Echinacea purpurea and Treatment of the Common Cold
By Ginger Ertel and Cydney E. McQueen, PharmD
Forty percent of time lost from work each year can be attributed to the common cold.1 More than 600 million cases are reported annually, with the average person experiencing 2.4 colds per year. Currently, no FDA-approved antiviral treatment exists for the common cold and treatment is symptomatic only: decongestants, expectorants, antitussives, antipyretics, and analgesics. Patients are eager to try other options including echinacea, which is promoted as boosting the body’s immune system to help fight bacterial and viral infections. In the United States alone, 1998 retail sales of echinacea totaled nearly $70 million.2
Clinical trials have used various preparations of three different Echinacea species: E. purpurea, E. angustifolia, and E. pallida. The German Commission E has approved only preparations of E. pallida root for "influenza-like infections," and E. purpurea herb as "supportive therapy for colds and chronic infections of the respiratory tract and lower urinary tract." The majority of trials, both for treatment and for prevention of colds and/or upper respiratory tract infections (URTIs), have used E. purpurea.
Because of possible differences in activities of the three species, this analysis will concentrate on the evidence for use of E. purpurea in acute treatment of the common cold.
History
Echinacea, or purple coneflower, is native to the United States and was used by American Indians as early as the 1600s for snakebites, for aches, as an antiseptic and analgesic, and for prophylaxis and treatment of the common cold. Echinacea was introduced into the U.S. Materia Medica in 1887. Widespread use of echinacea declined in the early 1930s with the development of antibiotics; however, it remained in the National Formulary until 1950.3,4 Most scientific studies on echinacea have been conducted in the last 50 years by European investigators, primarily in Germany.
Pharmacology
Echinacea has many constituents: caffeic acid derivatives (cichoric acid), flavonoids, polysaccharides, alkylamides, and polyacetylenes.4,5 Components vary between species and have various pharmacological effects. For example, polysaccharides stimulate macrophage activity: phagocytosis, enhanced T-cell binding and replication, and release of immune response modulating cytokines such as interferon, IL-1, IL-6, and TNF-a.6 Cichoric acid increases phagocytosis both in vitro and in vivo. Despite some knowledge of component activity, the pharmacology of whole plant extracts is not well characterized due to lack of testing of whole extracts and great variability in composition of extracts. For example, those containing alcohol, or prepared with an alcohol extraction process, contain no polysaccharides or only negligible amounts. Cichoric acid will not be present in most prepared extracts, but may be present in dried products. Increased phagocytosis in vivo has been demonstrated with some echinacea products, but the clinical relevance of many of these tests remains controversial.7
Mechanism of Action
Alteration in phagocytosis and cytokine levels have been extrapolated to explain the purported clinical effects of echinacea, but the actual mechanism of action, as with most herbal products, has not been definitively established.
Clinical Trials
Three randomized, double-blind, controlled trials (RDBCTs) of E. purpurea for treatment of the common cold or related viral URTIs have been published in the past 10 years.1,8,9 All trials were conducted outside the United States. The trial by Braunig et al compared two doses of standardized E. purpurea radix (root) liquid extract (1:5, 55% EtOH) to placebo.8 One hundred eighty patients 18-60 years old who had cold or flu-like symptoms for less than three days were randomized into one of three treatment groups: placebo, 450 mg/d of E. purpurea (2 droppersful), or 900 mg/d E. purpurea (4 droppersful), for a total of 10 days. Primary outcomes were decreases in duration of illness and patient-rated symptom scores. Patients were assessed on days 1, 3-4, and 8-10 for duration of illness, symptom scores, and clinical observations of physical symptoms. Patients in the 900 mg group showed a statistically significant (P < 0.05) reduction in symptom scores compared to placebo. Outcomes in the 450 mg dose group were similar to placebo. All treatment groups showed a statistically significant (P < 0.0001) decrease in symptom scores during the trial period.
