12 Month study proves Guaifenesin therapy doesn't work for FM

Discussion in 'Fibromyalgia Main Forum' started by AJME, Dec 15, 2002.

  1. AJME

    AJME New Member

    REPORT ON

    A RANDOMIZED, PROSPECTIVE, 12 MONTH STUDY TO COMPARE THE EFFICACY OF GUAIFENESIN VERSUS PLACEBO IN THE MANAGEMENT OF FIBROMYALGIA

    Principal Investigators:

    Robert M. Bennett, MD, FACP, FRCP, FACR

    Professor of Medicine and Chairman Division of Arthritis and Rheumatic Diseases OregonHealth Sciences University, Portland, Oregon, USA

    Sharon R. Clark, Ph.D., FNP

    Assistant Professor of Medicine OHSU and Associate Professor of Nursing OHSU

    Co.-Investigator:

    Pat De Garmo MUP, RN, ANP

    Study Advisor:

    Paul St. Amand MD, (UCLA)


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    Financial Support:

    National Fibromyalgia Research Foundation, Salem, Oregon


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    TABLE OF CONTENTS

    I. INTRODUCTION

    II. OBJECTIVES

    III. PATIENTS, MATERIALS AND METHODS

    A. Study Design

    B. Patient Population

    C. Inclusion Criteria

    D. Exclusion Criteria

    E. Randomization

    IV. STUDY MEDICATION

    V. EVALUATIONS

    A. Baseline Period

    B. Intervention Period

    C. Final Evaluations

    VI. ENDPOINTS

    VII. STATISTICAL ANALYSIS

    VIII. LABORATORY INSTRUCTIONS

    IX. ADVERSE EXPERIENCES

    X. CASE REPORT FORMS

    XI. INFORMED CONSENT

    XII. INSTITUTIONAL REVIEW BOARD

    XIII. DRUG ACCOUNTABILITY

    XIV. STUDY DISCONTINUATION

    XV. DISCLOSURE OF DATA

    RESULTS
    COMMENTS



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    I. INTRODUCTION

    Over the past decade there has been a growing realization that the fibromyalgia syndrome is a very common cause of widespread musculoskeletal pain and fatiguability. The pain experienced by fibromyalgia patients arises from their muscles and often results in functional disability that causes a significant curtailment in their quality of life affecting both vocational and avocational activities. Despite the high prevalence of fibromyalgia and the resultant functional disability, treatment remains largely empirical and there are no tested pharmacological agents that have been shown to produce remission of symptoms.

    This study is based upon the extensive experience of Dr. St. Amand in treating fibromyalgia patients using medications which have the general property of increasing uric acid excretion (uricosuric agents). Some thirty four years ago, Dr. St. Amand noted that uricosuric agents helped reduce the symptoms of fibromyalgia. Medications such as Allopurinol, which prevent the formation of uric acid, did not work for fibromyalgia. It was hypothesized that the effect was on a yet unknown "metabolite" which is excreted by the kidneys as a result of uricosuric agents.

    The rationale given by Dr. St. Amand for the use of these agents is as follows. He reasons that several lines of evidence point towards the fundamental "lesion" in fibromyalgia as being a focal disturbance of mitochondria function. Some support for this notion is found in the paper by Bengtsson and Henriksson in the Journal of Rheumatology, Vol 16, supplement 19 (November 1989) – they described a roughly twenty percent decrease in ATP and phosphocreatine in the tender point areas of fibromyalgia muscles. Adjacent uninvolved muscle showed no such decrease. This would suggest that the defect is not a structural one but a problem caused by a disturbance of metabolism in the normal formation of ATP. It is hypothesized that an excess of phosphate enters the affected sarcomeric units of the involved areas of muscle in fibromyalgia patients. It is envisaged that this is brought about by an inherited enzymatic deficiency which does not permit the kidney to excrete absorbed phosphate. Ninety percent of ingested phosphate is absorbed and is dependent on renal mechanisms for excretion of excesses. Since phosphate diffuses freely into cells, any substantial rise in phosphate would be reflected by such an accumulation. However, it must be buffered; this is ordinarily accomplished by the activation of the calcium sodium channels which permit cytosolic entry of both sodium and calcium. Thus water would enter the cell. Excess free calcium, in the cytosol of a sarcomere, causes contraction of the affected sarcomeric units. This contraction would continue until calcium is pumped out or enters the sarcoplasmic reticulum (ATP activated). Dr. St. Amand has suggested that this focal contraction of several contiguous sarcomeres results in the discrete areas of muscle swelling which have been referred to as "tender points". It has been his experience that uricosuric agents diminish the size and tenderness of tender points until a remission of symptoms is achieved.

    Dr. St. Amand stresses that the successful treatment of patients with uricosuric agents requires more than simply prescribing the medications. Reversal of fibromyalgia, as in gout, is a cyclic process. As these reversals occur, all previous manifestations are reproduced and patients experience pain and associated symptoms identical to their previous ones, but now, in reverse. Gradually "good days" appear and eventually begin to cluster. This occurs only after the proper dosage has been found for an individual. Then, similar to a bouncing ball, the symptoms gradually lessen. It has been his experience that three months at a proper dosage reverses about one year of accumulated disease. Thus, the longer the patient has had the illness, the longer it will take to clear the symptoms completely.

    Initially he treated patients with two uricosuric agents, Probenecid and Sulfinpyrazone and found both to be effective. More recently he has noted that Guaifenesin was also a uricosuric and has no known adverse effects. Currently he is using Guaifenesin in a dosage of 600 mg bid or tid. Successful treatment invariably reproduces all the symptoms including considerable pain as the "deposits" are excreted. This is a crucial time for patients, who often require much encouragement during this initial stage of intense cycling.

    Dr. St. Amand's experience has been in the uncontrolled setting of his private clinical practice using these agents to treat over 1,000 patients. He was so impressed with the results of guaifenesin therapy that he initiated the study that is reported here. The study was a single-center, randomized, placebo controlled and prospective double blind study comparing guaifenesin vs placebo in female patients with the fibromyalgia syndrome.




