This is a supplement to our paper written for patients with fibromyalgia that describes the disease and our method of treatment. The following is a more technical paper intended for medical personnel. It includes a theory that might explain the chemistry involved in the disease and our therapeutic results. A knowledge of the entity is presumed. 
 

In Fibromyalgia, malfunction of affected tissues determines the presenting, chief complaint. Possibilities include a preponderance of musculoskeletal symptoms; "brain" symptoms (fatigue, irritability, depression, apathy, nervousness, difficulty with memory and concentration) or the irritable bowel syndrome (gas, bloating, cramps, constipation alternating with diarrhea). Initial symptoms of widely separated cycles are often forgotten by patients who present later in their illness. We do not find tender "points" but distinct, swollen lesions in varied distributions. Involved areas are sites of total or partial tendinous, ligamentous, fascial and muscular swellings or contractions. We "map" palpable lesions on a preprinted body caricature that shows the induration, size, shape and location of each (see illustration) There are usually many more than the accepted "eleven out of eighteen." Lesions may not correspond to sites of patient complaints, but are objectively felt and recorded for future comparison. These steadily "working" structures, augmented by involvement of multiple organs, readily induce pain and fatigue. 
 

The symptoms and maps of patients with the "chronic fatigue syndrome" identify them as fibromyalgics. Because of higher pain thresholds, they are most aware of fatigue and cognitive difficulties. We have not seen the myofascial pain syndrome or systemic candidiasis as separate entities. Therefore we treat all as the same disease, in the same manner. 

Over thirty-six years ago we found uricosuric medications helped patients with an ill-defined, multifaceted illness that later became known as "fibromyalgia." Two gout medications, probenecid and sulfinpyrazone proved effective and, because we had no other treatment, were godsends. We tailored the dosage raising it progressively until cyclic reversal of the illness began. In less responsive individuals titration took considerable time. Some patients were allergic to sulfonamides (probenecid) and suffered hyperacidity with sulfinpyrazone (Anturane^TM). We had no alternate treatment. 
 

A few years ago we realized the expectorant, guaifenesin, is weakly uricosuric.¹ It is not sufficiently potent to treat gout, but has proven invaluable in our hands for fibromyalgia. Analysis of two hundred sixty-four consecutive patients showed cumulative success: 300 mg. bid was effective for 20% of patients; 600 mg. bid, for 70%; 1800 mg. per day, for 90%. Some 10% have required 2400 mg. or more daily. Guaifenesin is distinctly more effective than our previous medications and has no listed side effects. Only rarely has a patient had slight nausea, hyperacidity, or rash. It must be dispensed without other ingredients that do cause complaints. There is no patent on guaifenesin and it is inexpensive. Though serum serotonin levels of patients on guaifenesin have not been investigated, its metabolite, 5 HIAA (5-hydroxyindoleacetic acid), is increased in the urine.¹
 

Treatment reproduces symptoms, often markedly, which signals the onset of disease reversal. This is a crucial time for patients who can require much encouragement during initial, intense cycling. I encourage them to record periods of intensification or improvement. Remapping on subsequent visits reveals, at a glance, areas of partial or total clearing to confirm adequacy of dosage. Newly involved areas reverse sooner than older ones. Regression with guaifenesin occurs at a rate of about one year for every two months of treatment. The lowest dosage patients (300 mg. bid) show their responsiveness by greatly accelerating this process. Improvement is sustained initially for only a few hours, later for days and eventually, weeks. Duration of illness and responsiveness to the medication determine recovery time. 
 

I believe Fibromyalgia is inherited. Usually there is a family history of similar symptoms or of osteoarthritis that also "maps" with the same muscular, tendinous and ligamentous lesions as in fibromyalgia. It is tempting to conclude from our spectrum of patients (onset ages four to seventy-four) that fibromyalgia today is the prelude to osteoarthritis tomorrow. The age spread suggests multiple gene involvement. The four to one ratio, women to men, dictates at least one of these should lie on the X chromosome. Symptoms are noticeable in adolescence or earlier if both parents are afflicted. A history of "growing pains" is common. We have treated five four year-olds, all girls, one of whom complained of pains at age two. She frequently awakened at night and required hot baths and massage. 
 