The study has several limitations: Power was not calculated a priori, no demographic information was provided, and no information is included on patient compliance or the time of year the study took place. Study duration coincided with the time a cold may last with no treatment, so that results from day 3-4 assessments would be of more import than day 8-10 results. Also, some patients may have had bacterial infections rather than colds, as indicated by differing granulocyte and lymphocyte levels. Level II, major limitations
Hoheisel et al conducted a parallel group trial between December 1996 and March 1997 to determine the therapeutic effect of Echinagard, a standardized extract from the squeezed sap of the fresh herb.9 One hundred twenty patients were enrolled and randomized, and treatment was started at the first signs of a cold or URTI. Participants worked in a large furniture factory, had at least three respiratory tract infections in the past six months, and then presented with signs of an acute URTI. Those with signs of an URTI the week prior to the study were excluded. Patients were instructed to take 20 drops of medication every two hours on day 1, then three times a day for a total of 10 days. Placebo and active treatment were identical. Outcome measures included daily patient-ranked and recorded subjective symptoms and a questionnaire administered by the physician at the end of the trial. At the onset of symptoms, 60% of patients receiving Echinagard did not develop fully expressed cold symptoms, as compared to 40% of patients taking placebo (P = 0.044). This subgroup of patients was further analyzed; Echinagard patients had a 50% greater reduction in symptoms and duration of illness than the placebo group (P = 0.0001).
A priori power calculations indicated the need for 48 patients per group; this was exceeded for the initial period of assessing the number of patients who presented with symptoms and then developed definite illness, but was not met for the secondary analysis for time to improvement—a major limitation. Intensity of symptoms was stated not to vary between groups, but no supportive data were provided. There was no discussion of patient compliance issues or concomitant medication use, which might easily have affected symptom ratings. Level I for the development of full illness portion; Level II for time to improvement portion; major limitations for both
In the largest trial, Brinkborn et al attempted to determine efficacy and safety of different doses and preparations of E. purpurea in 246 patients with common cold.1 Patients with chronic diseases, serious non-related illnesses, or on medications that might affect the disease state were excluded. The trial was conducted between November 1996 and May 1997 with an active treatment duration of seven days. Patients were randomized to one of four treatment groups: placebo, Echinaforce (6.7 mg E. purpurea crude extract, 95% herb, 5% root), Echinaforce concentrate (48.27 mg E. purpurea crude extract, 95% herb, 5% root), and E. purpurea extract (29.60 mg crude extract of root). Patients were instructed to take two tablets of the assigned medication three times a day immediately after onset of cold symptoms and until they felt healthy again, but for no longer than seven days. They were to see the investigator on the first or second day after beginning treatment and again on the day they felt healthy or the seventh day. Patients recorded symptoms in a daily diary. The primary endpoint was a relative reduction in the complaint index as defined by 12 symptoms according to the doctor’s record. Secondary endpoints included a relative reduction of the complaint index according to the patient’s diary, assessments of efficacy and tolerance by both investigator and patient, and frequency and severity of adverse events. Reductions in the complaint index per the doctor from day 1-2 to day 5-7 were 64.3%, 62.7%, 44.8%, and 29.3% for the Echinaforce concentrate, Echinaforce, E. purpurea extract, and placebo groups, respectively. Reductions in the complaint index per the patients’ records were 55.9%, 50.6%, 35.2%, and 37.0%, respectively. Differences for the Echinaforce concentrate and Echinaforce groups were statistically significant in both per protocol and intent-to-treat analyses.
There was no discussion regarding interrater reliability of the investigators who scored the patients’ symptoms during the first and final visits. Level I, minor limitations
Adverse Events
Mild gastrointestinal side effects are occasionally associated with E. purpurea, but side effects were similar to placebo in most of the clinical trials. Overall, echinacea is well tolerated.
Contraindications
A contraindication is often stated for patients taking immunosuppressive agents or with HIV/AIDS, collagen vascular disease, leukemia, multiple sclerosis, or other autoimmune-type diseases.3,13,14 This theoretical contraindication is presumably based upon the polysaccharide component’s action in increasing T-cell activity. This warning may not be warranted due to the lack of polysaccharides in the majority of commercially available products.8
Allergic reactions (rash, dyspnea, urticaria, and anaphylaxis)10 have been rarely reported and there is controversy as to whether allergy to other members of the daisy (Asteraceae) plant family should be considered a contraindication.11 Toxicity studies in rats and mice were unable to induce acute or chronic (4 weeks) toxic responses at doses of 15 and 30 g/kg, respectively.12 Nonetheless, patients with severe allergy to the daisy plant family (chamomile, chrysanthemum, feverfew, and ragweed), should avoid echinacea products.
