Treatment of the Common Cold with Echinacea

Christopher Theberge

Outline

Introduction

Background

Negative Echinacea Findings

Positive Echinacea Findings

Future Research Recommendations

Introduction

2002 herbal-supplement sales of $4.28 billion dollars

Echinacea was 3rd leading supplement sold

Grossed $188 million in sales

“Immune system boosting” function

(Nutrition Business Journal, San Diego, CA; www.nutritionbusiness.com; Hobbs, C (1994) HerbalGram, 30, 33-47)

History

Plains Indians’ therapy for treatment of Colds

Respiratory tract infections

Sore throats

Topically for burns and snakebites

(Hobbs, C (1994) HerbalGram, 30, 33-47; Percival, SS (2000) Biochemical Pharmacology, 60, 155-158)

History

Plains Indians introduced it to European settlers 1920’s in National Formulary Interest dwindled with advent of anti-biotics

Brought to Europe where heavily studied

Gerhard Madaus early 1900’s First to report pharmacological activity Pharmaceutically prepared Echinacin®

(Borchers et al (2000) The American Journal of Clinical Nutrition, 72, 339-347)

Echinacea

Coneflower

Spiny flower heads, and cone-like receptacle

Greek for “echinos” meaning hedgehog

Part of the Native American Daisy Family

(Hobbs, C (1994) HerbalGram, 30, 33-47)

Genus includes 9 species in US and Canada

Three primary species used medicinally Echinacea purpurea (E. purpurea)

Echinacea angustifolia (E. angustifolia)

Echinacea pallida (E. pallida)

Echinacea

(Borchers et al (2000) The American Journal of Clinical Nutrition, 72, 339-347)

Most common forms taken include Liquid extracts

Fresh juice of E. purpurea tops in ethanol

Spray or freeze-dried extracts in caps or tabs

Simple herb powders

Echinacea

(Hobbs, C (1994) HerbalGram, 30, 33-47)

Pharmacology

Not standardized

“Active” components include Caffeic and ferulic acid derivatives

Cichoric acid Echinacoside

Polysaccharides Alkylamides Glycoproteins

(Hobbs, C (1994) HerbalGram, 30, 33-47; Percival, SS (2000) Biochemical Pharmacology, 60, 155-158)

Pharmacology

The stimulation of non-specific defense capacities Polymorphonuclear (PMN) neutrophil proliferation Phagocytic and macrophage activity Interferon production Cytokine production

Anti-inflammation

(Hobbs, C (1994) HerbalGram, 30, 33-47; Percival, SS (2000) Biochemical Pharmacology, 60, 155-158)

Echinacea

Three parts used medicinally E. purpurea root and herb

Most commonly studied

E. angustifolia root

E. pallida root

(Borchers et al (2000) The American Journal of Clinical Nutrition, 72, 339-347)

Echinacea

Formulations vary by preparation Parts from roots, herb, or both, and leaves

Either 3 echinacea species

Extraction procedures Alcohol, pressed juice, tea

Addition of other plant extracts or herbals Commonly adulterated with Parthenium

(Borchers et al (2000) The American Journal of Clinical Nutrition, 72, 339-347)

Plants vary by Growing conditions

Harvest time

Genetics

Storage methods and conditions

Echinacea

(Borchers et al (2000) The American Journal of Clinical Nutrition, 72, 339-347)

Previous Research: Human Studies

Positive results include Immune system stimulation Reduction in cold symptom severity and duration Prophylaxis of infection and colds Anti-inflammation

Injectible Echinacin® Topical Liquid extracts (most useful?) Oral administration with other plant extracts

(Hobbs, C (1994) HerbalGram, 30, 33-47; O’Hara et al (1998) Archives of Family Medicine, 7, 523-536

The majority of research conducted in Germany

Mostly clinical reports

Few well-controlled human clinical trials

Heterogeneity of supplements

Previous Research: Human Studies

(O’Hara et al (1998) Archives of Family Medicine, 7, 523-536)

Major flaws in research by improper use or description of Diagnostic criteria Randomization process Treatment interventions Methods for assessing outcomes Blinding assurance Detail of results Quality statistics

