Management of Fibromyalgia Syndrome: Review of Evidence
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- Okifuji, A. & Hare, B.D. Pain Ther (2013) 2: 87. doi:10.1007/s40122-013-0016-9
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Fibromyalgia syndrome (FMS) is a common chronic musculoskeletal pain disorder of unknown etiology and characterized by generalized body pain, hyperalgesia, and other functional and emotional comorbidities. Despite extensive research, no treatment modality is effective for all FMS patients. In this paper, we briefly review the history of FMS and diagnostic criteria, and potential pathophysiological mechanisms including central pain modulation, neurotransmitters, sympatho-adrenal and hypothalamic–pituitary–adrenal systems and peripheral muscle issues. The primary focus of the paper is to review treatment options for managing fibromyalgia symptoms. We will discuss FDA-approved medications and other pharmacologic agents, and non-pharmacologic treatments that have shown promising effects.
KeywordsClassification criteriaDuloxetineFibromyalgiaMilnacipranNon-pharmacologic treatmentPainPharmacologic treatmentPregabalin
Fibromyalgia syndrome (FMS) is a prevalent musculoskeletal pain disorder. The cardinal features are generalized body pain and hyperalgesic responses . FMS patients also commonly present a range of functional disturbances, including persistent fatigue, dysregulated sleep, cognitive slowness, functional bowel disorder, paresthesia, and mood disturbance . An earlier study  estimated the prevalence rate at 3–5% in North America. The National Arthritis Data Working group has estimated that up to 5 million people in the US suffer from FMS .
FMS is not a new disorder. One of the earliest descriptions can be found in the mid-ninth century in Germany when a cluster of FMS symptoms was collectively labeled as “Muskelschwiele” (muscle callus) and considered as generalized body tenderness with rheumatism . The term “fibrositis” appeared in the early 1900s to describe the condition, with inflammation of the connective tissues assumed to be the underlying pathophysiology . The assumption persisted until systematic scientific studies began to appear in the literature in the 1970s, when an underlying inflammation was ruled out and a more neutral term fibromyalgia proposed [6, 7]. Several criteria, based on common clinical presentations, were delineated in the 1970s and 1980s (e.g., [8, 9]), stimulating a proliferation of research in the field. However, these criteria were rarely applied consistently and the lack of standardization made integration of the study findings very difficult.
In the late 1980s, a multicenter study was conducted with the intention of developing empirically derived classification criteria for FMS . The study included approximately 300 patients with FMS and 285 controls with other (non-FMS) painful conditions. Comparison of a number of FMS-related variables revealed two criteria with good sensitivity and specificity that can differentiate between the two groups. These criteria, generally referred as the American College of Rheumatology (ACR) criteria, consist of (1) a history of widespread pain of 3 months or longer duration and (2) presence of pain responses at least 11 of 18 designated tender points (TPs) .
Since publication in 1990, the ACR criteria have become a standard in FMS research. They have been used by the vast majority of published reports on FMS to date, creating some cohesiveness in the literature. However, the ACR criteria are not free from criticisms. One of the major issues is the validity of the TP criterion; specifically, it is not clear what the number of positive TPs actually measures. It is possible that pain response to digital pressure to the TPs may represent the underlying central dysfunction of nociceptive processing, leading to diffuse hyperalgesia. However, the number of painful TPs has been found to be the parameter most associated with psychological distress [10–12], although pain sensitivity in the TPs seems relatively independent of distress . Furthermore, central sensitization is not FMS-specific. Patients with various other chronic pain states, including those with localized pain, exhibit evidence that central sensitization plays an important role in their disorder . In addition, there are a large number of individuals who report chronic widespread pain (CWP) without having 11 painful TPs, yet exhibit clinical and functional presentations very similar to FMS . There is no clear understanding of whether the presence of 11 or more TPs represents any clinical significance or relevance to FMS. Altogether, the validity of the TP count criterion is yet to be determined.