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    II. OBJECTIVES:

    The primary objective of this study is:

    1. Investigate whether therapy with Guaifenesin is more efficacious than a placebo in the treatment of adult fibromyalgia patients

    The secondary objective is:

    2. Correlate time of response to therapy with number of years of fibromyalgia and changes in urinary excretion of uric acid and phosphate

    III. PATIENTS, MATERIALS AND METHODS

    A. STUDY DESIGN

    This was a prospective, single-center, randomized, double blind, placebo controlled study of 48 weeks duration

    B. PATIENT POPULATION

    Forty subjects (20 per group) between 21 and 70 years of age who had been diagnosed with fibromyalgia, using the 1990 American College of Rheumatology criteria, were equally randomized into either the Guaifenesin or placebo group.

    C. INCLUSION CRITERIA:

    All subjects met the following criteria:

    1. Age 21-70 years

    2. Female; subjects of child bearing potential were using an accepted method of birth control.

    3. Diagnosis of fibromyalgia according to the 1990 American College of Rheumatology guidelines.

    4. Duration of fibromyalgia of less than 15 years

    5. Able to sign informed consent and comply with all

    study procedures

    D. EXCLUSION CRITERIA:

    1. Serious abnormality on physical or screening blood work.

    2. History of renal disease (serum creatinine >1.8 mg/dl),myocardial infarction within 6 months, angina pectoris, congestive heart failure, or insulin dependent diabetes

    3. Any chronic life-threatening disease including: active malignancy, chronic inflammatory bowel disease, active immunological disorders

    4. Impairment of intellectual or psychological functioning which would prevent understanding the consent form or achieving normal psycho-social function

    5. Participated in an investigational drug trial within the previous 30 days of enrollment.

    6. Any woman who is pregnant or intending to become pregnant during the course of study

    7. Unable or unwilling to discontinue salicylate therapy during the course of study.

    E. RANDOMIZATION

    Subjects were randomized equally into 2 groups: Guaifenesin and Placebo. Randomization was by computerized random number generation in the pharmacy at OHSU. The investigators and the patients were unaware as to whether Guaifenesin or Placebo was being given. The code was only broken at the end of the study when the data was entered into an Excel database by the statistical department at OHSU.

    IV. STUDY MEDICATION

    Guaifenesin was removed from Humabid capsules and made up into 600 mg capsules by the pharmacy at OHSU. Placebo powder was put into identical capsules. Each identical bottle dispensed to study subjects contained 60 capsules of prepared study drug and was labeled only with identification numbers -- according to the randomization protocol.

    Study drug (either 600 mg of Guaifenesin or Placebo) was taken by mouth twice daily. All subjects were given detailed instructions on how they should discontinue salicylate containing products – both obvious and hidden.




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    V. EVALUATIONS

    A. BASELINE PERIOD (week -4)

    History

    Complete physical examination

    Weight and height

    Blood pressure

    a. Standard Outcome Measures

    Number of tender points -- taken from the 18 tender points recommended by the American College of Rheumatology

    Total Myalgic Score – each point is rated on a scale of 0-3 (0 = no pain, 1= pain is reproduced, 2=focal response to pain, 3= flinches or withdraws), and the total score is summated. The maximum worst myalgic score is thus 54 (i.e. 3x18).

    Grip strength of dominant hand (lbs)

    Number of grip repetitions over 30 seconds of contractions

    Total grip work measured as cumulative kg over 30 seconds of contractions

    Distance walked in 6 minutes

    Quality of Life Scale (QOL)

    Fibromyalgia Impact Questionnaire (FIQ)

    b. Non-Standard Outcome Measures

    Fibromyalgia Nodule Evaluation

    It had been observed by Dr. St. Amand that the size, consistency and firmness of fibromyalgia nodules decreased during therapy with guaifenesin. Both Dr. Clark and Pat DeGarmo traveled to Los Angeles to learn the technique of these measurements from Dr. St. Amand.

    Size measured in cm (calipers/ruler)

    Consistency rated on scale of 1-3 (1=soft, 2=firm, 3=hard)

    Tenderness rated on scale of 1-3 (1=mild, 2=moderate, 3=severe)

    Laboratory:

    Standard chemistry screen

    CBC

    Urinalysis



    BASELINE EVALUATION (week -2 )

    Weight

    Blood pressure

    Adverse events

    Changes in concomitant medication

    24 hour urine



    B. INTERVENTION PERIOD

    All subjects were seen every four weeks.



    EVALUATIONS AT RANDOMIZATION (week 0)

    Weight

    Blood pressure

    FIQ and QOL questionnaires

    Number of tender points

    Total Myalgic Score

    Grip measurements

    Fibromyalgia nodule evaluation

    Distance walked in 6 minutes

    Adverse events

    Changes in concomitant medication

    Compliance with study drug

    Medication dispensed

    Patient symptom diary

    Chemistry screen

    CBC

    IGF-1

    24 hour urine

    EVALUATIONS DURING INTERVENTION PERIOD

    (WEEKS 4,16,28,40)

    Weight

    Blood pressure

    Adverse events

    Changes in concomitant medication

    Compliance with study drug

    Urinalysis with microscopic

    Medications dispensed

    Patient symptom diary

    EVALUATIONS DURING INTERVENTION PERIOD (WEEKS 8,20,32,)

    Weight

    Blood pressure

    Adverse events

    Changes in concomitant medication

    Compliance with study drug

    24 hour urine

    Medications dispensed

    Patient symptom diary



    EVALUATIONS DURING INTERVENTION PERIOD WEEKS 12,24,36

    Weight

    Blood pressure

    FIQ and QOL questionnaires

    Number of tender points

    Total Myalgic Score

    Grip measurements

    Fibromyalgia nodule evaluation

    Distance walked in 6 minutes

    Adverse events

    Changes in concomitant medication

    Compliance with study drug

    24 hour urine

    Patient symptom diary



    C. FINAL EVALUATIONS ( WEEK 48)

    Complete physical examination

    Weight

    Blood pressure

    FIQ and QOL questionnaires

    Number of tender points

    Total Myalgic Score

    Grip measurements

    Fibromyalgia nodule evaluation

    Grip measurements

    Distance walked in 6 minutes

    Compliance with medication

    Patient symptom diary

    Chemistry screen

    CBC

    IGF-1

    24 hour urine




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    VI. ENDPOINTS:

    1. Major: FIQ and number of tender points

    2. Others: Nodule evaluation (size, firmness and tenderness of the fibromyalgia nodules,) total myalgic score, QOL, grip measurements and distance walked in 6 minutes.


