ReviewFibromyalgia syndrome – Novel therapeutic targets
Introduction
The syndrome of fibromyalgia (FMS) poses a unique challenge to the medical community. Different in character from classical inflammatory and degenerative musculoskeletal disorders, eclectic in it research approach, subjective in its diagnosis and yet all around us – the field of FMS is what cynics would refer to as an acquired taste. At the same time, FMS poses a very real unmet challenge for the medical and scientific community. While as many as 2–3% of the entire population is estimated to fulfill diagnostic criteria for FMS and the syndrome is known to cause a significant impairment of quality of life and productivity, the therapeutic approach to FMS remains in many cases insufficiently effective. The long term follow-up of FMS patients indicates that in most cases the condition will be chronic despite variations in the clinical severity. Moreover, the degree of improvement achieved by many medications prescribed for FMS is modest at best. FMS patients are notoriously sensitive to the side effects of medications (as well as being hypersensitive in general) and all therapeutic interventions must be introduced gradually and with extreme caution. FMS patients also comprise a heterogeneous group. While some suffer from (or subsequently develop) co-morbid psychological problems such as anxiety and depression, other patients appear surprisingly mentally resilient despite the ongoing presence of chronic pain [1]. Thus, a highly personalized approach to the management of FMS appears to be in place in all cases and the existence of various co-morbid conditions, be they psychological, organic or functional must be taken under consideration when devising a therapeutic program.
In the current review we have attempted to describe recent therapeutic advances and future directions in the management of FMS.
In order to understand the current and upcoming approach to managing FMS, it is necessary to briefly go over the current concepts related to the pathophysiology of this condition. Fibromyalgia syndrome (FMS) is a clinical syndrome characterized by the presence of long-standing widespread pain involving all parts of the musculoskeletal system. Tenderness to physical stimulation, exemplified by such phenomena as allodynia and hyperalgesia, is considered a cardinal biological attribute of FMS; the diagnostic importance of tenderness however is less prominent than was previously considered. While the original 1990 American College of Rheumatology (ACR) criteria for the classification of FMS used the documentation of tender points as major criteria [2], the current 2010–2011 ACR diagnostic criteria [3] have dropped the tender-point requirement due to the subjective nature of this parameter.
FMS is considered to be a prototypical example of a central sensitization syndrome. The term “central sensitization”, introduced by Woolf [4] and applied by Yunus to FMS [5], implies a condition in which the central nervous system over-reacts to a variety of stimuli reaching it, thus causing what would normally be perceived as innocuous to end up being interpreted as painful and unpleasant. This basic neuro-physiological condition has been demonstrated, among other modalities, by the increased response of the CNS to experimental stimulation, documented through sophisticated neuro-immiging techniques, as well as by the decreased capacity of the brain to inhibit and modulate incoming pain signals, a phenomenon called decrease conditioned pain modulation (CPM) (previously called Diffuse Inhibitory Noxious Control or DNIC) [6]. CPM is an active process taking place at the spinal level and involving the activation of specific neurotransmitters (e.g. serotonin and norepinephrine) and medications acting at this level to modulate the spinal level of such neurotransmitters (e.g. serotonin–norepinephrine reuptake inhibitors – SNRI's) have the potential to improve CPM and ameliorate chronic pain caused by central sensitization. Multiple additional transmitters besides serotonin and norepinephrine also are involved in pain processing. This include (but are not limited to) GABA, cannabinoid receptors, substance-P, nerve growth factor and opiod receptors [7]. Manipulating these receptors is a possible novel approach to the modulation of chronic pain.
Sleep disturbances are a salient and well described part of the FMS as well. Sleep is disrupted at a variety of stages, and clinically patients describe difficulty falling asleep, frequent arousals, feeling un-refreshed after a night's sleep [8] as well as suffering from chronic fatigue. Thus, both medications which improve/induce sleep on the one hand, as well as medications which improve daytime alertness, have the potential of improving symptoms of FMS patients.
Pain processing within the CNS is not limited to manipulation at the spinal level. Various centers within the brain itself, including sensory, affective and cognitive centers, interact in the processing of pain and in producing the final subjective experience of pain. Over the last few years, research has been accumulating related to the increased connectivity between different areas of the brain in FMS. For example, an increase in connectivity can be demonstrated between the area known as the default mode network (DMN) and various other areas participating in pain, alertness and cognition [9].
Each of these areas is a potential target of therapeutic intervention and in addition, treatment modalities which can have an effect on the connectivity between different areas also can bring about a positive outcome in these patients [10].
While pharmacotherapy is an attractive approach for both physicians and patients dealing with the issue of FMS, this approach has its obvious draw-backs. As FMS is a chronic disorder, medications prescribed may be needed (if they work) for extended periods of time. This kind of intervention has high costs, both economically as well as in the price caused by side effects, organ dysfunction (e.g. liver impairment) and interaction with other medications used by the patient. This last problem becomes increasingly important among elderly patients, frequently using many additional medications and at high risk for drug interactions due to reduced rates of metabolism. For this reason it has become increasingly obvious, that implementation of non-pharmacological therapeutic interventions is at least as important as (and in many way more desirable than) relaying solely on medications. In fact, recent guidelines for the management of FMS published in various places [11] have stressed the importance of non-pharmacological treatments, including evidence-based alternative and complimentary treatment modalities in the management of FMS. These modalities are particularly suited for the long term management of a chronic (non-fatal) condition like FMS. For sake of example, prescribing life-long aerobic exercise is something most physicians would do with an easy conscience. Committing a patient at any age to decades of treatment with an anti depressant medication or an anticonvulsant seems considerably less appealing. While some patients are inclined to use (and expect) medications, others are distinctly unwilling or reluctant to accept pharmacological treatment. It is important to recognize that in a condition such as FMS, the fact that an individual has been diagnosed does not necessarily imply that a drug prescription must be handed over by the end of the visit. Many mild cases may be successfully handled with non-pharmacological treatment, which has the additional advantage of recruiting the active participation of the patient in the therapeutic enterprise.
Section snippets
α2δ ligands
Currently, only three specific medications have been approved in the US for treatment of FMS. The first of these has been Pregabalin, which is a α2δ ligand, acting by binding to the α2δ subunit of voltage-gated calcium channels. This binding leads to a decrease in calcium influx into nerve terminals, causing a decrease in release of pain-related neurotransmitters, such as glutamate and substance P [12], [13]. At a dose of 450 mg per day, pregabalin causes significant improvement in pain levels
Conclusion and future directions
As the fibromyalgia saga continues to unfold, novel and unexpected targets are added to the spectrum of treatments. The complexity of the syndrome, which encompasses issues related to pain, fatigue, and cognition as well as neuro-endocrine and sympathetic aspects, calls for a highly innovative, integrative and at times unorthodox approach on the part of both clinicians and researchers. Indeed, FMS diagnosis management in a decade may prove to be very different than what we know today. In the
Contributors
Jacob Ablin is involved in manuscript preparation, writing, research. Dan Buskila contributed in manuscript review and helped in preparation.
Competing interest
Jacob Ablin has received educational grants and speakers fee from Pfizer Inc.
Funding
The authors have received no funding.
Provenance and peer review
Commissioned and externally peer reviewed.
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