Another concern regarding the ACR criteria is the lack of consideration of common symptoms and dysfunctions. Chronic fatigue and sleep problems are ubiquitous in FMS patients; however, they were not included in the ACR criteria because they are also commonly experienced by other patients with chronic pain and thus yielded unsatisfactory discriminability. However, those symptoms are common enough to be characteristics of the disorder yet not a part of the diagnostic criteria; this is a stark contrast with other syndromes such as depression where a diagnosis relies on the presence of multiple common clinical phenomena.
2010 fibromyalgia diagnostic criteria
Criteria that must be met
1) Other disorders that would explain the pain must be ruled out
2) Symptoms must be present for minimum of 3 months at the stable level
3) Widespread Pain Index (WPI) and Symptom severity scale (SS) levels must be greater than specified as below
Shoulder girdle left
Shoulder girdle right
Upper arm left
Upper arm right
Lower arm left
Lower arm right
Upper leg left
Upper leg right
Lower leg left
Lower leg right
0: No problem
1: Slight or mild problems, generally mild or intermittent
2: Moderate, considerable problems, often present and/or at a moderate level
3: Severe, pervasive, continuous, light-disturbing problems
The etiology of FMS is unknown. However, accumulated evidence over the past 40 years suggests that several factors potentially underlie the disorder. Although the focus of this paper is primarily on the management of FMS, we will briefly review the literature, including the role of central pain modulation processes, muscle abnormality, neuroendocrine regulation, and sleep.
Central Pain Modulation
Research has consistently shown that FMS is associated with increased pain sensitivity that suggests dysregulation of the pain modulation process at the central level. As compared to healthy subjects, FMS patients exhibit lower pain thresholds to various types of experimentally induced noxious stimuli [18–21]. FMS is also associated with increased windup (WU) sensitivity (heightened pain perception when noxious stimuli are repeatedly presented) . Cortical activities in response to noxious stimulation are exaggerated in patients with FMS [19, 23, 24].
Low levels of serotonin (5-hydroxytryptamine) activity in FMS have been shown via decreased plasma tryptophan , serum serotonin , transfer ratio of tryptophan , and reuptake site density . Research also points to a dysregulated dopaminergic system. FMS patients show an augmented prolactin response to a buspirone challenge test, suggesting an increased sensitivity or density of dopamine D2 receptors . Positron emission tomography L-DOPA uptake studies also implicate disrupted presynaptic dopamine activities .
Sympatho-Adrenal (SA) and Hypothalamic–Pituitary–Adrenal (HPA) Systems
A large volume of evidence exists suggesting that patients with FMS show hyporeactive SA and HAP response to a wide range of stressors including exercise [31, 32]. FMS is also associated with altered basal catecholamine levels, independent of depression [33, 34], as well as abnormal reactivity of the HPA, such as abnormal adrenocorticotropic hormone (ACTH) levels, hypoglycemia and blunted cortisol response [35, 36]. Overall, these studies suggest the presence of hyperactive sympathetic activity with hyporeactive response to stress [37–40]. Furthermore, alteration of adrenergic gene polymorphisms seems to be present in FMS patients [41, 42]. Research indicates that there is a specific function-altering beta-adrenergic gene polymorphism in FMS patients , and they show a significant increase in gene expression of adrenergic molecular receptors in response to exercise, as well as at rest, as compared to healthy controls [44, 45], implicating a genetic vulnerability in at least some FMS patients.