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    VII. STATISTICAL ANALYSIS

    Data were independently entered into an Excel database by graduate students in the statistical department of the Office of Research Services. The accuracy of entry was verified by supervisor double-checking of all variables entered.

    Treatment groups were compared both as regards intergroup and intragroup changes at baseline and weeks 12, 24, 36 and 48 using ANOVA and t-tests.

    Statistical analysis was performed on a 133 M Hz computer using the Sigma-Stat statistical software.




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    VIII. LABORATORY SPECIMEN INSTRUCTIONS

    All laboratory specimens were processed according to the instructions of the clinical laboratory responsible for test analysis.

    The IGF-1 was analyzed at Endocrine Sciences; the remaining tests were analyzed by SmithKline Beecham clinical laboratories.




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    IX. ADVERSE EXPERIENCES

    Adverse experiences were be considered serious if:

    a. it is permanently disabling

    b. it is life threatening

    c. it requires hospitalization

    An unexpected event were be considered to have occurred if any adverse experiences not identified in the consent form or any event which is atypical of the population being studies.

    All serious adverse experiences were reported to the Institutional Review Board by the principal investigator.


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    X. CASE REPORT FORMS:

    The case report forms were designed and supplied by the Principal Investigator.

    Case report forms were completely filled out by the specified site investigator and/or study coordinator. All case report forms were reviewed and the final page signed by the site Principal Investigator.

    Facts pertaining to participation in the study, all changes in medications, adverse reactions, and inter-current illnesses were entered into the subject's medical record.




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    XI. INFORMED CONSENT:

    Each subject was informed of the nature of the study, its possible hazards, and their right to withdraw at any time from the study without prejudice to subjects future care by the investigators.

    A signed informed consent was obtained from each subject prior to enrollment.

    Signed consent forms was placed in the subject's medical record and was available for verification by the sponsor or IRB auditors at any time.


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    XII. INSTITUTIONAL REVIEW BOARD:

    The protocol and consent form was submitted to an Institutional Review Board for review and approval before the study is initiated. During the conduct of the study, the principal investigator kept the Institutional Review Board advised as to the progress of the study, any changes made in the protocol, and all major adverse reactions.




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    XIII. DRUG ACCOUNTABILITY

    All study drug was prepared by the pharmacy at the Oregon Health Sciences University. The bottle label contained the study number, subject's ID, expiration date of the drug and storage instructions. The pharmacy maintained a record of drug lot number and the drug identity.

    All unused drug was destroyed according to the Institutional Protocol.

    Accurate records were maintained of all study medications dispensed to patients.




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    XIV. STUDY DISCONTINUATION

    Subjects were discontinued for any of the following reasons:

    a. Medical conditions that may require study discontinuation.

    b. Inter-current illnesses which would, in the judgment of the principal investigator tend to effect the outcome assessments.

    c. Non-compliance with the protocol.

    d. Subjects wish to discontinue participation.


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    XV. DISCLOSURE OF DATA

    Individual subject medical information obtained as a result of this study was considered confidential and disclosure to third parties other than those noted below is prohibited.

    Appropriate medical information could be given to the patient's physician or other health care provider responsible for the patient's welfare with written consent.

    Data generated as a result of this study was made available for inspection on request by the Institutional Review Board and the sponsor.


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    XVI. RESULTS

    1. Patient entry and drop-outs

    The study was conducted on 40 subjects who participated for 52 weeks of study
    (4 weeks of baseline observation and 48 weeks of intervention). A total of 48 subjects began the initial enrollment; eight of these subjects did not meet all the criteria for study during the initial weeks and were not randomized. All subjects who met the criteria for entry (n=40) were randomized.

    Eight of the 40 randomized subjects dropped before the end of the trial. Because the study design is an intention to treat, the data for these subjects is included in the final analysis.

    Subject 1 was in the Placebo group. She moved from the area during

    the first month of study.

    Subject 2 was in the Placebo group. She moved from the area. She dropped at week 24.

    Subject 4 was in the Placebo group, felt that she was doing better but

    could not continue to do the 4 hour commute required for participation. She

    dropped at week 24.

    Subject 5 was in the Guaifenesin group. She did not believe that she was

    receiving any benefit and wanted to return to taking Aspirin. She dropped

    at week 24.

    Subject 15 was in the Guaifenesin group. She experienced an increase in

    migraine headaches and discontinued the medication. She dropped at week 4.

    Subject 23 was in the Placebo group. She experienced increased flu-like

    symptoms. She dropped at week 4.

    Subject 32 was in the Guaifenesin group. She moved from the area. She dropped at week 24.

    Subject 39 was in the Placebo group. She was unable to keep appointments due to work and school schedule. She failed to return after the week 0 visit.

    Thus a total of 5 subjects randomized to the Placebo group and 3 randomized to the guaifenesin group did not complete the study per protocol. Three subjects in the Placebo and one in the Guaifenesin discontinued the trial prior to week 4 of study.


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    2. Demographics of study patients

    Major Features

    Variable Placebo n=20 Guaifenesin n=20 Significance
    Age (range)
    Mean

    Std.Dev.
    25-59
    44.95

    8.73
    32-66
    47.90

    8.36
    n.s.
    Meets criteria for CFS

    yes = 8 yes = 6 n.s.
    Weight in kg (range)
    Mean

    Std.Dev.
    46.9-110.7
    80.65

    19.42
    56-129.6
    79.64

    18.73
    n.s.



    ONSET OF FIBROMYALGIA

    VARIABLE PLACEBO
    GUAIFENESIN

    Years of FM (mean)

    Std.Dev.
    3.95

    3.57
    4.16

    4.00

    Onset related to:

    accident

    operation

    major stress

    infection


    n=9

    n=1

    n=7

    n=3


    n=4

    n=3

    n=8

    n=2

    FM started with pain all over
    n=3
    n=7





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    Results of the standard outcome measures

    These results are first shown as 2 tables (one placebo and the other guaifenesin) of the mean and 1 standard variation for each "standard outcome"; secondly, selected outcomes are shown as graphs of placebo and guaifenesin values plotted against time.



