, called salicin, from white willow (Salix alba) in 1827,2,3 though salicin was poorly tolerated when taken internally due to gastrointestinal side effects.2,3 Another important step in the history of aspirin was the first isolation of salicylic acid from Filipendula ulmaira flowers in 1839.2 Salicylic acid is the compound to which salicin and related compounds are likely metabolized in the human body. Of note, the genus Filipendula was alternatively called Spiraea, part of the name given to the modern compound by the Bayer Corporation.2 After the discovery of salicin and salicylic acid, the "modern" era of aspirin therapy was ushered in with the production of a related compound, acetylsalicylic acid in Germany in 1899,2,3 which conveyed the analgesic, antipyretic, and anti-inflammatory effects of salicin and salicylic acid yet with a marked decrease in the adverse gastrointestinal effects.
Related Botanicals and Pharmacology
There are more than 300 species in the genus Salix (Family Salicaceae), many of which have a history of use for their anti-inflammatory effects.4 One of the most well-known is white willow (Salix alba), and a treatment from ancient Greece used a decoction of Salix alba leaves placed on painful areas.3 In addition to Salix alba, the bark of S. purpurea and S. fragilis, native to Europe and Asia, also are used. These two species are thought to have higher concentrations of the physiologically active phytochemicals than S. alba.4
Plants in the genus Salix have a variety of phenolic glycosides that account for the physiologic effects of these plants.4 For example, the primary glycoside, salicin, and related glycosides, such as salicortin, fragilin, and tremulacin, all are converted to the active salicylic acid in the intestines and liver.4 There is large species-by-species variability in the percentages of these glycosides, averaging about 7% by weight for S. purpurea and S. fragilis, but only about 1% for S. alba.4 Many species of poplars (Populus spp.) also are known to have salicin in varying concentrations.2
As mentioned above, salicylic acid is found in Filipendula ulmaria (Family Rosaceae), as well as in wintergreen oil (Gaultheria procumbens, Family Ericaceae), and birch (Betula lenta, Family Betulaceae).
Despite the long tradition of use of ALB, it took until the 1970s for chemists to determine the pharmacologic activity of ASA. ASA binds to isoform 1 of cyclooxygenase (COX-1), and less so to the COX-2 isoform (hence, a nonselective COX-1/COX-2 inhibitor), causing irreversible enzyme inhibition and preventing arachadonic acid from accessing the active binding site, thereby limiting the production of the downstream prostaglandins that mediate pain and inflammation.1 In addition, ASA has antiplatelet activity due to the inhibition of thromboxane A2 and decreased release of adenosine diphosphate; these effects can be achieved with low-dose daily ASA dosing.1 It is thought that salicin, the primary ALB compound, has less than 50% of the activity of the salicylates like salicylic acid and ASA.4
Clinical Evidence: Aspirin and Related Botanicals
The primary focus of the medical literature has been on anti-inflammatory effects and cardiovascular protection from ASA and/or ALB. Overall, there are only sparse data for ALB. Salix, and mostly Salix alba, is the subject of a few clinical trials, all of which focus on its anti-inflammatory effects. There are no clinical trials for other ALB such as Filipendula spp, Betula, or Gaultheria, though there is some basic science research about Gaultheria phytochemicals.
The traditional use of ASA for musculoskeletal complaints has been supported by numerous clinical trials and meta-analyses.5 Standard of care supports the use of NSAIDs, such as ASA, either as first-line or second-line therapy (after acetaminophen),6 although this approach needs to be balanced with recent evidence for the possible increased cancer risk with the use of acetaminophen.7 Predictably, perhaps, the ALB have less scientific evidence behind their clinical use as analgesics and anti-inflammatory treatments.
Salix alba is the most well-studied of the ALB for analgesia and anti-inflammatory activity, with clinical trails investigating its use for osteoarthritis, low back pain, headache (topical preparations), and rheumatoid arthritis. Three systematic reviews of herbal medicines found relevant articles for Salix. For example, between 1966 and July 2005, there were 10 studies examining herbal medicine for low back pain that met methodological criteria.8 Three of the studies in this review investigated S. alba, finding short-term analgesic effects with 120-240 mg of salicin daily, approximately equivalent to 12.5 mg of rofecoxib. The results seemed to indicate more convincing effects with 240 mg of salicin daily. Another review looked at herbal preparations for osteoarthritis, and one of the five studies included described the evaluation of a combination herbal product with 100 mg of powdered S. alba bark plus four other plants in each tablet, and found pain relief in people with osteoarthritis.9 With such a combination product, it is hard to tease out the specific contribution of willow to the clinical effects. Another review of botanical anti-inflammatory plants detailed one study of 21 patients with back osteoarthritis who had less pain when taking willow (240 mg of salicin daily) compared to a placebo group.10
One randomized trial was not part of the above reviews. The trial consisted of two parts: 127 people with osteoarthritis of the knee or hip randomized to 240 mg of salicin daily (from S. daphnoides bark), diclofenac 100 mg daily, or placebo, and 26 people with rheumatoid arthritis randomized to either 240 mg of salicin daily or placebo.11 After six weeks, an intention-to-treat analysis revealed no reduction in pain for the salicin group when compared to placebo for either the osteoarthritis or rheumatoid arthritis groups. The diclofenac group had significantly more adverse effects (including gastrointestinal) than either the placebo or salicin groups, as well as decreases in hematocrit and hemoglobin, and elevations in liver function tests that were not present in the salicin groups. The authors hypothesized that these negative results could have been due to the Salix species used; each Salix species has a unique phytochemical spectrum beyond simply the salicin content, and some of the other compounds may contribute to clinical effects.
