I got my medical degree from the University of Dhaka, East Pakistan (now Bangladesh), did my medical residency training in the UK and rheumatology training at the University of Massachusetts at Worcester, as well as the University of Illinois College of Medicine at Peoria.

While a Fellow in Rheumatology at the University of Massachusetts, I saw these patients with aches and pains and fatigue, and many of them did not fit into the stereotypical profile of anxiety, depression, and stress. I, therefore, searched the literature for any data-based publication on the characteristic of "fibrositis" (as it was called at that time). Seeing none, I initiated data collection on 50 patients with fibromyalgia syndrome (FMS) and 50 matched normal controls. This was the first data-based, controlled study on FMS showing its clinical characteristics, which was published in Seminars in Arthritis and Rheumatism in 1981 while I was an assistant professor at the University of Illinois College of Medicine at Peoria.

“A greater number of studies involving a large array of neurotransmitters involved in the pain pathway may be most relevant in fibromyalgia research in the future.”

This 1981 study suggested the first data-based criteria for FMS that was widely used by researchers until the American College of Rheumatology (ACR) criteria were published in 1990. This paper also added a few new associated features of FMS, such as irritable bowel syndrome (IBS), tension-type headaches, and migraine, thus introducing the concept of overlapping syndromes, which was further crystallized in a paper by me in 1984. In 1985, we published the first data-based paper on juvenile FMS.

The next most important paper by our group was a blinded study of muscle biopsy using normal controls (published in the Journal of Rheumatology in 1989) that showed no significant abnormality in the muscle tissue (this still remains the only blinded study of muscle histology in FMS). This paper, along with my editorial (also published in the Journal of Rheumatology) in 1992 that suggested an aberrant central pain mechanism in FMS, were thought to be very helpful in directing research attention and efforts towards the central nervous system (CNS) mechanisms in FMS.

The sheer suffering of very many patients that appeared so real, a paucity of data in the literature and physician apathy towards these patients are what drew me to this work.

Our study of FMS in men published in 2000 showed a few clinical differences between men and women as follows: women had more symptoms and tender points, more complaints of "hurting all over," more fatigue and more morning fatigue, and more IBS. However, there was no difference between men and women in pain severity, global severity, and function.

Our later study also showed no difference between men and women in psychological factors. (All these findings are similar to other chronic illnesses in the literature.) No convincing explanation exists for the differences between men and women in several features as mentioned above. Studies of sex hormones have been remarkably disappointing in providing a meaningful clue. The gender differences are likely to be due to other biologic mechanisms, including genetics and different mechanisms of pain and other symptoms among the genders, as well as the influence of psychosocial and cultural factors.

Our study had shown three broad subgroups by cluster analysis: (1) 51.5% - moderate pain control, moderate anxiety and depression, less catastrophizing, and fewer tender points; (2) 32% - low pain control, high depression and anxiety, high catastrophizing, and high tender points; (3) 15.5% - high pain control, low depression and anxiety, low catastrophizing, and high tender points. Thus, group 3 has relatively mild FMS with little psychological disturbance, group 2 has very high psychological distress, and group 1 (which comprises majority of patients) is in between. Thus, a majority of patients with FMS do not have severe psychological difficulties. We have not done studies with particular at risk groups, but group 2 shows that high psychological distress is associated with low pain control. As mentioned earlier, the female gender is a risk factor for more symptoms and greater tenderness in tissues.

We have learned many new aspects of this disease over the years. The first is that there are no histological changes in the muscles, and the most important mechanism of symptoms in FMS is likely to involve the CNS. Secondly, the ACR classification criteria have proved to be most useful in providing a uniform set of criteria for inclusion of patients for research purposes, which facilitated more research in FMS worldwide.

Recognition of fibromyalgia among the juveniles has helped physicians to help these children with pain and difficulty in functioning. Endocrine problems, e.g., low growth hormone and relatively low cortisol were later observed. They are most likely of central origin, but their actual role in pathogenesis of FMS is unknown.

The subgrouping studies have shown that all FMS patients are not the same in their severity of pain and other symptoms, in various biological and psychological aspects, or in their treatment response. Thus, FMS is not one single disease, but has several subgroups, and treatment of FMS needs to be individually tailored according to particular characteristics in a given patient.