    PLACEBO

    week of study

    VARIABLE 0 12 24 36 48
    FM Impact Question. (mean)
    Std.Dev.
    65.45
    16.66
    62.06
    22.55
    58.41
    16.28
    63.63
    21.41
    63.07
    23.20

    Number of tender points (mean)
    Std.Dev.
    17.21
    1.08
    16.12
    2.39
    16.25
    2.59
    16.53
    2.59
    15.20
    2.91

    Grip strength (mean)
    Std.Dev.
    16.89
    4.40
    18.47
    5.62
    17.69
    4.16
    18.33
    4.05
    18.94
    3.94

    Grip capacity (mean)
    Std.Dev.
    518.21
    207.76
    509.82
    244.53
    522.19
    240.15
    491.46
    224.97
    527.43
    263.70

    Number of repetitions (mean)
    Std.Dev.
    44.22
    15.00
    46.06
    16.05
    44.75
    19.31
    44.60
    13.80
    44.81
    15.69

    Quality of Life (mean)
    Std.Dev.
    65.54
    16.08
    60.17
    17.55
    66.13
    15.26
    64.40
    13.91
    59.13
    25.25

    Total myalgic score (mean)
    Std.Dev.
    36.20
    6.64
    34.12
    9.80
    34.28
    8.36
    31.70
    7.53
    29.00
    12.06

    6 minute walk (laps) (mean)
    Std.Dev.
    18.1
    3.58
    18.4
    4.37
    17.7
    2.56
    17.4
    2.69
    18.0
    2.91




    GUAIFENESIN

    week of study

    VARIABLE 0 12 24 36 48
    FM Impact Question. (mean)
    Std.Dev.
    52.85
    14.95
    43.51
    16.77
    50.62
    15.85
    49.54
    18.94
    48.73
    23.92

    Number of tender points (mean)
    Std.Dev.
    16.30
    2.47
    15.16
    2.61
    14.89
    3.59
    15.50
    2.80
    14.65
    2.85

    Grip strength (mean)
    Std.Dev.
    22.03
    4.96
    21.63
    4.03
    22.55
    4.14
    22.47
    3.87
    22.91
    5.48

    Grip capacity (mean)
    Std.Dev.
    663.20
    175.71
    721.11
    233.58
    696.82
    246.88
    644.03
    214.17
    676.29
    192.78

    Number of repetitions (mean)
    Std.Dev.
    50.50
    15.77
    56.05
    16.80
    63.95
    22.04
    64.88
    25.52
    58.59
    17.38

    Quality of Life (mean)
    Std.Dev.
    72.04
    18.21
    74.11
    20.31
    70.50
    20.46
    72.25
    21.70
    73.29
    21.22

    Total myalgic score (mean)
    Std.Dev.
    32.96
    9.24
    28.63
    12.27
    25.42
    7.89
    26.22
    11.58
    26.03
    10.86

    6 minute walk (laps) (mean)
    Std.Dev.
    19.9
    3.68
    20.6
    3.74
    20.3
    3.77
    20.3
    4.82
    20.4
    5.62


    It is seen from the tables that there was no significant differences between the guaifenesin treated and the placebo treated patients for the major standard outcome measures and the ancillary standard outcome measures. There was a trend for within group improvement in both the guaifenesin and the placebo groups – but this did not reach statistical significance. The graphs of individual outcome measures are shown below.


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    Graphs of Standard Outcome Measures

    The following graphs provide the major data contained in this study.















    One tenet of the guaifenesin mode of action is that patients experience a worsening of their symptoms before they get better. No worsening of symptoms was seen in the guaifenesin treated patients in this study.

    It is possible that some patients showed major improvements that are not apparent when the data are presented as averages. Thus we have plotted the percentage change from time zero to time 48 weeks for the 2 major outcome measures – fibromyalgia impact questionnaire (FIQ) and number of tender points.





    It is readily seen that some patients showed impressive improvements and/or deterioration in these major outcome measures between the start and finish of the study. However the number of patients showing significant improvements who were taking guaifenesin are the same as patients taking placebo.


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    Results of the non-standard outcome measures

    According to Dr. St. Amand there was a reduction in size and consistency of fibromyalgia nodules during the course of guaifenesin therapy. As these are not standard measurements that are in regular use in fibromyalgia research 2 of the investigators visited Dr. St. Amand in Los Angeles to learn his technique for measuring these features. Altogether 12 paired tender point sites (i.e. 24 in total) were evaluated in this way as well as the usual method of grading tenderness on a 1 to 3 scale. There were no significant differences in size of the tender point areas between the guaifenesin grup and the placebo group. The following graphs document these findings for the right trapezius tender points - the most commonly palpated tender point area.

    Although there was a good improvement in nodule size in both the guaifenesin and placebo groups this did not achieve statistical significance due to the large standard deviation of the measurements. The trapezius fibromyalgia nodule is representative and the following plot shows the size over 0 to 48 weeks in the right sided nodule. The slight end point difference in favor of guaifenesin is not significant.

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    4. Results of Laboratory Testing

    A major property ascribed to guaifenesin is that it has uricosuric properties. We therefore measured 24 hour urinary urate excretions – see next graph"

    It is seen that patients on guaifenesin did not excrete more urate than patients on placebo. It is possible that patients either knowingly or more likely, unknowingly, violated the study protocol by using salicylate preparations – low dose salicylates inhibit the renal tubular secretion of urate and thus have an anti-uricosuric action. However this was not the reason for the lack of uricosuric activity of guaifenesin, as the serum urate was not elevated in any of the study patients and its level remained the same throughout the study.

    It had been suggested that the mode of action of "uricosuric" drugs in fibromyalgia patients was to correct an inborn error of phosphate excretion – thus allowing phosphate to accumulate and interfere with ATP production. It was, therefore, of interest to measure urinary phosphate excretion both before and during guaifenesin therapy -- see next graph:

    The normal values for 24 hour phosphate excretion for the laboratory performing these tests are 0.4 to 1.3 grams. It is seen that the phosphate excretion is not depressed prior to the use of guaifenesin. Nor does it fluctuate to abnormally low levels during 48 weeks of placebo treatment. Lastly guaifenesin has no appreciable effect on phosphate excretion. These results seriously undermine the underlying pathophysiological tenets which led to the use of uricosuric drugs in the treatment of fibromyalgia.