Pregnancy and Lactation
Echinacea should be avoided in women who are pregnant or breast feeding due to lack of information regarding safety in this population.13,15
Interactions
There are no known drug interactions.15
Formulations/Dosage
Formulations of E. purpurea include fresh and dried herbs, tinctures, extracts, standardized extracts, capsules, and tablets. The Braunig and Brinkeborn trials are the only ones to attempt to obtain dose-response information. Recommended doses based on clinical data are 900 mg/d of Echinagard and Echinacin brand extracts, 48.27 mg/d Echinaforce concentrate, or 6-9 ml/d E. purpurea pressed juice.14 Historically recommended doses include: tincture, 0.75-2.5 ml (15-30 drops) two to five times daily or 60 drops tid;16 capsules containing powdered whole herb, 900 mg to 1 g tid; and tea (2 teaspoons [4 g] of coarsely powdered herb simmered in 1 cup of boiling water for 10 minutes) three to five times daily.15
Evidence on use in the pediatric or geriatric populations is not adequate to reliably recommend dosing for treatment of the common cold. Clinical trials in children have not evaluated use of echinacea for this purpose.17,18 They have, however, demonstrated safety.
Evidence on long-term safety and efficacy of E. purpurea is lacking. The idea that long-term use of echinacea will result in suppression rather than stimulation of the immune system is probably false, and there is some minimal evidence that benefit may continue.11
Conclusion
The three clinical trials analyzed above have provided evidence that when started at the onset of symptoms of the common cold, E. purpurea can reduce the symptoms and decrease the length of illness. It has been shown to be safe and well tolerated with minimal adverse reactions.
Recommendation
Based on the available evidence, the absence of severe adverse effects, and the limited conventional treatment options, E. purpurea extract can be responsibly offered as a complementary treatment for the common cold. However, not all E. purpurea preparations can be recommended with confidence due to differences in formulation and lack of information from formal dose-response trials.
Those patients who wish to treat cold symptoms with E. purpurea should start treatment at the first signs and symptoms of infections. Patients who worsen or have severe symptoms remaining after an 8- to 10-day treatment period should be seen by their primary health care provider.
Larger clinical trials are needed to determine which types of products have the greatest clinical benefit. Until then, it would seem prudent to limit recommendations to those products that have shown efficacy in the clinical trials. Grade B
Ms. Ertel is a doctoral candidate at the University of Missouri-Kansas City School of Pharmacy.
References
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2. Blumenthal M. Herb market levels after five years of boom. HerbalGram 1999;47:64-65.
3. Micozzi MS, ed. Physician’s Guide to Alternative Medicine. Atlanta, GA: American Health Consultants; 1999: 155-157.
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5. Hobbs C. The chemistry and pharmacology of Echinacea species: Supplement to echinacea literature review. HerbalGram 1994;30:1-8.
6. Burger RA, et al. Echinacea-induced cytokine production by human macrophages. Int J Immunopharmacol 1997;19:371-379.
7. Bone K. Review of chemistry and pharmacology of Echinacea: Rethinking use in HIV-AIDS. British J Phytotherapy 1998;5:3-7.
8. Braunig B, et al. Echinacea purpureae radix for strengthening the immune response in flu-like infections. Zeitschrift fur Phytotherapie 1992;13:7-13.
9. Hoheisel O, et al. Echinagard treatment shortens the course of the common cold: A double-blind, placebo-controlled clinical trial. European J Clin Research 1997;9:261-268.
10. Mullins, RJ. Echinacea-associated anaphylaxis. Med J Aust 1998;168:170-171.
11. Bone K. Echinacea: Useful for auto-immune disease? European J Herbal Med 1997-98;3:13-17.
12. Mengs U, et al. Toxicity of Echinacea purpurea. Acute, subacute and genotoxicity studies. Arzneimittelforschung 1991;41:1076-1081.
13. Pepping J. Echinacea. Am J Health Syst Pharm 1999;56:121-122.
14. Schulz V, et al. Rational Phytotherapy: A Physicians’ Guide to Herbal Medicine. Berlin: Springer-Verlag; 1998:273-278.
15. Fetrow CW, Avila JR. Professional’s Handbook of Complementary and Alternative Medicines. Springhouse, PA: Springhouse Publishing; 1999:232-234.
16. Blumenthal M, et al, eds. The Complete German Commission E Monographs. Austin, TX: American Botanical Council; 1998:122-123.
17. Parnham MJ. Benefit-risk assessment of the squeezed sap of the purple coneflower (Echinacea purpurea) for long-term oral immunostimulation. Phytomedicine 1996;3:95-102.
18. Kohler G. Esberitox: Clinical Expert Report. Salzgitter, Germany: Schaper & Brummer; 1997.
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