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)

Financial Support:

National Fibromyalgia Research Foundation, Salem, Oregon

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

1. RESULTS
2. COMMENTS

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

2. Demographics of study patients

Major Features

ONSET OF FIBROMYALGIA

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

GUAIFENESIN                                              week of study

 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.

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

PLACEBO

GUAIFENESIN

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.

1. 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.
2. 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.
3. 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.