    Finally we found no evidence that guaifenesin was a significant uricosuric agent, as is shown in the following graph of urate excretion over 12 months of therapy. It is seen that the urate excretion is essentially the same whether the patients were taking guaifenesin or placebo.



    The overall laboratory results are shown in the following 2 tables:

    PLACEBO

    Week 0 Week 12 Week 24 Week 36 Week 48
    Calcium (mean)
    Std.Dev.
    132.39
    77.87
    138.50
    113.40
    182.93
    191.17
    126.93
    102.05
    156.00
    93.17

    Phosphorous (mean)
    Std.Dev.
    0.76
    0.26
    0.74
    0.34
    0.73
    0.32
    0.79
    0.36
    0.78
    0.25

    Uric Acid (mean)
    Std.Dev.
    493.11
    164.22
    452.29
    184.14
    510.00
    175.34
    491.80
    139.10
    528.43
    145.13

    Oxalate (mean)
    Std.Dev.


    31.37
    13.15
    34.59
    13.77
    41.94
    19.22
    36.34
    12.38
    36.71
    11.81

    Creatinine (mean)
    Std.Dev.
    1.19
    0.28
    1.21
    0.44
    1.26
    0.36
    1.21
    0.32
    1.26
    0.40




    GUAIFENESIN

    Week 0 Week 12 Week 24 Week 36 Week 48
    Calcium (mean)
    Std.Dev.
    111.06
    74.65
    161.23
    111.83
    137.43
    102.58
    191.31
    100.44
    169.00
    102.49

    Phosphorous (mean)
    Std.Dev.
    0.78
    0.30
    0.75
    0.43
    0.75
    0.24
    0.78
    0.24
    0.81
    0.25

    Uric Acid (mean)
    Std.Dev.
    501.50
    168.41
    486.95
    150.02
    495.68
    156.71
    460.81
    125.77
    506.33
    127.15

    Oxalate (mean)
    Std.Dev.
    35.10
    11.16
    38.89
    20.35
    36.74
    19.36
    34.07
    10.19
    31.60
    6.45

    Creatinine (mean)
    Std.Dev.
    1.28
    0.38
    1.27
    0.38
    1.24
    0.28
    1.24
    0.23
    1.27
    0.24


    --------------------------------------------------------------------------------

    XVII. Comments

    This study achieved 2 "firsts" in fibromyalgia research: (1) it is the longest double blinded controlled trial that has ever been undertaken in fibromyalgia patients – most studies have only lasted 12 weeks or less; (2) it is the first fibromyalgia study that evaluated fibromyalgia nodule size and consistency in 24 separate locations. Due to the large number of variables that were tested and the length of the study, a very large data base was generated – altogether 21,000 separate cells were used in the Excel database. Unfortunately this study was not able to confirm the anecdotal observations on the efficacy of guaifenesin in the treatment of fibromyalgia patients. There are several possible reasons for this observed lack of efficacy that need to be considered.

    Lack of statistical power. The number of subjects in each group was 20. Using, as an example, the average fibromyalgia impact questionnaire (FIQ) score of about 52 with a standard deviation of 15, a 50% improvement would have been demonstrable with 97% certainty and a 30% improvement with 90% certainty. Similar calculations can be made for number of tender points and other major outcome variables. Thus the lack of efficacy cannot be attributed to lack of statistical power – especially as many patients were said to have been cured of their fibromyalgia, a 100% improvement.
    Insufficient treatment time. It is claimed that the longer a patient has fibromyalgia the longer it takes for guaifenesin to take effect. The approximate relationship of disease duration to improvement has been stated as being about 3 months of therapy for every year of fibromyalgia symptoms. The average duration of fibromyalgia symptoms of the study patients was 4 years, thus many patients should have been experiencing some improvement towards the end of the study – this was not seen. Furthermore it has been stated that most patients go through cycles of worsening before good days appear and eventually begin to cluster into a worthwhile and sustained improvement. In this study a worsening of symptoms was not observed in the guaifenesin treated patients. It is suggested that the apparent symptomatic worsening of patients on guaifenesin is merely the natural tendency of fibromyalgia symptomatology to wax and wane over time, aided by the powerful reinforcer that bad days are positive evidence that the guaifenesin is "working" – everybody wants to believe good omens.
    The uricosuric action of guaifenesin was blocked. It has been hypothesized that the efficacy of guaifenesin is dependent upon its effects on the renal excretion of phosphate – an increased excretion of phosphate leads to less entering muscle cells which, in turn, is thought to depress the production of ATP. The surrogate marker that has been used to screen for drugs with this property is urate excretion – it has been claimed that uricosuric drugs in general will be of benefit in the treatment of fibromyalgia. The study reported here did not show that guaifenesin was a uricosuric agent and it did not increase the excretion of phosphate. The uricosuric action of some drugs can be blocked by low doses of salicylates, due to a paralysis of the secretion of urate by the proximal tubules. Interestingly high doses of salicylates enhance urate excretion by inhibiting the tubular reabsorption of secreted urate. As many over the counter medications (and even some cosmetics) contain small amounts of salicylates the unknowing consumption or even application of such substances could negate the uricosuric action of guaifenesin. It is unlikely that this is the explanation for the lack of uricosuric activity seen in this study (and hence lack of efficacy) as : (a) none of the patients were hyperuricemic at the beginning of the study and none showed any elevation of serum urate levels during the study – low dose salicylates invariably cause an elevation of serum urate over the baseline value; (b) looking at the 40 individual urate excretion values (see Appendix) no significant reduction of urate excretion was observed – as would be expected if any patient was being exposed to low dose salicylates. (c) it is highly unlikely that all the subjects would have been exposed to low dose salicylates, as would have to be assumed in the light of these results.
    There is no doubt that many fibromyalgia patients have been helped by Dr. St. Amand and one can only speculate as to why they improved. This study provides persuasive evidence that the improvement was not due to a disease specific effect of guaifenesin on the underlying pathophysiology of fibromyalgia.