Previous Research: Human Studies

(O’Hara et al (1998) Archives of Family Medicine, 7, 523-536)

1992 Commission E approved only use of Alcoholic root extracts of Echinacea pallida Juice pressed from E. purpurea

External wounds Upper respiratory tract infections Urogenital infections

(O’Hara et al (1998) Archives of Family Medicine, 7, 523-536)

Say: So I chose these studies

Treatment of the Common Cold with Unrefined Echinacea

A Randomized, Double-Blind, Placebo-Controlled Trial

Barrett et al., 2002

Annals of Internal Medicine, 137(12), 939-945

Purpose

To determine if a dried, encapsulated, echinacea preparation would be efficacious towards treatment of the common cold

Methods

Designed for 150 subjects

At least 80% power to detect 2 day duration benefit Average 2 point reduction in cold symptoms on a 9-

point severity scale No valid measures for common cold Considered clinically significant

(Jaeschke et al (1989) Controlled Clinical Trials, 10, 407-415)

Methods: Inclusion Criteria

Registered students

Answer “Yes” to the question “Do you believe you are coming down with a cold?”

Report at least 2 of the 15 listed cold symptoms 1 related to the respiratory tract

Having any of the listed symptoms > 36 hours

Using antibiotics, antihistamines, or decongestants

Specified chronic diseases HIV Autoimmune disease

Methods: Exclusion Criteria

Methods: Primary Outcomes

Defined by severity and duration of self-reported symptoms

Duration = number of days from enrollment to last day before subject answered “No” to “Do you think you are still sick today?”

Severity measured on 9-point Likert scale by “How sick do you feel today?”

Global severity measured by similar 9-point scale

Methods: Assessments

Nine point scale used to measure severity 1 = very mild 3 = mild 5 = moderate 7 = severe 9 = extreme

Paper and electronic version of questionnaire each day

Adverse events monitored daily

Methods: Supplements

Echinacea – unrefined dried preparation

50%

E. angustifolia root

25% E. purpurea root

25%

E. purpurea herb

ThymePeppermintCitric Acid

250 mg

Methods: Supplements

Four capsules = 1 g of echinacea 6 g for the first 24 hours 3 g for a maximum of 10 days

Placebo contained alfalfa

Methods: Statistical Analyses

Simple inspection Frequency analysis Analysis of variance (ANOVA) 95% confidence intervals

Subject Characteristics

Echinacea Group Placebo Group

Entered the study, n 73 75Completed study

protocol, n69 73

Mean age ± SD, y 20.8 ± 2.4 21.0 ± 3.4Women, n (%) 50 (72%) 48 (66%)

Current tobacco users, n (%)

15 (22%) 15 (21%)

Non-protocol medications, n (%)

27 (39%) 25 (34%)

Taken echinacea before, n (%)

30 (43%) 28 (38%)

(Adapted from: Barrett et al (2002) Annals of Internal Medicine, 137(12), 939-945)

Descriptive Statistics for Subjects Assessed

Compounds Lab 1 Lab 2

Cichoric acid 0.77% 0.84%

Echinacoside 0.26% 0.20%

Chlorogenic acid N/A 0.03%

Alkylamides 0.82% N/A

Cafeolytartaric acid N/A 0.33%

(Adapted from: Barrett et al (2002) Annals of Internal Medicine, 137(12), 939-945)

Results from Echinacea Laboratory Analysis

Lab 3 First day dose increased tumor necrosis

factor (TNF) 189 ± 23 ng/L to 3679 ± 154 ng/L

Follow-up doses increased 2347 ± 66 ng/L

Results from Echinacea Laboratory Analysis

Mean onset time for first symptom 27 hours

Adherence rate of 92% from pill count

Results from blinding showed that 49% in the echinacea group guessed correctly 46% in the placebo group guessed correctly P > 0.2

Results

No difference in cold duration between both groups Trend towards longer duration in echinacea group

Durations ranged 2 to 10 days

Largest echinacea potential benefit of 0.22 days

Results

Mean Cold Duration for Echinacea and Placebo Group

0

1

2

3

4

5

6

7

Da

ys

Echinacea Placebo

6.27 5.75

(Adapted from: Barrett et al (2002) Annals of Internal Medicine, 137(12), 939-945)