Muscular Abnormalities and Peripheral Pain Modulation
Although an early study found abnormal biopsy results in the painful muscles in FMS patients , the investigation of local muscle tissue has yielded conflicting results. In general, evidence supporting the microscopic evidence of definitive pathology in the muscle tissues in FMS is scarce . However, a peripheral abnormality, albeit limited, may contribute to FMS pathophysiology. For example, affected (i.e., painful) muscles of FMS patients show hypoxia . Some studies using P-31 magnetic resonance spectroscopy [49, 50] have also shown reduced levels of adenosine triphosphate and phosphocreatine in FMS, suggesting that these metabolic abnormalities may contribute to muscle weakness and fatigability in FMS. Decreased muscle blood flow, as compared to healthy individuals, has also been shown . Problems with muscular vasoconstriction (e.g., Raynaud’s syndrome) are common in FMS . These results suggest that peripheral ischemia may contribute to muscle pain. Furthermore, a significantly greater number of active myofascial trigger points in the trapezius muscles are found in FMS patients relative to healthy people . The number of active trigger points seems to be related to diffuse mechanical hyperalgesia in FMS , suggesting that peripheral noxious inputs play a critical role; peripheral abnormality may create a biochemical environment that contributes to local sensitization, leading to central pain sensitivity .
Treatment of FMS
Over the past four decades, a large variety of modalities have been tested for treating FMS. Overall, no single modality has been found to be universally effective for all FMS patients, or all FMS symptoms in an individual patient. Below, we will review commonly used FMS treatments as well as some treatments that have attracted much public attention.
There are three medications that were approved by the federal drug administration (FDA) to treat FMS. Pregabalin, a γ-aminobutyric acid (GABA) analog and antiepileptic agent, was the first to be approved, in 2007. A multicenter, double-blind, randomized controlled trial (RCT) was conducted in 750 patients who were randomized to receive pregabalin 300, 450 or 600 mg per day or placebo for 14 weeks; significant improvement in pain and other functional measures was achieved in all the pregabalin groups as compared to the placebo group . A systematic review evaluating the efficacy of pregabalin  found a benefit of pregabalin relative to placebo in pain reduction, improvement in sleep and quality of life measures (except for mood variables). A meta-analysis of 4 RCTs with more than 3,000 patients has shown that a 30% pain reduction was reported by 40% of patients receiving pregabalin versus 28% of those receiving placebo .
One of the common criticisms of a pharmacologic RCT is the lack of long-term follow-ups. Recently, Arnold et al.  published data from the open-label extension studies from the pregabalin RCT with a total of 1,207 patients who were treated for up to a year, in order to assess the long-term tolerability profile and maintenance of pain reduction. Approximately 81% of patients completed treatment. On average, the pain reduction observed in the RCT was maintained throughout the treatment period and the tolerability profile was comparable to that seen in the RCT.
There are two other medications, both serotonin norepinephrine reuptake inhibitors (SNRIs), approved by the FDA to treat FMS. Duloxetine was approved in 2008 and milnacipran in 2009. Double-blind RCTs evaluating duloxetine doses ranging between 60 and 120 mg per day have typically shown greater improvement in pain reports and self-report functioning than those in the placebo arm [60–62]. Analysis of pooled data from the 4 RCTs  indicates that 48% of treated patients and 32% of patients receiving placebo reported >30% pain reduction. Secondary analyses have shown that duloxetine was beneficial for reducing fatigue in FMS . An extension trial  of up to 1 year showed comparable tolerability and maintenance of pain reduction. However, a recent trial with duloxetine 30 mg failed to show improvement in pain severity relative to placebo, mostly due to the marked placebo effects , consistent with the earlier finding that 20 mg duloxetine did not improve pain . Similarly, double-blind RCTs [67–69] evaluating milnacipran (100–200 mg daily) showed significant improvement in pain reports and a range of symptoms as compared to placebo. Pooled data from 2 RCTs  showed approximately 52–61% of treated patients reporting >30% pain reduction, versus 36% of the placebo group. A recent update of the 3-year open-label study  suggests that the clinical benefit is sustained during the long-term treatment.
A comparative evaluation of pregabalin, milnacipran and duloxetine  showed similar efficacy of the three drugs with regard to pain reduction. However, there were some differences in the secondary outcome measures and adverse effects, suggesting that these differences may guide a clinical decision as to which of these agents to use for a particular patient.