    Dr. Bennett's comments on the "apparent efficacy" of guaifenesin

    There is no doubt that many fibromyalgia patients have been helped by Dr. St. Amand. Thus it is instructive to consider why guaifenesin use was associated with a beneficial outcome in many fibromyalgia patients when used by Dr. St. Amand. This current study provides compelling evidence that guaifenesin has no beneficial action by itself in the treatment of fibromyalgia. Thus the real benefits reported by Dr. St. Amand, over many years, probably have an alternate explanation. This is most likely in the realm of a placebo response aided by powerful cognitive restructuring. Dr. St. Amand was very convinced that uricosuric drugs were of benefit. This was at a time when many fibromyalgia were told that "the problem was all in their head" and nothing could be done. Patients want to hear that they have a legitimate disease for which their is a cure. Dr. St. Amand provided this hope to numerous patients and backed it up by an infectious enthusiasm and a pleasant engaging personality. Gradually many patients started to experience "good days" (as all do at some time) and attributed these to the effects of guaifenesin. This was reinforced by Dr. St. Amand's caveat that worsening (a self fulfilling prophecy in fibromyalgia patients) would precede the promised improvement. The arrival of the promised improvement, with its renewed sense of optimism, would lead many individuals to attempt vocational and avocational experiences that they had given up as being too daunting. Inevitably many patients found that they were indeed more functional than they had thought and took this as a further sign that guaifenesin was all that had been promised. This sequence of events would be a classical example of cognitive changes leading to increased self efficacy.

    A simple definition of self-efficacy is the enhanced sense of control that derives from a perceived ability to manage symptoms. Interestingly, it is the perception and not the actual capability that determines enhanced self-efficacy and resulting positive behaviors. Four techniques for altering beliefs about self capabilities that can enhance self-efficacy have been described

    1. Social persuasion -- health-care professional and peer pressure that persuades people that they have the capability to be more functional. Mastery experiences -- actually performing a previously off-limits activity. Modeling -- observing someone who is similarly afflicted being successful in performing the desired activity.


    2. Physiological feedback. This is basically "listening to one's body" by monitoring pain, fatigue, anxiety levels, etc., as a way of optimizing the timing of the new activities.


    3. Although self-efficacy enhancement is an exercise in positive thinking, it is the element of "mastery learning" that is the most powerful technique --nothing succeeds like success. In other words, success in performing a function, that was previously off-limits, promotes confidence in repeating that activity and moving on to new activities. success of a few encouraging others. Repetition and mastery of new behaviors using the feedback from small successes, as well as observing successes in one's peers, seem to be critical features in promoting self-efficacy.

    All these ingredients were present in Dr. St. Amand's approach to treating fibromyalgia patients. Indeed he often used testimonials from "recovered patients" to encourage patients to persevere with the prescribed treatment regimen. In this way Dr. St. Amand has unknowingly used guaifenesin as a powerful focus in a program of cognitive behavioral therapy, in which his empathy, enthusiasm and charisma were the real instruments in effecting a beneficial change.


  2. Mikie

    Mikie Moderator

    This is old, old news. Dr. Bennett has, for some unknown reason, done his best to discredit Dr. St. Amand. My guess is professional jelousy, but that's just a guess.

    The study which Bennett always cites was done in the early days in Oregon before as much was known about the Guai protocol. It was fatally flawed. It rears its ugly head here from time to time.

    First, the study was way too small to have statistical reliability and many of the participants dropped out before the study was completed.

    Everyone received the same dose. We now know that getting the dose just right can be tricky and takes time.

    Finally, the effect of salicylates was not well understood at the time. The participants did not eliminate all sals from their routines.

    Dr. St. Amand explains this in his book. He says that since there is no money to be made from Guaifenesin, there will likely never be another study.

    While double-blind placebo studies are the standard by which medications are judged, if there are other factors which are not taken into consideration, the study has no value.

    All we have now is the anecdotal evidence that if one follows the protocol and gets the dose correct, the Guai will work. There are thousands who have been helped immensely. I am one of those people. Guai has made it possible for me to go from using Morphine routinely to rarely having to use it at all. My tender points are much, much less tender. That is real, concrete evidence to me that the Guai works.

    The problem with this study is that it makes its way to boards like ours and may have the effect of discouraging people from even trying the Guai, as Dr. Bennett is a respected expert in our illness(es). That is why I don't understand why he so adamently attacks Dr. St. Amand's work. He doesn't need to do this. Surely, he is aware of the successes in the Guai treatment. Perhaps he is just of the old school of Western medecine, unable to accept something despite overwhelming evidence that it works unless there is a study to prove it. He, of all people, should recognize the flaws in the Oregon study.

    To anyone thinking of trying the Guai, I would say that you have nothing to lose and everything to gain. It isn't the easiest protocol to follow in the beginning, but it soon becomes routine and is easy once the proper dose is determined. It also isn't a quick fix. It takes two-three months, as a rule of thumb, to reverse the symptoms of FMS for every year the patient has been sick. I've been sick 12 years, so reversal is two-three years. I've been on the Guai for 1 1/2 years and feel that I am about 3/4 reversed. I am now taking 2400 mgs of Guai per day because a prescription skin care regimen contains a few sals.

    If I didn't also have CFS, I would be home free, but my fatigue and cognitive problems continue. Right now, I'm as close to being in a remission as I get. Hopefully, no one will take this info from Dr. Bennett seriously and will not be detered from trying the Guai.

    Love, Mikie
  3. BonnieQ

    BonnieQ Member

    I have to agree with Mikie. I haven't been around for quite awhile on the boards, but thought I would pop in and see if anything was new. I have been on the Guaifensin for over a good year. I am doing MUCH better with the guaifensin and will continue taking it!! This is not to say we don't still have flares but it takes time and I will continue, I originally started taking it for sinus problems, but found out it also helped with the fibro so what harm can it do to take it? Good luck to all taking the guaifensin!!!
  4. Sky

    Sky New Member

    Exactly what was the purpose of your post? Have you even tried Guaifenesin?

