Understanding the Fibromyalgia Syndrome

Srinivas G. Rao, MD, PhD; Judith F. Gendreau, MD; Jay D. Kranzler, MD, PhD


Psychopharmacol Bull. 2008;40(4):24-56. 

In This Article

Abstract and Introduction

The fibromyalgia syndrome (FMS) is the most frequent cause of chronic, widespread pain. This review, which is targeted at the psychiatry and psychopharmacology communities, summarizes the state-of-the-art as it relates to both the pathophysiology and treatment of FMS. Toward this end, the anatomy and physiology of pain pathways are summarized, followed by a review of the altered biology of pain processing, neurotransmitter function, and neuroendocrine systems in FMS. The categories of current drugs employed to treat the disorder are detailed, along with a critical review of the literature supporting such use.

The fibromyalgia syndrome (FMS) is the most frequent cause of chronic, widespread pain, with estimates of world-wide prevalence ranging from 0.5 to 5.0%.[1,2] FMS is second only to osteoarthritis (OA) as the most common diagnosis among patients seen in rheumatology offices, and it is diagnosed approximately 4 times more frequently in women than in men. There are presently no diagnostic tests for fibromyalgia. Rather, the accepted diagnostic criteria require that spontaneous pain be present for over 3 months duration along the spine and in all four quadrants of the body, and pain upon digital palpation must be elicited at 11 out of 18 "tender points" (Figure 1).[3] It should be appreciated that a number of treatable and/or life-threatening conditions may present with symptoms that resemble those of FMS, and these obviously need to be excluded before a definitive diagnosis is made.[4]

Fibromyalgia Tender Points

Patients with FMS display quantitative abnormalities in pain perception under experimental conditions, in the form of both allodynia-perceiving pain even from a non-painful stimulus, such as light touch-and hyperalgesia-an augmentation of pain processing in which a painful stimulus is magnified and perceived with higher intensity than it would be by a normal volunteer.[5,6,7,8,9,10] These data are suggestive of a state of sensitized pain perception in FMS.[8,11] In theory, such a state can conceptually result from widespread changes within the target organs (i.e., skin, muscles, etc.), from alterations in nociceptive processing within the central nervous system, or some combination of both processes. Indeed, some early theories of FMS pathophysiology posited that FMS pain was a result of peripheral abnormalities, particularly alterations in skeletal muscle.[12] However, more recent studies have generally failed to confirm the presence of such alterations,[12,13,14,15] though it is recognized that peripheral insults may play a role in instigating or maintaining FMS.[11,16] On the other hand, several lines of inquiry support the role of altered central pain processing (ie, "central sensitization") as underlying the pain of FMS, as will be discussed in detail below.

Though not reflected in the diagnostic criteria, FMS patients typically present with a number of symptoms beyond pain. Fatigue is cited as a significant cause of morbidity for the vast majority of FMS patients.[17] Subjective sleep disturbances, particularly in the form of non restorative sleep, are reported to occur in over three-quarters of FMS patients.[18] A majority of patients complain of difficulties with concentration and memory, a situation that has been termed "fibro fog."[19] Approximately 20-40% of individuals with FMS have an identifiable current mood disorder such as depression or anxiety disorder at the time of diagnosis, with a lifetime incidence as high as 70%.[20,21,22,23] Taken on the whole, FMS can result in severe disability, comparable to that seen in other rheumatic diseases such as OA or rheumatoid arthritis, despite the absence of "objective" findings.[24,25]

FMS has been included as one of the so-called "unexplained clinical conditions"[26,27] or "functional somatic syndromes"[28,29] that are characterized more by symptoms, suffering, and disability than by consistent tissue abnormality. As such, there have been suggestions that FMS and other related syndromes may represent a form of somatization disorder.[30] Nonetheless, FMS is treated today primarily within the medical model. It is most often diagnosed in the primary care setting and almost half of the office visits are to internal medicine and family practitioners 1998 National Ambulatory Medical Care Survey.[31] Rheumatologists are the leading specialty group seeing FMS patients, representing 16% of office visits. The remainder of office visits are to a variety of tertiary care providers, including pain centers, physical medicine specialists, and psychiatrists.

FMS remains a controversial diagnosis almost 15 years after the establishment of the diagnostic criteria. Some authors express concern that placing the label of FMS on these individuals promotes helplessness and disability.[32,33,34] Others focus on the legal and social consequences of identifying FMS as a disorder that can be caused by certain exposures (eg, motor vehicle accidents), thus promoting litigation.[35] Others question the validity of the criteria for diagnosis, especially the requirement for a certain number of tender points.[36,37]

This paper is intended as follow-up to a previous review by the same authors,[38] detailing some of the changes in the FMS landscape that have occurred in the intervening 2 years. Overall, FMS has attracted a great deal of attention recently, both within the lay and scientific press. The overall validity of FMS as a therapeutic indication has been augmented by the FDA's recognition of the significant unmet medical need that FMS represents.[39,40] This need has also lead to interest in FMS on the part of pharmaceutical companies; indeed, the results of several relatively large, well-controlled industry-sponsored clinical trials have recently been published and will be detailed below.

Like the predecessor publication , the primary goal of the current article is to provide a summary of the state-of-the art pertaining to FMS, with psychiatrists as the target audience,focusing primarily its pathophysiology and current therapeutic options . Historically, pain has not been the typical purview of psychiatrists , despite the fact that a relationship between pain and affective disorders has been known to exist for sometime.[41] However, this connection has come under increasing scrutiny lately.[42,43] Of particular relevance to the practicing psychiatrist is the finding that over 50% of patients that are ultimately diagnosed with depression present initially only with asomaticsymptoms.[44] Further more, the inadequate treatment of pain makes the task of treating comorbid depression much more challenging.[45] Conversely, it should be noted that cognitive behavioral therapy has been used successfully in some patients with FMS and other related chronic pain conditions , even in the absence of an overt affective disorder.[27,46,47,48]

The body of the review will be divided into three parts: First, as FMS is a clinical demonstration of the existing links between pain sensation, the stress response, and mood, we briefly describe the neuroanatomy, pharmacology, and connectivity of the relevant pathways. Second, we review the neurochemical and neuroendocrinological differences that exist in FMS patients and compare these observations to other conditions where appropriate. Finally, we summarize the literature on the effectiveness of drugs in treating FMS and will try, where possible, to tie the empirical findings back to both normal physiology and FMS pathophysiology.


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