Adverse Effects

15 Subjects22 Times

Echinacea8 Subjects13 Times

Placebo7 Subject9 Times

sleeplessness, heartburn, nausea, stomachache, upset stomach, bad taste

stomachache, nausea,belching, thirst, abdominal pain with diarrhea

(Adapted from: Barrett et al (2002) Annals of Internal Medicine, 137(12), 939-945)

Conclusions – Study 1

Results do not support echinacea for treatment of the common cold Effect size for 2 days’ duration and two points in

average severity on 9-point scale not detected

No significant trends noted

All differences between groups could be explained by natural variability of the symptoms

Conclusions – Study 1

The number of previous echinacea users represents its widespread use

This echinacea preparation appeared to be well-tolerated

Limitations – Study 1

This study only shows that this preparation of echinacea was not effective Preparation used not previously tested

May be ineffective because of bioavailability and phytochemical properties

Previous trials have used extracts rather than whole plant parts, and combinations with other herbs

Phytochemicals vary depending on harvest time, growing conditions, etc…

Limitations – Study 1

Subjects studied may not benefit from echinacea Previous trials have used older adults and

those with a history of frequent colds Echinacea may benefit only those who are

immunocompromised

Smokers?

Limitations – Study 1

No valid measurements for assessing the common cold

Self-reported assessments subject to bias

Alfalfa been shown effective in treatment of allerigic rhinitis

(Mittman P. (1990). Planta Medica,56, 44-47)

Modest-size trial and an effect size of 5% to 10% may be easily lost among natural variability of symptoms in type of subjects used

Subjects were studied for 10 days maximum Frequency of longer illnesses is unknown

Five had symptoms 36 hours prior to study Could have masked a benefit of echinacea given

earlier for treatment of colds

Limitations – Study 1

The Efficacy of Echinacea Compound Herbal Tea Preparation on the Severity and Duration of Upper Respiratory and

Flu Symptoms

A Randomized, Double-Blind, Placebo-Controlled Trial

Lindenmuth, G. F. & Lindenmuth, E. B. 2000. The Journal of Alternative and Complementary

Medicine, 6(4), 327-334

Purpose

To test the efficacy of Echinacea herbal tea preparation on duration and severity of symptoms of scratchy throat, runny nose, and fever

Methods: Sample

Pennsylvania nursing home Registered nurses, dietary aids, physicians,

accountants, maintenance staff, administration

Eligibility criteria Subjects who had early symptoms of a cold

Ineligibility criteria Allergic to coneflowers, different flowering plants

and pollens Acute infections and being treated with antibiotics

Methods: Assignment

Randomized into echinacea or placebo group Alternation for assignment to keep groups balanced

Echinacea group received Echinacea Plus® Leaves, flowers, and stems of organically grown E.

purpurea and E. angustifolia Water soluble dry extract of E. purpurea Flavor corrigents 1.275 g of herbs and roots per tea bag

Methods: Assignment

Eater’s Digest® herbal preparation Peppermint leaf, sweet fennel,

ginger, rose hip, papaya leaf, alfalfa leaf, cinnamon

No caffeine or recognizable differences from echinacea blend

All tea bags individually sealed 12 lb heat sealed Saran Wrap

coating 15 lb polyethylene surlyn layer

Supplement Instructions

Steep for 10 to 15 minutes in 8 fl. oz water

Drink 5 to 6 cups on first day of symptoms

Titrate to 1 cup by the fifth day

Methods: Questionnaire

1. Rate the effectiveness of the tea at relieving your cold and/or flu symptoms:

1

Not effective

2

Fair

3

Medium

4

Good

5

Excellent

2. Circle the number of days your cold or flu lasted:

Less than 5 6 7 8 > 10

3. Circle the number of days it took before you began to notice a difference in your symptoms:

Immediately 2 3 4 > 5 Not at All

(Adapted from: Lindenmuth, GF & Lindenmuth, EB (2000) The Journal of Alternative and Complementary Medicine, 6(4), 327-334)