Studies of neurotransmitters involved in pain physiology have been most useful, showing that there is increased substance P and low serotonin in the cerebrospinal fluid (CSF). Brain imaging studies showed abnormalities in functions of structures that modulate pain, including central sensitization (CS). An impressive accumulation of evidence for the presence of CS in FMS, along with demonstration of neurotransmitter abnormalities is one of the most important areas of progress in this disease in the past 15 years. The phenomenon of CS simply means that FMS patients are much more sensitive than normal controls to various stimuli, such as pressure pain, heat, and noise, and that such hypersensitivity occurs as a result of remarkable functional changes in the neurons of the CNS among these patients. There is growing evidence that the binding pathophysiological glue of the overlapping syndromes (IBS, headaches, chronic fatigue syndrome, restless legs syndrome, etc.) is likely to be CS (although these studies remain incomplete in several of these syndromes). Based on these observations, I have suggested a group terminology of central sensitivity syndromes (CSS) for these overlapping conditions.

Demonstration of genetic factors in FMS, and epidemiological studies showing a high prevalence of FMS (2-4%) in the general population are among other important developments in FMS research. Our genetic research, for example, showed that there is a linkage of fibromyalgia with the HLA as well as 5-HT2A receptor genes.

I expect to see further confirmation of various aspects of CS in all members of the CSS family with appropriate studies (including brain imaging, which is expected to be further refined in the next 15 years). Use of neuroimaging employing radioisotopes is likely to be very helpful in characterization of the receptors and their distribution in the CNS of the patients with FMS and other related syndromes.

A greater number of studies involving a large array of neurotransmitters involved in the pain pathway may be most relevant in fibromyalgia research in the future. There will be more drug studies involving many neurotransmitters, their receptors and subtypes. Serotonin, norepinephrine, dopamine, substance P, NMDA receptors and their subtypes, among others, are likely targets of more fruitful research with better identification of agonists or inhibitors that will be helpful in developing new drugs without significant side-effects. Thus, research on the basic science of FMS and related syndromes may lead to discovery of new pharmacological agents for better treatment of the suffering patients (as has been the case with rheumatoid arthritis in recent years).

Roles of ion channels and cytokines released from microglia and astrocytes need to be carefully investigated. Among the inhibitory pathways, the opioid system has so far not been studied earnestly. The effect of both pharmacological and non-pharmacological interventions on CS can be tested in a human pain laboratory setting or by neuroimaging prior to their large scale clinical trials. Researchers should also focus on further genetic studies of FMS and other members of the CSS family.

Most remarkably, little research has been done in the area of fatigue, a common and disabling symptom of FMS and chronic fatigue syndrome (CFS) in particular. It is fair to say that we know very little about the mechanisms underlying fatigue as compared with pain. Similarly, success in treating fatigue has been less than that in fatigue. Various neuroendocrine and immunological abnormalities have been described in CFS, but their actual pathophysiological role in causing fatigue is unknown.

There is always a question of whether these endocrine abnormalities are the cause or effect of the chronic disease. However, some studies showed a state of hypocortisolemia in asymptomatic subjects who subsequently developed FMS or CFS, suggesting that some of the neurohormonal aberrations may in fact predispose to the development of these syndromes. Further similar research is badly needed. Most likely a combination of endocrine abnormalities, dysfunction of certain areas of the CNS along with particular neurotransmitter abnormalities, as well as psychological distress are involved in causing fatigue, but we need data to prove this. Bothering stiffness in fibromyalgia remains another black box for future research. Drugs that may help pain do not always help stiffness in my experience.

The consistent finding of a greater frequency of FMS among rheumatoid arthritis, systemic lupus, Sjogren’s syndrome, and other chronic diseases is quite intriguing to me at this time. The real mechanisms of such associations need to be explored, that in turn, may help a better understanding of both FMS and these chronic inflammatory diseases. A common genetic factor may be operative in some cases.

The role of childhood adverse experiences, depression, and stress, as well as other psychosocial factors, may be predictors of developing FMS in a subgroup of patients, and should be further investigated. Effect of these psychosocial parameters on CS is largely unknown at this time, and is an important area for research. Subgrouping by various variables (including genetics and neurotransmitter profile) is a very important area of research, since they may determine particular treatment approach in a particular group of patients that is different from the other groups.

More studies are expected involving the factors that may trigger FMS (and other CSS conditions), such as viral infection, mental and physical trauma, poor sleep, environmental factors (such as noise and chemicals) and various psychosocial stresses in childhood and their probable ability to cause long term neuronal plasticity among the adults.