I feel fibromyalgia is a retention disease like most cases of gout but with more varied tissue dispersion. Though patients respond to uricosuric agents, urates are not involved. The ubiquitous symptoms, number of organs and systems affected, point to a metabolic misadventure induced by the accumulation of a different anion. This putative ion wreaks havoc throughout many systems and yet evokes no inflammatory response. It is obviously perceived as a normal tissue constituent. For several reasons I suspect a partial role for inorganic phosphate (Pi). This is supported by some observations. Patients note cyclic chipping or peeling fingernails (calcium phosphate). Dental calculus, tartar, (calcium phosphate) often breaks off and, sometimes, no longer forms during treatment. Calcium added to meals allowed lower dosages of medication (phosphate binding and fecal elimination). Twenty-four hour urine examinations upon beginning guaifenesin showed large increases in phosphate excretion and, in lesser amounts, calcium and oxalate. Though other anions might be involved, the preceding suggest a primary defect in phosphate (and possibly pyrophosphate) metabolism. If so, the following formula would account for depressed mitochondrial ATP generation: 

G= ATP (Pi= inorganic phosphate) 

ADP+Pi (G=energy change) 

Bengtsson and Hendrickson biopsied fibromyalgic, trapezial lesions and reported a roughly 20% decrease in ATP despite specimen dilution with normal tissue.² They also noted a similar decrease in phosphocreatine, the high energy reservoir. No such changes were present in unaffected muscle. A decrease in red blood cell ATP has also been documented. An energy deficit in affected cells would explain the entire syndrome: all symptoms and the multiple chemical abnormalities of fibromyalgia. 
 

Eighty to 90 percent of ingested phosphate is absorbed. We depend on proximal renal tubular function for coordinating its retention or excretion according to need. We postulate an enzyme, receptor or pump defect that leads to systemic accumulation. Phosphates readily enter cells and maintain equilibrium with those in the outer mitochondrial chamber. Excess H⁺ (phosphoric acid in equilibrium with phosphate) in this organelle would seriously blunt the ion's egress from the matrix to the outer chamber. Electron generation and transport for ATP formation depend on reversal of H⁺ direction back to the matrix. Even a minor inborn error anywhere in the chemiosmotic sequence including ATP synthase would increase susceptibility to blockade. The most plausible theory of fibromyalgia is that of defective ATP generation from a fully operational citric acid (Krebs') cycle that produces heat instead of energy. 
 

Others have proposed the name "energy deprivation syndrome" rather than "fibromyalgia," which connotes only pain in muscles and fibers. Such change would more accurately describe the metabolic error resulting in symptoms and findings of this illness. Some, such as decreased growth hormone, IGF-1, serotonin, free ionic Ca²⁺, free urinary cortisol, certain amino acids; increased serum prolactin, substance P and angiotensin converting enzyme, make it obvious this is a widespread, fundamental disease. Other highly phosphorylated systems (ITP³, GTP³ etc.) would share in this dynamic, shifting chemistry that fails to provide energy for needs in an ever-changing, neurohormonal milieu. The cycling fibomyalgic at times almost meets full energy demands, on occasion barely, often, not at all. Moments of energy availability permit some bursts of effort but expenditures from activating any system readily deplete the marginal energy bank. Thus, an accident, emotional stress, infection or surgery sometimes seem to have initiated the first attack of fibromyalgia. It is difficult to postulate a less basic cause of the disease. 
 

