Treatment of the Common Cold with Echinacea

1
Treatment of the Common Cold with Echinacea

• Christopher Theberge

2
Outline

• Introduction
• Background
• Negative Echinacea Findings
• Positive Echinacea Findings
• Future Research Recommendations

3
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)
4
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)
5
History

• Plains Indians introduced it to European settlers
• 1920s in National Formulary
• Interest dwindled with advent of anti-biotics
• Brought to Europe where heavily studied
• Gerhard Madaus early 1900s
• First to report pharmacological activity
• Pharmaceutically prepared Echinacin

(Borchers et al (2000) The American Journal of
Clinical Nutrition, 72, 339-347)
6
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)
7
Echinacea

• 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)

(Borchers et al (2000) The American Journal of
Clinical Nutrition, 72, 339-347)
8
Echinacea

• 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

(Hobbs, C (1994) HerbalGram, 30, 33-47)
9
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)
10
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)
11
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)
12
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)
13
Echinacea

• Plants vary by
• Growing conditions
• Harvest time
• Genetics
• Storage methods and conditions

(Borchers et al (2000) The American Journal of
Clinical Nutrition, 72, 339-347)
14
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 OHara et
al (1998) Archives of Family Medicine, 7, 523-536
15
Previous Research Human Studies

• The majority of research conducted in Germany
• Mostly clinical reports
• Few well-controlled human clinical trials
• Heterogeneity of supplements

(OHara et al (1998) Archives of Family Medicine,
7, 523-536)
16
Previous Research Human Studies

• 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

(OHara et al (1998) Archives of Family Medicine,
7, 523-536)
17

• 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

Say So I chose these studies
(OHara et al (1998) Archives of Family Medicine,
7, 523-536)
18

• 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

19
Purpose

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

20
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)
21
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

22
Methods Exclusion Criteria

• Having any of the listed symptoms gt 36 hours
• Using antibiotics, antihistamines, or
  decongestants
• Specified chronic diseases
• HIV
• Autoimmune disease

23
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

24
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

25
Methods Supplements

• Echinacea unrefined dried preparation

25 E. purpurea root

• 50
• E. angustifolia root

Thyme Peppermint Citric Acid

• 25
• E. purpurea herb

250 mg
26
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

27
Methods Statistical Analyses

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

28
Descriptive Statistics for Subjects Assessed
Subject Characteristics Echinacea Group Placebo Group
Entered the study, n 73 75
Completed study protocol, n 69 73
Mean age SD, y 20.8 2.4 21.0 3.4
Women, 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)
29
Results from Echinacea Laboratory Analysis
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)
30
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

31
Results

• 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 gt 0.2

32
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

33
Mean Cold Duration for Echinacea and Placebo Group
5.75
6.27
(Adapted from Barrett et al (2002) Annals of
Internal Medicine, 137(12), 939-945)
34
Adverse Effects
15 Subjects 22 Times
Echinacea 8 Subjects 13 Times
Placebo 7 Subject 9 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)
35
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

36
Conclusions Study 1

• The number of previous echinacea users represents
  its widespread use
• This echinacea preparation appeared to be
  well-tolerated

37
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

38
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?

39
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)
40
Limitations Study 1

• 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

41

• 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

42
Purpose

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

43
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

44
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

45
Methods Assignment

• Eaters 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

46
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

47
Methods Questionnaire
1. Rate the effectiveness of the tea at relieving your cold and/or flu symptoms 1. Rate the effectiveness of the tea at relieving your cold and/or flu symptoms 1. Rate the effectiveness of the tea at relieving your cold and/or flu symptoms 1. Rate the effectiveness of the tea at relieving your cold and/or flu symptoms 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 2. Circle the number of days your cold or flu lasted 2. Circle the number of days your cold or flu lasted 2. Circle the number of days your cold or flu lasted 2. Circle the number of days your cold or flu lasted
Less than 5 6 7 8 gt 10
3. Circle the number of days it took before you began to notice a difference in your symptoms 3. Circle the number of days it took before you began to notice a difference in your symptoms 3. Circle the number of days it took before you began to notice a difference in your symptoms 3. Circle the number of days it took before you began to notice a difference in your symptoms 3. Circle the number of days it took before you began to notice a difference in your symptoms 3. Circle the number of days it took before you began to notice a difference in your symptoms
Immediately 2 3 4 gt 5 Not at All
(Adapted from Lindenmuth, GF Lindenmuth, EB
(2000) The Journal of Alternative and
Complementary Medicine, 6(4), 327-334)
48
Methods Statistical Analysis

• Two tailed t tests
• 95 Confidence Intervals
• Significance set at p lt 0.05

49
95 subjects
Mean Age 39.7 Age range 24 to 62
Echinacea Group 48 subjects
Placebo Group 47 subjects
41 Women
7 Men
40 Women
7 Men
(Adapted from Lindenmuth, GF Lindenmuth, EB
(2000) The Journal of Alternative and
Complementary Medicine, 6(4), 327-334)
50
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)
51
Results Question 1
1. Rate the effectiveness of the tea at relieving your cold and/or flu symptoms 1. Rate the effectiveness of the tea at relieving your cold and/or flu symptoms 1. Rate the effectiveness of the tea at relieving your cold and/or flu symptoms 1. Rate the effectiveness of the tea at relieving your cold and/or flu symptoms 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 lt 0.001
(Adapted from Lindenmuth, GF Lindenmuth, EB
(2000) The Journal of Alternative and
Complementary Medicine, 6(4), 327-334)
52
Results Question 2
2. Circle the number of days your cold or flu lasted 2. Circle the number of days your cold or flu lasted 2. Circle the number of days your cold or flu lasted 2. Circle the number of days your cold or flu lasted 2. Circle the number of days your cold or flu lasted
Less than 5 (5) 6 (4) 7 (3) 8 (2) gt 10 (1)
Echinacea Group Placebo Group
4.333 0.93 2.340 1.10
P lt 0.001
(Adapted from Lindenmuth, GF Lindenmuth, EB
(2000) The Journal of Alternative and
Complementary Medicine, 6(4), 327-334)
53
Results Question 3
3. Circle the number of days it took before you began to notice a difference in your symptoms 3. Circle the number of days it took before you began to notice a difference in your symptoms 3. Circle the number of days it took before you began to notice a difference in your symptoms 3. Circle the number of days it took before you began to notice a difference in your symptoms 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) gt 5 (1)
Echinacea Group Placebo Group
3.854 0.97 2.297 1.20
P lt 0.001
(Adapted from Lindenmuth, GF Lindenmuth, EB
(2000) The Journal of Alternative and
Complementary Medicine, 6(4), 327-334)
54
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

55
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

56
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

57
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

58
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

59
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

60
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

61
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

62
Thank You
63
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