References were made above to salicylic acid being present in common wintergreen, Gaultheria procumbens, but related Gaultheria species also may have ALB effects. For example, a favorite plant of northwest Native Americans is salal (Gaultheria shallon), known to be high in antioxidants, though likely due mostly to the catechin and epicatechin polyphenols.12 In addition, two basic science studies have been conducted on Gaultheria yunnanensis, a plant from China that has traditional use as an anti-inflammatory. This plant has high concentrations of salicylate-related phytochemicals, including gaultherin, similar in structure to salicylic acid.13 It seems that gaultherin is metabolized to salicylate, leading to similar analgesic and anti-inflammatory effects as aspirin in animal models, but without the adverse gastric COX-1-mediated effects, though the authors were not entirely clear as to its exact mechanism of action.13,14
As mentioned above, no clinical trials are listed in PubMed for ALB and stroke, myocardial infarction, or all-cause mortality prevention, as there are for ASA. The ASA literature is extensive, with numerous clinical trials, reviews, and meta-analyses on the topic.1 For example, the Cochrane Collaboration has review articles on ASA and prevention of stroke or other serious cardiovascular events in high-risk adults,15 the prevention of cardiovascular disease,16 the treatment of acute ischemic stroke,17 and the prevention of stroke in atrial fibrillation patients who had prior transient ischemic attacks or strokes,18 among others. Aspirin, in the dose range of 50-325 mg daily, is considered adequate secondary preventive therapy for people with a history of stroke or transient ischemic attacks, with a stroke risk reduction of 15%-18% compared to placebo; the benefits of aspirin in this scenario may be augmented with extended-release dipyridamole.19 Medical researchers also have explored the use of aspirin with and without clopidogrel for people with various cardiovascular risks; specific situations warrant certain combinations of these antiplatelet agents balancing the risk of hemorrhage with clinical benefits (see references 1 and 19 for a comprehensive discussion of the topic).
Dosage and Administration
Trying to connect the dosing of ALB to aspirin dosage recommendations is a challenge, primarily due to unknowns regarding the concentrations of salicin and related compounds in a given species and product. Some authors have attempted to calculate the amount of ALB needed to be ingested every day to meet current recommendations, and the volume of willow bark decoction is generally very high. For example, to obtain an anti-inflammatory effect similar to that of 4.5 g ASA, and assuming 50% clinical activity of salicin compared to the salicylates, more than five gallons of Salix purpurea bark tea would have to be ingested daily, a seemingly impossible amount.4 Another estimate was that the 240 mg of salicin studied in some clinical trials for pain relief was probably equivalent to approximately 50 mg of ASA.20 The fact that such a low amount of ASA equivalents induced clinically significant pain relief has led some experts to postulate that the analgesic effect of Salix must be due to more than just the compound salicin. These dosages would be difficult to achieve even with raw herb in capsule form when 1 teaspoon is approximately 1.5 g of raw herb, and about 130 g of bark would have to be ingested daily to meet the dosages mentioned above.
The adverse effects of ALB would be expected to mimic those of ASA, including bleeding, allergic reactions in people with salicylate allergies, and hemolysis in people with glucose-6 phosphate deficiency.21 ALB, as with ASA, should be avoided in any child suspected of having a viral infection due to concerns about the development of Reye's syndrome. With respect to antiplatelet effects, there is some indication that ASA blood thinning effects may not occur in the same way with ALB. For example, in one clinical trial, blood coagulation was said to be only "slightly affected" by 240 mg salicin daily from S. alba,20 and in another trial, 240 mg of salicin (from S. purpurea and S. daphnoides) was compared to 100 mg of ASA and placebo in 68 people, finding that ASA was a better inhibitor of platelet aggregation than salicin (P = 0.001).22 In fact, salicin's ability to inhibit platelet aggregation was similar to placebo in all but one of the parameters measured.
Aspirin-like botanicals predate acetylsalicylic acid, or aspirin, for use as analgesics and to fight inflammation. Most ALB have either salicin or its metabolite, salicylic acid, effective nonspecific COX inhibitors, though with an unacceptable gastrointestinal adverse effect profile in the purified forms. As powdered bark extracts, through some clinical trials of Salix alba, or white willow, there seems to be some anti-inflammatory effect in the setting of arthritis, with less antiplatelet effects and acceptable gastrointestinal tolerability. It is difficult to compete with the numerous clinical trials proving aspirin's cardioprotective effects, and its use as an anti-inflammatory. The fact that there is significant variability in salicin content and unpredictable, or unstudied, hematological effects with ALB speaks against the replacement of proven anti-coagulants or antiplatelet therapy for primary or secondary prevention of cardiovascular events.
Aspirin needs to be the mainstay of our antiplatelet therapy for patients at risk of cardiovascular events. Its pairing with other antiplatelet agents may be necessary depending on the clinical scenario. Though at this point ALB don't appear to have a role in cardioprotection, they may be useful in the short-term, primarily as adjunctive therapy, for musculoskeletal pain in a dose of 240 mg salicin daily.
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