Whatever anion is involved, its entry into any cell requires cation buffering. Sodium would allow water retention that occurs during attacks. Only free, cytosolic Ca²⁺ can sustain the palpable, muscular contractions. ATP controlled pumps are responsible for returning calcium to the endoplasmic reticulum to clear the sarcoplasm and permit relaxation. As in muscle, the ion must be cleared from the cytosol to allow cessation of activities peculiar to any cell. Failure forces an attempt to continue reactions that lead to eventual cellular "fatigue" and malfunction. Even small, localized, calcium sparks from the endoplasmic reticulum can trigger equally-selective, cellular activities. Small, site-specific ATP action exists to control or modify the effects of these bursts. Muscular contractions of rigor mortis are an extreme example of this process as ATP formation ceases and calcium accumulates freely in the sarcoplasm of the dying structure. 
 

"Amorphous crystals" seen on urinalysis may be the concentrated precipitates of our putative abnormality. In concentration, these can abrade the distal bladder and urethra causing denuded surfaces and dysuria. Vaginal and vulval involvement leads to dyspareunia and further trauma with intercourse in many patients. Frequent bouts of cystitis (superficial or interstitial), vaginitis, urethritis and often, candidiasis, are the sequelae. These occurrences and the frequent symptoms of eye irritation; scalded or metallic oral sensations; pruritus; various rashes; faulty hair texture and growth; fingernail defects, all strengthen our belief in a generalized abnormality affecting not only the brain, musculoskeletal and intestinal systems but is also reflected in body fluids and the integument. 
 

The multiple, overstimulated areas of fibromyalgia burn fuel steadily. This results in sugar craving in a futile attempt to create energy. Increasing carbohydrate intake yields little due to the impediment to ATP formation. Sugars and starches induce repetitive insulin surges that, in susceptible individuals, initiate the "hypoglycemia" syndrome. Over 50% of fibromyalgics suffer frontal headaches, tremulousness, sweats, heart palpitations or pounding, often with tachycardia and the sudden feeling of anxiety. Symptoms last approximately twenty to thirty minutes and occur a few hours postprandially, often nocturnally. Genter and Ipp reported on the release of counter-regulatory hormones during glucose tolerance tests on normal individuals.³ Blood samples taken every few minutes showed an epinephrine rise fully ten minutes before the nadir of the blood sugar. One-half of these young, healthy subjects became maximally symptomatic as epinephrine neared its peak, some at perfectly normal glucose levels. Obviously, each of us has an individual, brain set point for glucose below which threshold, glucopenia is signaled and well-defined, corrective measures are induced. Epinephrine is the trigger for the preceding symptoms, which when most intense, are labeled "panic attacks." 

We no longer perform glucose tolerance tests since symptoms suffice for diagnosis. It must be noted, however, that the central nervous system becomes inured to repetitive hypoglycemic attacks and, as a result mounts no neurohormonal, counter-regulatory response. Epinephrine symptoms cease but cognitive disorders continue.⁴ This situation can only be surmised by the past history. Within two weeks of proper carbohydrate restriction epinephrine signaling of dietary indiscretion is restored.. 

The term "hypoglycemia" is too often inappropriate. It would be better named "carbohydrate intolerance syndrome" and treated accordingly. Our companion paper, "Hypoglycemia," written for patients, describes the entity and outlines the appropriate diet. This syndrome overlaps strikingly with fibromyalgia but is distinguishable mainly by the epinephrine symptoms. Patients with the dual afflictions do not feel better without dietary control, although examination reveals the anticipated, cyclic resolution of guaifenesin-treated fibromyalgia Therefore, despite improved physical findings documented on mapping, there would be no change in the standard, patient wellness questionnaire. 
 

Many fibromyalgics gain considerable weight. Arguably, this is due to diminished activity imposed by the disease. Those with carbohydrate craving, whether intolerant, suggest an added factor. One paper has shown an increase in serum pyruvate, but normal or low serum lactate in some fibromyalgics.⁵ The absence of lactate accumulation points to intact aerobic metabolism. There is ample pyruvate for acetyl CoA formation within the mitochondrial matrix. One would expect normal citrate formation and the full, sequential chemistry of the Krebs' cycle to continue. When this chemical cascade does not form ATP normally, energy is dissipated as heat. Increased citrate, a powerful signal of energy abundance, would strongly stimulate acetyl CoA carboxylase and therefore malonyl CoA and fatty acid formation. This could be the mechanism for the hot flushes, sweats, and weight gain. Insulin causes increased reabsorption of phosphates and sodium in proximal renal tubules--a known effect of that hormone. Thus, the more patients yield to sugar craving, the more confusing and intense is the interplay of hypoglycemia and fibromyalgia.
 