Other Pharmacologic Treatments
Sodium oxybate is a commercially produced form of the sodium salt of γ-hydroxybutyric acid (GHB). It has been approved by the FDA to treat excessive daytime sleepiness and cataplexy in narcolepsy. The distinction between GHB and sodium oxybate should be noted. GHB is a Schedule I controlled substance due to the high abuse potential whereas sodium oxybate is Schedule III. Illicit GHB is said to produce euphoric, aphrodisiac and relaxing effects  and is considered one of the most popular party drugs. It also causes amnesia and increased passivity that has been used to aid criminal activity (e.g., “date rape”). However, in general, the problems related to illicit GHB have been declining significantly since the turn of the century; nevertheless the risk associated with the illicit GHB seems to greatly exceed that of legally prescribed sodium oxybate . Abuse and misuse complications of sodium oxybate are relatively rare according to the post marketing data [75, 76].
Patients reporting >30% reduction in pain and FIQ scores for sodium oxybate vs placebo
The application for the FDA approval of sodium oxybate for treating FMS was denied in 2010. The advisory committee  concluded that the efficacy data, although promising, do not show superior results to currently approved medications. They also expressed significant concern with the safety issues of the drug, with a potential for abuse and misuse with serious consequences. They felt that adequate safety measures were not available at the time.
Tricyclics and Other Antidepressants
Early studies have shown that low dose amitriptyline and cyclobenzaprine, two tricyclic compounds, have beneficial effects on FMS symptoms. A meta-analysis  demonstrates that these agents help to reduce pain, fatigue, and sleep disturbance in FMS. However, there seems to be a large individual variation in the treatment response, and it has been estimated  that approximately 30% of patients may benefit from tricyclics. The introduction of selective serotonin reuptake inhibitors (SSRIs) was received with much enthusiasm as they were considered to be a safer alternative to TCAs and could regulate serotonin reuptake. However, the results from RCTs were marginal for improving pain, sleep and mood in FMS patients [89, 90], even with a flexible dose .
Corticosteroids were one of the first classes of medications to be tested for FMS; however, a double-blind RCT evaluating prednisone showed no clinical benefit . Common over-the-counter analgesics such as non-steroidal anti-inflammatory drugs, although widely used by FMS patients, also do not appear to have any appreciable benefit . The use of opioid analgesics in FMS does not seem to be very common , and they are generally not recommended for treating FMS, due to the lack of demonstrated efficacy . Tramadol with the combined actions of weak opioid and norepinephrine and serotonin reuptake inhibitor (SNRI) effects has shown reduced pain and better functioning in a RCT . The results are promising but need to be replicated.
Benzodiazepine and non-benzodiazepine hypnotics are commonly used to treat FMS patients, often targeting sleep and anxiety. However, controlled studies failed to demonstrate significant benefit [93, 97]. It has also to be argued that hypnotics/sedatives should not be used chronically due to potential complications and tolerance .
There have been a few small studies evaluating the efficacy of dopamine agonists that are commonly used to treat Parkinson’s disease and restless leg syndrome. A double-blind RCT  testing pramipexole for 14 weeks showed significant improvement in FMS symptoms relative to placebo. These preliminary results need to be replicated in a larger trial.
