Outline
1.      Abstract
2.      Introduction
3.      Prevalence of Fibromyalgia
4.      Symptom-Complexes of Fibromyalgia
5.      Inadequacy of the Diagnostic Criteria of the American
         College of Rheumatology  
6.      Pathophysiology of the Muscle, Nerve, and the
         Central Nervous System in fibromyalgia
7.      IgE-Mediated Responses in Fibromyalgia
8.      The Oxygen Order of Human Biology
9.      Oxidative Coagulopathy
10      Oxidative Lymphopathy
11.     Oxidative-Dysoxygenative Lactosis (Type C Lactate Acidosis)
12.     Oxidative Cell Membrane and Ligand Receptor Injury
13.     Oxidative Regression to Primordial Cellular Ecology (Orpec)
14.     Oxidative Dysautonomia
15.     Oxidative Cellular Dehydration
16.     Disruptions of the Bowel, Blood, and Liver Ecosystems in
            Fibromyalgia
17.     Oxidative Phenomena in Fibromyalgia
18.     Dysoxygenative Phenomena in Fibromyalgia
19.     Genetic and Acquired Enzyme Defects in Fibromyalgia
20.     Insights from Dysoxygenosis in Marine Life
21.     Strong Explanatory Power of the ODD Hypothesis
22.     Rational Basis for Therapeutic Strategies for Reversal of ODD
23.     Clinical Outcome Evidence in Support of the ODD Hypothesis
24.     Conclusions

1. ABSTRACT

An "oxidative-dysoxygenative" disorder (ODD) is proposed as a pathogenetic model for fibromyalgia. This model of molecular dynamics extends beyond the conventional view of the pathophysiology of the muscle and nerve in fibromyalgia, abnormalities which are regarded as epiphenomena in the context of the proposed (ODD) hypothesis. Rather, the proposed model focuses on accelerated oxidative stress (oxidosis), abnormal cellular oxygen metabolism caused by oxidative injury to enzyme pathways involved in redox homeostasis, oxygen transport to tissues and utilization in the cell ("dysoxygenosis"), and acidosis. Such injury is caused by the cumulative effects of all operant endogenous and exogenous oxidants and results in impaired oxygen transport and utilization as well as cellular anoxia. Oxidosis, dysoxygenosis, and acidosis (the three principal elements of ODD) feed upon each other and create a dysoxygenative state in which the cellular oxygen metabolism is severely hampered and cellular energy pathways are impaired. The oxidative-dysoxygenative disorder so produced causes (and fully explains) the entire spectrum of symptom-complexes of fibromyalgia. Direct morphologic and biochemical evidence supporting the ODD hypothesis is marshaled. Data obtained with a clinical outcome study of 150 patients with fibromyalgia presented in a companion article in this issue of the Journal provide strong clinical support for the ODD hypothesis.

2. INTRODUCTION

The ODD hypothesis evolved as an extension of the authors' previous studies of oxidative phenomena in health and disease, including the following: (1) the fundamental duality of oxygen and spontaneity of oxidation in nature and its central role in the aging phenomenon as well as in all disease processes1-4; (2) oxidative injury as the core pathogenetic mechanism of chronic fatigue syndrome5,6; (3) oxidative coagulopathy as one of the basic mechanisms of injury in chemical sensitivity syndromes7,8 ; (4) AA oxidopathy as the core pathogenetic mechanism in coronary artery disease9,10 ; (5) oxidative disruption of the receptor-ligand-nucleotide dynamics in oligomenorrhea and other menstrual irregularities in patients with chronic fatigue syndrome (CFS) and fibromyalgia9; (6) the role of accelerated oxidative molecular injury in menopausal syndrome12; (7) the efficacy of predominantly antioxidant nutrient therapies for restoring growth in children with arrested growth13; (8) oxidative phenomena in altered states of bowel,14 blood,15 and liver ecosystems16; (9) oxidative triggers in asthma17; (10) oxidative-genetic brain dysfunction (the spectrum of attention/hyperactivity syndrome, autism, obsessive-compulsive disorder, and Tourette's syndrome18; and (11) immune disorders, such as atopic skin disorders19 and autoimmune diseases.20 This article focuses on how accelerated oxidative injury to molecular pathways of redox homeostasis, oxygen transport and utilization, and acid-base equilibrium result in an oxidative-dysoxygenative disorder. Furthermore, it discusses the roles those two mechanisms play in the pathogenesis of symptom-complexes of fibromyalgia.

3. PREVALENCE OF FIBROMYALGIA

Employing the diagnostic criteria established by the American College of Rheumatology (ACR),21 estimates of the prevalence of fibromyalgia in the United States (by random population studies) vary over a broad range, extending from 1 to 10.5 percent.22 The top number in that range is astonishing because, if correct, that means more than one in ten Americans suffers from fibromyalgia or fibromyalgia-like symptoms. Other prevalence studies of individuals in the primary care clinics have reported prevalence rates ranging from 2-6 percent, while rates published from rheumatology centers extend from 5 to 20 percent.23 It is noteworthy that fibromyalgia, a disorder for which no established criteria existed until 1990, now ranks second among the rheumatologic disorders consuming more time (16%) than any other disorder in rheumatology clinics, except rheumatoid arthritis (24%).24 The above statistics, however, must be regarded with reserve. The ACR diagnostic criteria for fibromyalgia are based on occurrence of pain and the presence of tender points in at least 11 of 18 sites on the body. Those criteria hardly qualify as reliable for a disorder that is distinctly systemic in nature, as is evident from the descriptions of symptoms in the following section.

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