Two tailed t tests

95% Confidence Intervals

Significance set at p < 0.05

Methods: Statistical Analysis

95 subjects

Echinacea Group48 subjects

Placebo Group47 subjects

41 Women

7Men

40 Women

7Men

Mean Age = 39.7Age range = 24 to 62

(Adapted from: Lindenmuth, GF & Lindenmuth, EB (2000) The Journal of Alternative and Complementary Medicine, 6(4), 327-334)

Results from Echinacea Plus® Phenolic Compound Analysis

Compound Amount Present

2 Caffeoyl tartaric acid 10.463 mg

Cichoric acid 16.98 mg

Chlorogenic acid 0

Echinacoside 4.06 mg

Total Phenolic Compounds 31.5 mg

(Adapted from: Lindenmuth, GF & Lindenmuth, EB (2000) The Journal of Alternative and Complementary Medicine, 6(4), 327-334)

1. Rate the effectiveness of the tea at relieving your cold and/or flu symptoms:

1

Not effective

(1)

2

Fair

(2)

3

Medium

(3)

4

Good

(4)

5

Excellent

(5)

Echinacea Group Placebo Group

4.125 ± 0.96* 2.787 ± 0.95

* P < 0.001

Results: Question 1

(Adapted from: Lindenmuth, GF & Lindenmuth, EB (2000) The Journal of Alternative and Complementary Medicine, 6(4), 327-334)

2. Circle the number of days your cold or flu lasted:

Less than 5

(5)

6

(4)

7

(3)

8

(2)

> 10

(1)

Echinacea Group Placebo Group

4.333 ± 0.93* 2.340 ± 1.10

Results: Question 2

* P < 0.001

(Adapted from: Lindenmuth, GF & Lindenmuth, EB (2000) The Journal of Alternative and Complementary Medicine, 6(4), 327-334)

3. Circle the number of days it took before you began to notice a difference in your symptoms:

Immediately

(5)

2

(4)

3

(3)

4

(2)

> 5

(1)

Echinacea Group Placebo Group

3.854 ± 0.97* 2.297 ± 1.20

Results: Question 3

* P < 0.001

(Adapted from: Lindenmuth, GF & Lindenmuth, EB (2000) The Journal of Alternative and Complementary Medicine, 6(4), 327-334)

Conclusions – Study 2

Treatment with echinacea tea at the early onset of a cold or flu Effective at relieving symptoms vs placebo

Less days vs placebo

Conclusions – Study 2

Echinacea group Symptoms subside 1 to 2 days leaving only “slight drip”

Placebo group Symptoms subside 6 to 10 days with little or no relief

No side effects were reported

Limitations – Study 2

Flavored teas are not generally not perceived as medicinal Subjects may have needed to believe it was medicinal

Echinacea Plus® Adding any new flavor or formula changes

composition of drug in commerce

Limitations – Study 2

Sample was not representative of the population Cannot generalize results to men because

primarily women studied Healthcare population may have better habits

Alternation of assignment process was used for simplicity but may be biased

Effectiveness of the blinding was not assessed

Limitations – Study 2

Compliance with the tea bags not assessed

Questionnaire not validated and may have been too simple Did not quantify symptoms Subject to biases because self-reported method

Different steeping times Bioavailability not known

Overall Conclusions

There are no validated tools to assess the common cold

Echinacea did not decrease severity and duration of cold symptoms as dried preparation Tea did have a benefit

Echinacea appears to be well-tolerated

More studies need to be conducted to determine if echinacea is efficacious

Future Research Recommendations

Validated tools for assessing the common cold

Active compounds need to be discovered Standardization Dosage

No serious adverse effects have been noted with use Long-term use for frequent periods of time need to

be addressed

Future Research Recommendations

Improved methodology and reporting in clinical trials

A single main outcome measure should be predefined for statistical analysis

Larger sample sizes needed

Future studies should focus on evaluation of well-characterized preparations in well-controlled studies with clearly defined endpoints

15 symptoms

Dry cough Productive cough Cough interfering with

sleep Sore throat Scratchy throat Hoarseness Runny nose

Plugged or stuffy nose

Sneezing Headache Fever Sweats Muscle aches Feeling “run down” Loss of appetite