Cannabinoids have recently emerged as an analgesic option for various pain conditions. A synthetic cannabinoid (nabilone) has been approved by the FDA for use as a second-line treatment for chemotherapy-induced nausea and vomiting. An early retrospective chart review study  of 20 patients with non-cancer chronic pain found some improvement in pain and sleep, suggesting a potential benefit for chronic pain patients in general as an analgesic. In the first double-blind RCT , 40 FMS patients received either placebo or nabilone (titrated to 1 mg twice daily) for 4 weeks. The nabilone group showed significant decrease in pain and FIQ score relative to the placebo group at the post-treatment assessment, although the benefit seemed to disappear at the 8-week follow-up. The nabilone group had a greater dropout rate (25%) versus the placebo group (10%) and reported more drowsiness (50%), dry mouth (30%) and vertigo (27%). Ware et al.  compared nabilone to amitriptyline in a crossover trial where patients received a 2-week trial of each drug with a 2-week washout in between. Adverse effects (dizziness, nausea, dry mouth, drowsiness) were more prominent with nabilone. The two drugs showed a comparative decrease in sleep disturbance, although it is not clear whether there was a between-group difference in the degree of benefit. The groups did not differ with regard to the other FMS-related symptoms, although it was not clear whether they showed any improvement with either treatment. Unfortunately, recruitment was difficult, with approximately half of patients who were approached declining to participate, making it difficult to ascertain the representability of the study sample. A systematic review of cannabinoids for treating non-cancer chronic pain  suggests that they are safe and may have some modest benefit for FMS, although the results are very preliminary at this point. The issues of long-term benefit and adverse effects need to be thoroughly investigated.
Physical deconditioning is common in FMS patients. Generally, incorporation of some physical fitness program as a part of FMS treatment is considered essential. The literature indicates that the efficacy of exercise seems to depend upon the content and intensity of the program. Generally, submaximal aerobic exercise, along with strengthening and stretching elements, is beneficial in reducing symptoms and hyperalgesic response [104, 105]. At least a moderate level of exercise intensity seems to be needed to derive clinical benefit but low intensity exercise tends to yield limited benefit . Unfortunately, it is not easy to implement relatively vigorous exercise for FMS patients, as many patients are exercise-intolerant. The general recommendations for providing exercise therapy include (1) starting at a low level where patients can engage without significant distress, (2) gradual increase of the intensity level, (3) incorporating different types of exercise, and (4) reduction of exercise intensity/duration, while maintaining the frequency of exercise, if not tolerated [106, 107].
Several behavioral modalities that are commonly used to treat chronic pain patients have been evaluated, although the methodological constraints and variations across studies make the quality of evidence rather weak. Generally, inconsistent and modest effects have been reported with hypnosis and biofeedback [108, 109]. Mindfulness-based stress reduction (MBSR) is an increasingly popular approach to treat various chronic illnesses. For FMS, an early study  showed some promising reduction in pain and symptoms with MBSR training relative to a control group. However, a subsequent 3-arm study comparing MBSR training to both active control (supportive group with relaxation training) and wait list group failed to show any benefit . Complementary and alternative (CAM) approaches are very popular with FMS patients. Unfortunately, many of the trials are not well-controlled or included small numbers of patients. Because of the methodologic concerns, the level of clinical benefit of CAM therapies for FMS cannot be determined from the current literature .
One of the most widely accepted behavioral therapy modalities is cognitive-behavioral therapy (CBT). Clinical trials testing CBT alone, however, tend to be small with various methodologic problems, making it difficult to interpret its efficacy. In general, CBT monotherapy is effective in improving the target variables (e.g., maladaptive cognition, mood, quality of life; QOL) [113–115] although the effects on the primary FMS symptoms may be limited. The efficacy seems to improve when CBT is included as a part of a multidisciplinary treatment program (see below).
Given the complex, multifactorial nature of FMS, it is reasonable to assume that multimodal therapy targeting multiple factors may work well. However, systematic evaluation of studies evaluating multidisciplinary therapy for FMS is difficult because of the wide variability in the parameters of the treatment. Unfortunately, the lack of methodological vigor is not uncommon, reflecting the difficulty of conducting costly, logistically demanding trials using multimodal approaches.
