The Journal of Informed Pharmacotherapy 2003;12:203.
Reviewer: Doson Chua, BSc(Pharm),
Reviewer’s e-mail address: firstname.lastname@example.org
Reviewer's profession/specialty: Critical Care Pharmacy Resident
Barrett BP, Brown RL, Locken K et al. Treatment of the common cold with unrefined Echinacea. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2002;137:939-46 PubMed Citation
This was a randomized, double blinded, placebo controlled trial that was conducted to investigate the effects of unrefined echinacea (E. angustifolia, E. purpurea herb and E. purpurea root preparation) on the duration and severity of cold symptoms when administered for the early treatment of the common cold.
The investigators enrolled 148 consenting students at the University of Wisconsin who were recruited through advertisements during a 14-week period in 1999. Subjects were required to be at least 18 years of age; answered "yes" to the question "Do you believe that you are coming down with a cold?"; reported at least 2 of 15 listed cold symptoms, of which one had to be specific to the respiratory tract; and were willing and able to adhere to the study protocol. Subjects were excluded if they reported having any of the listed symptoms for more than 36 hours before enrollment; were pregnant; currently using antibiotics, antihistamines or decongestants; had specific chronic diseases (autoimmune disease, chronic bronchitis, HIV infection, lupus, rheumatoid arthritis); or had a history of asthma or allergic rhinitis with associated corresponding symptoms.
Patients were randomized to self-administer either placebo (333 mg alfalfa) or unrefined echinacea capsules (Shaklee Tecnica; each capsule contained E. angustifolie 123 mg, E. purpurea root 62 mg and E. purpurea herb 62 mg) according to a regimen of four capsules six times (6 grams) during the first 24 hours of the study, then four capsules three times a day (3 grams/day) thereafter until resolution of symptoms with a maximum of 10 days of treatment. The bottles of placebo or echinacea were given to the subject for self-administration.
The primary endpoint of the study was duration of illness and severity of symptoms, measured on a daily basis using self-reported questionnaires. The duration of illness was defined as the number of days from enrollment to the last day before the subject responded "no" to the question "Do you think that you are still sick today?". Severity of symptoms was determined using 9-point Likert scales designed to assess 15 cold symptoms (the same symptoms as defined by entry criteria) with a value of 1 reflecting "very mild symptoms" while 9 reflected "extreme symptoms". Global severity of illness ("How sick do you feel today?") was also measured using a similar nine-point scale.
Adherence to the study regimen was assessed by pill counts using bottles returned at the end of the study. Adverse effects were monitored daily with questionnaires. How the adverse effects were assessed and reported on the questionnaire was not discussed. Adverse effects were also assessed and reported at the exit interview, but details regarding this assessment and the results were not presented. Five potential confounding variables (i.e. duration of symptoms before entry, severity of illness at enrollment, date of enrollment, use of nonprotocol drugs and sex) were assessed as well.
1. Was assignment of patients randomized?
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
Yes. 148 patients (73 in the echinacea group, 75 in the placebo group) were enrolled with 142 successfully completing the study. Two subjects in the placebo group withdrew (1 felt too sick to continue, 1 for undisclosed reasons) and 4 in the treatment group (2 were reported to be too sick to follow the protocol, 1 had difficulty swallowing capsules, and 1 for undisclosed reasons). This study was not conducted according to an intention-to-treat design, however the exclusion of the 6 participants that withdrew did not appear to influence the final results.
1. How large was the treatment effect?
The trial was designed with an 80% power to detect a benefit of 2 days duration or an average reduction of two points in severity scores between the two groups. The study was conducted using a superiority design to detect a benefit with echinacea. Extrapolations from other illness studies suggest that an average 2-point reduction on a nine-point symptom severity scale or a 2-day reduction in duration would be clinically significant.(10)
There was no difference between groups in terms of the primary endpoint of cold symptoms duration (mean duration 5.75 days in placebo group vs. 6.27 days in echinacea group; difference of 0.52 days [95% CI -1.09 to 0.22 days]). After adjustment for potential confounding variables, there was no statistical difference in cold duration between the two groups (adjusted hazard ratio 1.24 [95% CI 0.86 to 1.78]).