Though highly theoretical, there are facts in this paper. Guaifenesin has proven our most effective medication to date. Any source of salicylate will block its benefit at a renal, tubular level as it does in gout. Salicylates are readily absorbed through skin. Even small amounts in cosmetics and other topicals will negate or slow the effects of all agents we have used. All plants make varying amounts of salicylate. We have many maps made during treatment that illustrate lesions becoming static or worsening in previously improving patients who, unwittingly, began using such preparations. Individuals once warned, find that over one-half of their usual skin preparations could have been deleterious. Susceptibility to blockade seems genetically determined and highly variable. Some are blocked by tiny amounts of offending agents yet others improve despite moderate usage. Many patients are carbohydrate intolerant and must also be treated dietarily. These statements are factual and must be respected or there will be no improvement. 
 

A double-blinded study of guaifenesin versus placebo was completed at the University of Oregon in June 1995 by Doctor Robert Bennett. Both groups improved equally over the course of this one year study, a finding that suggested placebo effect. Three months into the study, I first observed blockade from Ben Gay and Myoflex. In the seventh month I saw the same effect from oral, herbal medications and suspected a defect in the study at least for the earliest patients. Although Doctor Bennett was warned of this problem on a timely basis, it was not until six weeks after the study was completed that I learned of the widespread, and increased presence of plant extracts or salicylates in cosmetics and lotions. It is more astounding how thoroughly, small amounts of these additives can block the medication a fact not known to me or Doctor Bennett. Hypoglycemics were not systematically excluded and would have confounded the patient wellness questionnaires. As consultant with the only experience in this treatment, I accept full responsibility but I contend the study was doomed for lack of knowledge of these pitfalls. The reader may take this as a lame excuse for failure, or accept my disclaimer. In our hands and those of other physicians nationwide, results from guaifenesin have been too obvious to dispute. 
 

My sole purpose in writing this paper is to promote, among patients and physicians, an effective treatment for fibromyalgia where there is none. I seek to replace the dismal set of medications currently in use, with a simple, non-toxic one that works at some very fundamental level. I am pleased to help any physician who is interested in using this approach. I have no vested interests in a drug without patent made generically by several companies. I do however have a moral obligation to pursue dissemination of this information and experience. 
 
 
 

R. Paul St. Amand, M.D. 

Assistant Clinical Professor Medicine 

Endocrinology--UCLA 
 

September 1996 
 
 
 
 
 
 
 
 
 

REFERENCES:
 
 
 
 
 

1. PDR, 1996. Adams Laboratories. "Humibid" p. 463. "Drug/laboratories test interactions." 
 
 
 

2. Bengtsson, A. and Hendriksson, K. G.: The Journal of Rheumatology, Vol 16:supplement 19, Nov.1989 pp 144-149. 
 
 
 

3. Genter, P. and Ipp, E.: Metabolism, Vol. 43, No. 1 (January), 1994, pp 98-103. 
 

4. Hvidberg, A. et al. Diabetes, Vol. 45, No. 8, 1996. Impact of Recent Antecedent Hypoglycemia on Hypoglycemic Cognitive Dysfunction in 
 

Nondiabetic humans. 
 
 
 
 

5. Eisinger, J.; Plantamura, A.; Ayavou, T, Journal of The American College of Nutrition. 13(2) 144-148, 1994. 
 

6. Delaney, T.P. et al ; Science, Vol. 266, Nov. 18, 1994. A Central Role of Salicylic Acid in Plant Disease Resistance.