    Surely you realize that there are two sides to everything. And the motto here is that 'what works for one, might not work for another'.

    Good post Mikie.
    Hiya BonnieQ, missed you.

    Hugs,
    Sky

  5. AJME

    AJME New Member

    Dear Sky,

    Your right there are 2 sides to every controversial treatment. From what I see the study is scientific and unbias with Doctor Amand as the study advisor. Doctor Amand was behind getting this study done because of his
    success rate.

    If you read "Dr. Bennett's comments on the "apparent efficacy" of guaifenesin" at the end of the Study Report you will see that there is probably a HIGH degree of cognitive restructuring with the Patients. Doctor Amand dealt with patients directly and because of his Infectous enthuasim patients started to *BELIEVE* and have hope which is a powerful healer.

    I don't doubt that the GUAI therapy helps some but one should never underestimate the power of BELIEF and the MIND
    in helping Physical ailments.

    I get Psychological therapy in addition to trying to eat right and taking supplements. I don't think we should let the STIGMA (found so often in society) of mental disorders make FM totally a physical problem which could persuade people from seeking Psychological help (and getting better) as augmentation therapy to the treatment of the physical body.

    If you think about it, reading and posting messages here at the message board is a form of positive Psychological supportive therapy that helps many here with their FM symptoms.

    Thanks!
  6. Sky

    Sky New Member

    You failed to answer my question. Have you tried the guaifenesin protocol?

    Have you ever read "What your doctor may not tell you about Fibromyalgia?"

    I'm not trying to be a pain. I'll explain myself when you answer the questions above.

    -Sky
  7. Mikie

    Mikie Moderator

    Dr. St. Amand addresses this in his book. He is the first to admit that the study was fatally flawed. He did, however, learn a great deal about the protocol, including the importance of salicylates.

    Guaifenesin success isn't just in the mind. You can actually see the phosphate debris in your urine when you are on the treatment.

    Yes, there are two sides to every story, but if one is determined to try to discredit a doctor's work, one isn't very open to the facts which I outlined in my post as to why the study was flawed. A flawed study shows nothing, negative or positive. Everyone who has been to college and had to do a study, no matter how simple, would recognize that the study group was way too small, especially with so many dropping out of the study before it was completed.

    You are certainly entitled to your own opinion as to what to believe, but it always disturbs me when this article is posted. It is as flawed as the study, if not more so. I think that often there are people who feel guilty because they are not trying the only treatment which offers the possibility of reversing FMS symptoms; therefore, they want to find a reason to not do it because of the work involved in getting the dose just right and eliminating the sals. It's easier to just say, "Oh, Dr. Bennett says it doesn't work."

    This kind of thinking isn't rational or logical, but it's the same kind of thinking people use all the time. I really believe some people are afraid of failure, so they look for reasons to not even try. Some people have become their illnesses and identify with them so closely that they resist getting well. What would the world expect of us if we were not longer sick? Again, this isn't logical, but people are very complex and often don't think logically.

    Love, Mikie
  8. Sky

    Sky New Member

    Mikie, once again you are on the money.

    I really just wanted to know if AJME even tried the protocol or understood it by reading the book.

    How can you post and article that says guai doesn't work if you don't know what the protocol is or haven't tried it yourself.

    I'm at work, so I can't write long posts. But Mikie, you can explain/address issues so well.

    I hope this post has not discouraged anyone from looking into Guaifenesin as a treatment option.

    Hugs,
    Sky
  9. Mikie

    Mikie Moderator

    Thanks for the compliment, but I just happen to have more time than you do right now to sit here answering posts. You are eloquent and logical and always post good info.

    It isn't AJME who worries me (it appears that her mind is made up) but the countless people who can be harmed by the spread of invalid info.

    To anyone considering the treatment, don't be afraid to try it. Just read the book, understand the protocol, eliminate the sals before starting, and be patient until the dose is adjusted to your needs. Then, sit back and wait for the Guai to do its thing. Also, be ready for a Guai flare in the beginning. This is a sign that the correct dose has been arrived at and the Guai is working.

    Love, Mikie
  10. Sky

    Sky New Member

    I know what you are saying, that is why I was worried about this message discouraging people.

    You and I both take this subject very seriously.

    And for all of you that don't know, Mikie and I have been on the guaifenesin treatment since May 14th & 16th of 2001. We both researched the protocol extensively before beginning. And luckily for us, it's working.

    Hugs,
    Sky
  11. AJME

    AJME New Member

    I have read parts of the book. Not the entire book.

    I have not tried the GUAI protocol therapy program.

    I really hope this therapy program works.

    I posted a "Responses to Misconceptions" article addressing
    some of the flaws with the 12 month study that might have
    influenced the outcome.

    Thanks!
  12. AJME

    AJME New Member

    I'm sorry that you think my mind is made up and I spread invalid information. I couldn't find a scientific study that confirms GUAI works. This is the only scientific study available I could find and I don't think it's in appropriate to post it. If you notice I also posted a "Responses to Misconceptions" article after seeing seeing the reaction over suggesting the GUAI protocol doesn't work.

    With people like you and Sky posting (saying GUAI has worked and rebutting) I think both sides of the story are adequately represented. Fair and Balance. I will soon post another message suggesting that the GUAI protocol does indeed work.

    Thanks!
  13. Hippo

    Hippo New Member

    Just wanted to say that I am new to the Guai protocol and am hungry for any and all info. Very encouraged to hear that there are at least two of you out there who are indeed experiencing results.

    Hippo
  14. Sky

    Sky New Member

    Okay, so you have only read 'parts' of the book, not the entire thing. And you have not personally tried the guaifenesin protocol yourself.

    So WHAT was the reason for the post? Out of the blue you come here and post a very OLD article stating that guai doesn't work. WHY? For what? I agree we can post what we want (abiding by the rules), but I don't understand the point you were trying to make at all.

    To show only one side (at first), with no real knowledge on the subject? Something just doesn't sit right with me here.

    Good day to you,
    Sky
  15. Mikie

    Mikie Moderator

    I didn't say it was inappropriate for you to post this or anything else that is allowed under the rules. It just always concerns me when this report is posted; believe me, this happens each time someone "uncovers" what he or she thinks is a big discovery of a hoax or deception. This report is so fatally flawed, it should not be allowed to be printed as fact.