There was no difference between groups in terms of primary endpoint of severity of cold symptoms. The authors also reported that there was no difference in average symptom score for all 15 types of symptoms between the two study groups. The average symptom scores between the placebo and echinacea group followed a similar temporal trend.
The global severity of illness score was similar between the groups as well. When the pool of 15 cold symptoms were categorized into four symptom dimensions (i.e. cough, throat, nasal and fever and aches) and the groups were compared, no difference was found.
2. How precise was the estimate of the treatment effect?
The difference in cold duration between the study groups was -0.52 days [95% CI -1.09 to 0.22 days] and was not statistically or clinically significant. The confidence intervals for the symptom scales were only graphically reported.
2. Were all clinically important outcomes considered?
Yes. The main clinically relevant outcomes of illness duration and severity of symptoms were studied. As the common cold is a self-limiting illness in the healthy adult population, it was appropriate that only symptomatic outcomes were considered.
There is no established standard for the types of symptoms that would accurately represent the clinical presentation of the common cold given its heterogeneous presentation, and no established standard for quantification of illness severity.
The popularity of alternative medicine and especially echinacea has dramatically risen in the past decade. The negative results of this study adds to the conflicting pool of literature currently available. Some randomized, double-blinded, placebo controlled studies have demonstrated a benefit of echinacea in the treatment of the cold based on duration and severity of illness.(1-4) However, other similarly designed trials have failed to demonstrate a benefit. (5,6)
A recent review of past trials assessing
the efficacy of echinacea for the treatment of
treating upper respiratory
tract infections reveals concluded that there is some evidence to support the use of echinacea in the treatment of cold, but its efficacy still remains unclear.
trials assessed employed differing species of echinacea, different formulations and
dosages. A Cochrane review of past studies concluded that the majority of
studies report positive results, but a solid base of evidence for the efficacy of echinacea in the
treatment of the common cold is still lacking. (8) However, there is some suggestion from this analysis and
other systemic reviews that single echinacea preparations (i.e.
those containing one
species of echinacea) may provide benefit while unrefined/combination echinacea
products did not demonstrate any benefit. (9)
There have been several
methodological problems common to these previously conducted studies
such as including the
use of unvalidated assessment tools, subjective assessment of disease severity,
different formulations of echinacea administered and the patient population
studied. Of the nine species of echinacea, E. angustifolie, E. purpurea root and
E. purpurea herb are the most studied. There have been no definitive study
results which demonstrate that one species of echinacea has greater
immunostimulating activity than another. As well, there were no standardized
formulations used in previous studies of echinacea in the treatment of the
common cold. All previous studies used Likert based scales to assess illness
severity which have not been validated. Most studies enrolled only healthy adult
patients into the trial. These factors make it difficult to draw definitive
conclusions about the efficacy of echinacea.
This trial suffers from the same methodological issues as previous trials. Entry into the trial was based on subjective measures (i.e. a simple affirmative reply to a question regarding perceived onset of a common cold and the presence of predefined symptoms). Assessment of the duration of illness was based on the patient's qualitative perception that they felt better. Severity of illness was measured by self-administered questionnaires on a nine-point scale which have not been validated. This study involved a population of young, healthy adults who are the most likely to quickly recover from the cold. And finally, there was a high and uncontrolled use of nonprotocol medications in this study, making it difficult to interpret any potential response to the study drug. Future studies of echinacea must involve the use of standardized echinacea products, better markers for assessing cold symptoms and duration of illness and closer control over nonprotocol medications. Alfalfa has no documented immunomodulatory or antimicrobial properties and would not have any potential activity in cold studies.(11) This makes alfalfa an appropriate control in this study.
This study demonstrates that the use of unrefined echinacea has no apparent benefit in the treatment of the common cold in young, healthy adults. The efficacy of unrefined echinacea in other patient populations and other preparations of echinacea requires further study. The role and benefit of echinacea as an immunostimulant remains to be determined.
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