The Use Of Uricosuric Agents in Fibromyalgia
Information For Physicians
by R. Paul St. Amand, MD

     This is a supplement to our paper for patients with fibromyalgia describing 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 of 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 (Figure 1). There are usually many more than the accepted "11 out of 18." 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 "chronic fatigue syndrome," identify them as fibromyalgics. They are most aware of fatigue and cognitive difficulties, because their pain thresholds are higher than other fibromyalgia patients. We have not seen the myofascial pain syndrome or systemic candidiasis as separate entities. Therefore, we treat patients with these different diagnoses in the same manner.

History of uricosuric use and our current guaifenesin treatment:

     Over 36 years ago we found uricosuric medications helped patients with the ill-defined, multifaceted illness that later became known as "fibromyalgia." Two gout medications, probenecid and sulfinpyrazone proved effective. Because we had no other treatment, these 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, p 463] It is not sufficiently potent to treat gout but has proven invaluable in our hands for fibromyalgia. Analysis of 264 consecutive patients showed beginning lesion reversal at varying dosages: 300 mg. bid was sufficient for 20 percent of patients; at 600 mg. bid, another 50 percent were improving; and at 1800 mg. per day, another 20 percent showed reduction of palpable lesions. Thus, 90 percent of our patients were shown to have attained a sufficient dosage at 1800 mg a day or less. Obviously, 10 percent required 2400 mg or more. 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. Guaifenesin 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, guaifenesin increases the metabolite of serotonin, 5HIAA (5-hydroxyindoleacetic acid) in 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. We 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, for weeks. Duration of the illness and responsiveness to medication determine recovery time.

Hypothesis and mechanisms:

     We 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 (age at onset ranges from 4 to 74) that fibromyalgia today is the prelude to osteoarthritis tomorrow. The age spread at onset suggests multiple gene involvement. The 4:1 ratio of affected women to men dictates that 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 4-year-old girls. One of these complained of pains at age 2. She frequently awakened at night and required hot baths and massage.

     We feel that 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 and number of organs and systems affected point to a metabolic misadventure induced by the accumulation of an anion different from urates. 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 we 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 (calcium phosphate) often breaks off, and sometimes no longer forms, during treatment. Calcium added to meals allows lower dosages of medication, probably because calcium binds to phosphate as calcium phosphate and increases fecal elimination. Examination of 24-hour urine samples of patients who had begun guaifenesin show large increases in the excretion of phosphate 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:

Delta G =
ATP (Delta G = energy change)
ADP + Pi (Pi = inorganic phosphate)

     Bengtsson and Hendriksson biopsied fibromyalgic, trapezial lesions and reported roughly a 20-percent 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.

     Of ingested phosphate, 80 percent to 90 percent is absorbed. We depend on proximal renal tubular function for coordinating the retention or excretion of phosphate according to need. We postulate an enzyme, receptor or pump defect that leads to systemic accumulation. Phosphates readily enter cells and maintain equilibrium with phosphates already 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 operation 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 a change in terminology would more accurately describe the metabolic error resulting in symptoms and findings of this illness. Some findings, such as decreased growth hormone, IGF-I, serotonin, free ionic Ca2+, free urinary cortisol, certain amino acids; increased serum prolactin, substance P, and angiotensin converting enzyme, make it obvious that 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 every-changing neurohormonal milieu. The cycling fibromyalgic at times almost meets full energy demands; on occasion barely, or not at all. Moments of adequate 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 may initiate the first attack of fibromyalgia. It is difficult to postulate a more 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 during 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 also the 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. Some 40 percent of fibromyalgic females and 20 percent of males suffer from this as manifested by frontal headaches, tremulousness, sweats, heart palpitations or pounding, often with tachycardia and the sudden feeling of anxiety. Symptoms occur a few hours postprandially and often nocturnally. Episodes last approximately 20 to 30 minutes. Genter and Ipp reported 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 10 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 this 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, "panic attacks" end, 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. 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 or not fully 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 the proximal renal tubules -- a known effect of that hormone. Insulin also drives tryptophan into cells, as it does other amino acids, where they are metabolized. The lowered serum levels of L-tryptophan diminishes availability for brain uptake and formation of serotonin. These higher insulin surges probably account for lowered serum levels of several amino acids as well as serotonin. Thus, the more patients yield to sugar-craving, the more confusing and intense is the interplay of hypoglycemia and fibromyalgia.

Conclusion:

     Though highly theoretical, there are facts in this paper. Guaifenesin has proven our most effective medication to date. Any source of salicylate will block guaifenesin's benefit at a renal, tubular level as it does in gout. All plants make varying amounts of salicylate. Salicylates are readily absorbed through skin. [7][8][9][10] Even small amounts in cosmetics and other topicals will negate or slow the effects of all agents we have used. We have many maps made during treatment that illustrate lesions becoming static or worsening in previously improving patients who, unwittingly, began using such preparations. Once warned, some patients find that over one-half of their usual skin preparations could have been deleterious. Susceptibility to blockade seems genetically determined and highly variable. Some patients 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.

References

1. Physicians' Desk Reference, Medical Economics Co., Inc., Montvale, NJ, 1996.

2. Bengtsson, A. and Henriksson, K. G.: The Muscle in Fibromyalgia: A Review of Swedish Studies. J. Rheumatol., 16(Suppl. 19): 144-149, 1989.

3. Genter, P. and Ipp, E.: Plasma Glucose Thresholds for Counter regulation After an Oral Glucose Load. Metabolism, 43(1): 98-103, 1994.

4. Hvidberg, A., Fanelli, C.G., Hershey, T., et al.: Impact of recent antecedent hypoglycemia on hypoglycemic cognitive dysfunction in nondiabetic humans. 45(1):1030-1036, 1996.

5. Eisinger, J.; Plantamura, A.; and Ayavou, T.: Glycolysis abnormalities in fibromyalgia. J.Am. Coll. of Nutri., 13(2)144-148,1994.

6. Delaney, T.P. Uknes, S., Vernooij, B., et al.: A central role of salicylic acid in plant disease resistance. Science, 266: 1247-1249, 1994.

7. Winter, R.: A Consumer's Dictionary of Cosmetic Ingredients. New York, Crown Trade Paperbacks, 1994.

8. Taylor J.R., Halprin K.M.: Percutaneous absorption of salicylic acid. Arch. Dermatol. 111(6):740-743, 1975.

9. Brubacher J.R., Hoffman R.S.: Salicylism from topical salicylates: review of the literature. J.Toxicol. 34 (4) : 431-436, 1996.

10. Yip A.S., Chow W.H., Tai Y.T., Cheung K.L.: Adverse effect of topical methylsalicylate ointment on warfarin anticoagulation: an unrecognized potential hazard. Postgrad Med J. 66 (775): 367-369, 1990.

11. Bennett, R.: Poster presentation of the Oregon guaifenesin study, Academy of Rheumatology meeting, Orlando, FL, 1996.