    I assumed that your mind was made up because even after I pointed out the flaws of the study, you remained convinced that the study was valid unless another study confirmed that the Guai does work. You probably will never get your scientific proof that Guai works.

    Sometimes in life, one must take a leap of faith if one wants results. I have a very good PCP who told me that the best medicine is often practiced empirically. In other words, without proof and lab tests. Really good docs treat the patient and not the "numbers." Anecdotal evidence has always been taken into consideration in science and medicine. I suppose one could have one's urine analized for phosphates both before and after the Guai, but what would be the point. It would just be a waste of money to confirm what the patient can see with the naked eye in the toilet.

    You can no more accurately post that the Guai works than you can post that it doesn't. There is no proof that it works. There are only thousnads of people like Sky and me who have greatly benefitted from it. I hope others will try the Guai treatment because it is the only hope for reversing the symptoms of FMS and not just covering them up with meds. The Guai is so safe that almost everyone can take it without side effects and without adverse interactions with other meds.

    The only thing the treatment demands is commitment to the protocol and patience. Very little is known about our illnesses and about many of the treatments we use. This is just another case of the "Chicken Soup" rule: It might help; it won't hurt.

    Love, Mikie
  16. Spedding

    Spedding New Member

    I'm sure the last thing she needs is a punk like me poking his nose in but I can't resist.

    Mikie, please tell me you're joking when you suggest Dr. Bennett did that study out of professional jealousy. You must be kidding around.

    Dr. Bennett has contributed more to the understanding of Fibromalgia than most, and has always followed the scientific method in his approach to studying the problem. When he sees thousands of people all over the world start taking something called guaifenesin for their Fibromyalgia, it only makes sense that he'd want to check it out and see if there's any scientific validity to the claims Mr. St. Amand is making. So, he began a clinical trial in an effort to determine whether these people were wasting their money. It's important to know. The level of scientific understanding we have today wasn't acheived on people's blind faith in things. Everything needs to be proven or disproven before you can build on that knowledge and get to the next step. If some good scientific studies do show that guaifenesin works, then further studies should be undertaken to find out why. But if the initial studies fail, then there's no point is there? And if you want to understand the real cause of Fibromyalgia, you need to know what the facts are, build on them with further studies, and ultimately find the answer.

    As a physicist, I have life easy. We come up with a hypothesis, and then do an experiment to prove or disprove it. A few other people do similar experiments to confirm it, and that's it. We have the answer.

    Not so in medicine. The process can only be done through statistical means, and you are almost guaranteed to have studies with contradictory results. There are many more variables - many of them interdependent - and placebo effects abound. Only through many studies done in different ways can you eventually convince yourself and the rest of the medical community that you have the right answer with some stated confidence.

    Why did AJME post that study? Because she found a valid scientific study that seems to suggest that Guaifenesin does nothing. I would think that it would be useful information for someone spending money on it.

    Anyway, I'm wasting my breath because I'm pretty sure that you all want to believe it works so much that you discard Bennett's study out of hand. Mikie, do you really have the statistics knowlege to state whether that study is significant or not? To call Dr. Bennett professionally jealous is really not called for. You should kiss his boots (as should we all) for getting us to the level of knowledge about Fibromylagia we're at now.

    I used to post about how people could solve their Fibromyalgia by just changing their sleeping position. It drew a strong negative response because everybody here really really wants these herbs/extracts/devices to work. And this website is here to sell them, so I shouldn't be surprised if that's what people here are looking for.

    And placebo is a very powerful force.

    Spedding
  17. Spedding

    Spedding New Member

    ...that to say Dr. Bennett did that study out of professional jealousy is to imply that he had predetermined a negative outcome prior to starting the study.

    Pretty insulting stuff.

    Spedding
  18. AJME

    AJME New Member

    Hi,

    Thanks for the support!

    I would like to hear about your sleeping positions for helping Fibro. I have slept in my Lazy Boy a couple of times and I seem to have slept better.

    Thanks!
  19. Spedding

    Spedding New Member

    It's a lot of stuff, so I put it all up on a website.
    If you have a hotmail or Yahoo email account, you could email me at XXXXXXXXXXX@XXXXXXXXX.com and I'll send you the link. We can't post URLs here.

    Spedding
    [This Message was Edited on 12/19/2002]
  20. Mikie

    Mikie Moderator

    I'm not implying that Dr. Bennett DID the study out of professional jelousy; I'm saying that that is the only reason I can see why one doctor would CONTINUE to discredit a treatment and the doctor who discovered it when it is obvious that the study was flawed.

    While Dr. Bennett is considered an expert in our illnesses and has contributed to knowledge, he continues to infer certain things based on a worthless study. What kind of scientific person does that? BTW, it's not Mr. St. Amand; it's Dr. St. Amand.

    One thing you are correct about is that another study is needed. Dr. St. Amand would welcome another study but who is going to fund it? Certainly not the companies who sell the cheap Guaifenesin; there's no money to be made and that is what propells the pharmaceutical companies. Perhaps Dr. Bennett would like to fund it but I doubt it. He's got his flawed ammo to use and I doubt that the truth is of much importance to him. Some people elevate themselves by tearing down others. I hope I am wrong about this, but like I said, even an undergraduate student doing a study can see that the Oregon study was too flawed to be of use.

    You tell me which is better, to be stubborn and demand scientific proof while you continue to suffer the symptoms of FMS or to take the leap of faith and give the Guai a try and have the amazing results which so many have had? If the Guai were a dangerous drug, I would take a different approach, but it meets my "Chicken Soup Criterium:" It can't hurt; it might help.

    Life is passing by as you wait for your scientific proof which may never come. By the rules of aerodynamics, the bumble bee can't fly, but we see them flying all the time. We are lucky that there are people who are very left brained as the world needs all kinds of people; however, balance in life is a good thing. Developing the creative right brain is helpful for left-brain scientific types.

    I'm not suggesting you are wrong and I am right. It's just a matter of approach. If you are more comfortable always having scientific proof for everything, that is your personal choice, but please don't give credit to a flawed study. That is not a scientific approach.

    Love, Mikie