Introduction

Fibromyalgia syndrome (FMS) is a prevalent musculoskeletal pain disorder. The cardinal features are generalized body pain and hyperalgesic responses [1]. FMS patients also commonly present a range of functional disturbances, including persistent fatigue, dysregulated sleep, cognitive slowness, functional bowel disorder, paresthesia, and mood disturbance [1]. An earlier study [2] 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 [3].

History

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 [4]. The term “fibrositis” appeared in the early 1900s to describe the condition, with inflammation of the connective tissues assumed to be the underlying pathophysiology [5]. 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.

Diagnostic Criteria

In the late 1980s, a multicenter study was conducted with the intention of developing empirically derived classification criteria for FMS [1]. 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) [1].

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 [11]. 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 [13]. 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 [14]. 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.

However, there is no question that the ACR classification criteria provided much-needed consistency in defining fibromyalgia for research studies. Unfortunately, the clinical utility of the ACR criteria is quite limited [15] and the concordance between the ACR criteria and clinical diagnosis is rather poor [16]. In order to address these concerns, new diagnostic criteria for FMS were proposed recently, based on data from another multicenter study [17]. The new criteria involve the assessment by clinicians of common symptoms such as fatigue, unrefreshed wakening and cognitive symptoms. The authors of the 2010 ACR criteria specifically note that these new classification criteria are not intended to replace the 1990 ACR classification criteria, but to be used as a clinical tool in primary care and specialized clinics. Eliminating the need to perform a physical examination for the new criteria would facilitate the use of the standardized measure to diagnose fibromyalgia in clinical settings. Furthermore, for certain research studies, such as a large epidemiological project where conducting TP examination is not feasible, the new criteria will provide a degree of standardization in the study samples. The details of the ACR criteria are listed in Table 1.

Table 1 2010 fibromyalgia diagnostic criteria
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Pathophysiology

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) [22]. Cortical activities in response to noxious stimulation are exaggerated in patients with FMS [19, 23, 24].

Neurotransmitters

Low levels of serotonin (5-hydroxytryptamine) activity in FMS have been shown via decreased plasma tryptophan [25], serum serotonin [26], transfer ratio of tryptophan [27], and reuptake site density [28]. 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 [29]. Positron emission tomography L-DOPA uptake studies also implicate disrupted presynaptic dopamine activities [30].

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 [43], 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 [46], 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 [47]. However, a peripheral abnormality, albeit limited, may contribute to FMS pathophysiology. For example, affected (i.e., painful) muscles of FMS patients show hypoxia [48]. 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 [51]. Problems with muscular vasoconstriction (e.g., Raynaud’s syndrome) are common in FMS [52]. 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 [53]. The number of active trigger points seems to be related to diffuse mechanical hyperalgesia in FMS [54], 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 [55].

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.

Pharmacologic Options

FDA-Approved Agents

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 [56]. A systematic review evaluating the efficacy of pregabalin [57] 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 [58].

One of the common criticisms of a pharmacologic RCT is the lack of long-term follow-ups. Recently, Arnold et al. [59] 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 [63] 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 [64]. An extension trial [65] 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 [66], consistent with the earlier finding that 20 mg duloxetine did not improve pain [62]. 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 [70] 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 [71] suggests that the clinical benefit is sustained during the long-term treatment.

A comparative evaluation of pregabalin, milnacipran and duloxetine [72] 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.

One of the concerns with these trials is the relatively high placebo response rates. For the purpose of illustration, Fig. 1 shows the results (% of patients reporting >30% pain reduction) from the 3 trials [56, 60, 69] by dose. A recent analysis [73] of data from 18 placebo-controlled trials in over 3,500 patients estimates that approximately 50% of treatment in response to these drugs can be attributed to placebo effects.

Fig. 1
figure 1

Percentage of patients reporting >30% pain reduction by dose for pregabalin [56], duloxetine [60], and milnacipran [69] versus placebo. BID twice daily, QD every day

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Other Pharmacologic Treatments

Sodium Oxybate

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 [74] 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 [75]. Abuse and misuse complications of sodium oxybate are relatively rare according to the post marketing data [75, 76].

Its ability to restore slow wave sleep (SWS) [77] has led to a series of trials to evaluate the efficacy of sodium oxybate for treating FMS and an application to the FDA. An early small, crossover RCT [78] showed that sodium oxybate 6 g a day at bedtime for 4 weeks significantly improved pain, fatigue, and sleep (restored SWS) as compared to placebo. More recently, multicenter studies [79–81] have shown that sodium oxybate 4.5–6 g per night significantly improved clinical pain and FMS-related symptoms relative to placebo. Table 2 [79–81] compares the percentage of patients who reported >30% reduction in pain and FMS symptoms (total scores from the fibromyalgia impact questionnaire (FIQ) [82]) for sodium oxybate 4.5 and 6 g and placebo. The outcomes for the two sodium oxybate doses do not seem to differ. All studies found relatively high placebo response rates. The dropout rates were also relatively high due to adverse effects, particularly for the higher dose group (see Table 3 [79–81] for treatment completion rates for each study). Another concern regarding the use of sodium oxybate is its very short elimination half-life of approximately 30 min to 1 h [83]. For this reason, the dose was divided into two half doses, and the patients were required take a half dose at bedtime and wake up 2.5–4 h after bedtime to take another half dose. Interrupting the sleep of patients with existing sleep disturbance seems rather counterproductive [84]. Nevertheless, a polysomnographic study [85] demonstrated that sodium oxybate 6 g per night in a divided dose led to a significant improvement in the sleep measures in FMS, including total sleep time, waking after sleep onset, slow and wave sleep time.

Table 2 Patients reporting >30% reduction in pain and FIQ scores for sodium oxybate vs placebo
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Table 3 Percentage of patients completing treatment in randomized controlled trials evaluating sodium oxybate
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The application for the FDA approval of sodium oxybate for treating FMS was denied in 2010. The advisory committee [86] 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 [87] 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 [88] 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 [91].

Analgesics

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 [92]. 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 [93]. The use of opioid analgesics in FMS does not seem to be very common [94], and they are generally not recommended for treating FMS, due to the lack of demonstrated efficacy [95]. 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 [96]. The results are promising but need to be replicated.

Sedatives

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 [98].

Dopamine Agonists

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 [99] 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

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 [100] 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 [101], 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. [102] 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 [103] 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.

Non-Pharmacologic Options

Exercise

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 [106]. 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].

Behavioral/Complementary Modalities

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 [110] 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 [111]. 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 [112].

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).

Multidisciplinary Treatment

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 [109]. A systematic review [116] 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 [117]. A recent recommendation [118] 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 [119]. 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.

Future Directions

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) [120] 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) [121] 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 [122], 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 [123]. 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 [124]. 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. [119] 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.