Although there are some other variations, a typical trial testing a multidisciplinary approach includes education, exercise and psychological (typically cognitive behavioral) therapy. Programs aimed at acquisition of coping and pain management skills seem to provide better results than those that mostly aim to provide information/education . A systematic review  points to the methodological weakness, yet provides some evidence of the effectiveness of the approach for various chronic pain conditions including FMS. The effectiveness seems to last beyond the therapy; reduction in pain and other symptoms was observed 12 months later . A recent recommendation  by FMS experts strongly emphasizes the importance of educating patients, establishing working goals, and applying multimodal therapy approaches consisting of education, medications, exercise and CBT. There has only been one published study thus far that specifically tested the combination of CBT with medication . In this trial, patients were randomized to a combination of CBT and milnacipran, drug monotherapy or CBT alone. The results suggest that the combination approach and CBT monotherapy were equally beneficial in reducing symptoms, i.e., milnacipran added very little to the clinical benefit of CBT.
Despite extensive efforts to delineate an effective treatment in the past 30 years, FMS continues to be a very difficult chronic pain condition to treat. Some prominent challenges in interpreting the literature are the poor quality of the methodology, particularly for non-pharmacologic approaches, and the large placebo effects in drug trials. Furthermore, although clinical benefits are typically evaluated by statistical comparisons of the treatment groups, there remains a large within-group variation in treatment response. This makes it nearly impossible to know whether a particular patient would benefit from a certain treatment. Well-controlled RCTs could indicate whether the treatment would likely benefit an average patient, but not a particular patient.
Recently, novel approaches have been proposed to expand our ability to evaluate the therapeutic effects for each patient. For example, the new statistical framework, dynamically modified outcomes (DYNAMO)  could estimate the causal effects of therapy for each patient and help determine the true effects of therapy for a specific patient. The individually customized statistical causal model can then provide guidance for matching treatment to patients. Similarly, the sequential multiple assignment randomization trials (SMART)  approach, in which patients undergo multiple randomization to sequential treatments, may provide adaptive analyses of efficacy at the individual patient level that could help establish the most effective clinical algorithm. Given the heterogeneous treatment responses, these approaches may greatly enhance the ability to produce clinically significant and relevant evidence in FMS clinical research.
The heterogeneity of FMS patients is not limited to treatment response. A number of reports note heterogeneity with respect to a range of the disease parameters including history and disease expression , suggesting the importance of patient-centered, individualized treatment planning. One of the important, yet often neglected, aspects is the variation in symptoms over time. Negative mood/stress, poor sleep, and fatigue often trigger an overall symptom exacerbation . Daily longitudinal analyses of the symptom fluctuation suggest that worsening in one symptom often intensifies other symptoms, although the degree to which one symptom affects another varies across individuals . In other words, although all symptoms influence other symptoms to some level, each person may have one symptom that exerts more influence than others, presenting a unique causal covariation pattern for this particular patient. If we can identify which symptom drives others in a patient, treatment certainly can be customized to prioritize a particular target symptom.
Many clinical trials face the dilemma of balancing the internal versus external validity. Clearly, well-controlled studies are needed: however, by making the study “clean” one often creates an unrealistic clinical situation where the results may not apply to the population at large. In the real world, FMS patients vary in a range of clinical variables with often complicated issues such as mood disorders and polypharmacy; however, in the current clinical research environment, such complication is not appreciated and is often minimized by patient selection criteria. How we can delineate an evidence-based approach that is truly based on reality is a lingering question with no easy answers. One approach may be to test an agent/method of therapy to be combined with another that has yielded relatively good outcomes. For example, the pharmacologic trials are mostly restricted to testing the agents alone against placebo. Drugs with promising results can be combined with exercise or a multidisciplinary approach. The recent study by Ang et al.  of a combination of CBT and milnacipran is one of the first published reports and more should be done employing this type of approach. FMS clinical research will require going beyond the traditional RCT models and applying innovative and novel conceptual and methodologic ventures.
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Dr. Okifuji is the guarantor for this article, and takes responsibility for the integrity of the work as a whole.
Conflict of interest
Dr. Okifuji and Dr. Hare declare no conflicts of interest.
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